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  • 71P Correlation between toxicities and outcomes during treatment with immune checkpoint inhibitors in non-small cell lung cancer patients
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    de Miguel P, Díez S, García I, et al.

    BackgroundImmunotherapy of cancer has changed the paradigm of treatment of many tumours, especially non-small cell lung cancer (NSCLC). The use of immune-checkpoint inhibitors (ICI) is associated in some patients with the development of new immune-related adverse effects (ir-AEs). Our aim was to study if there is any correlation between the appearence of ir-AEs and the efficacy of ICI. MethodsWe collected data of 66 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and May 2019. Several variables as clinical, tumour-related and therapeutical were included and univariate and multivariate Cox regression analysis were performed. ResultsCohort of 50 men and 16 women, median age of 67 years and 80% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 66% were active or ex-smokers and 34% had never smoked. 62% of patients had adenocarcinoma histology, 32% scamous and 3% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 36% M1a, 35% M1b and 24% M1c. 2 patients had driver mutations in EGFR gene. 53% of patients had unknown PDL1 status; 9% had no PDL1 expression, 9% low expression and 27% high expression. 82% of patients had progressed to prior line of treatment, while 18% were treatment-naive. irAEs occured in 55% of patients; 11% developed grade 3 to 4 toxicities. More frequent irAEs were fatigue (61%) and rash (32%). Significant statistical variables in univariate analysis were included in multivariate analysis by Cox regression. The appearence of any grade of toxicity was associated with improved progression-free survival (PFS) (median 5.2 months vs 2.7 months; HR 3.53; p = 0.018; 95% CI [1.24-10.07] ). The use of corticosteroids during treatment with ICI was not related to PFS. ConclusionAppearance of immune-related adverse effects during treatment with ICI was associated with better outcomes in our population. The use of corticosteroids during immunotherapy didńt have any deleterious effect on the efficacy of treatment. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 88P A study on analysis of clinical efficacy factor and exploring prognostic factors for reimbursement policy after immunotherapy being introduced in South Korea
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    YI J.

    BackgroundNivolumab and pembrolizumab have been covered in South Korea for mNSCLC as 2nd line or subsequent for PD-L1 expression more than 10% and 50% respectively. The lack of robust evidence makes it challenged for HIRA to identify to which extent benefit standard could be taken as the best to ensure patient access to needed medicines. In that circumstance drug authorizations have been added and HIRA need evidence for expanding reimbursement. MethodsThis study is to investigate nivolumab, pembrolizumab efficacy and possible side effects for mNSCLC patients. Efficacy and adverse event data were collected through patient medical chart trying to find factors for patients have better efficacy and survical results. ResultsIn total, 1018 out of 1181 patients got response rate and the rest 163 patients couldn't. 1181 patients, No. of treatment was 10.5 and 7.9 for nivolumab and pembrolizumab separately and Duration of treatment (DOT) was 99.9 and 88.9 days. 1018 patients who could get RR, No. of treatment was 9.9 and DOT was 168.7 days. For 163 patients who could not get RR, No. of treatment was 1.4 and DOT was 8.0 days. For 1018 patients, objective RR was 33.6%. Considering 156 of 163 patients died (133 died within 90 days), almost of 163 might be no response. When it comes to considering all patients include 163 patients, RR could be 29%. 163 had differences comparing all patients. They were older (69 vs. 67), had poor performance status (ECOG 2 or more 29% vs. 11%) and liver meta (22.7% vs. 11.8%) and were poor RR of previous therapy. Factors associated with response were Smoking (+), Previous RT (-), irAE(+) and PD-L1 over 50%(+), for OS were PS(+), EGFR(-), Previous RT(-) and irAE(+) and for PFS were stage(-), EGFR(-), Previous RT(-) and irAE(+). ConclusionThis study's clinical benefit and toxicity for mNSCLC were comparable to those of clinical trials, although population tended to be more heavily treated and have poorer performance status. A favorable outcome could be expected in patients accompanying irAE during immunotherapy and unfavorable in patients who got previous RT. Reimbursement's PD-L1 criteria might be rational according to this study but need further study and analysis. Legal entity responsible for the studyHIRA. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

    更新日期:2019-12-17
  • 114P Targeting the EGF-receptor and CD38 in solid and haematological malignancies with nanobody-based heavy chain antibodies and AAV vectors
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Baum N.

    BackgroundAlthough monoclonal antibodies binding the EGF-receptor (cetuximab, panitumumab) or CD38 (daratumumab) show therapeutic efficacy, many cancer patients still develop resistance. Therefore, new therapies are necessary. Nanobodies are highly soluble immunoglobulin domains derived from heavy chain antibodies (hcAbs) that naturally occur in camelids. Replication defective AAV (adeno associated virus) vectors, when equipped with a tumor targeting ligand, can be used for the delivery of (suicide) genes to tumor cells. MethodsWe generated recombinant chimeric nanobody-based human IgG1 hcAbs, by fusing EGFR- or CD38-specific nanobodies derived from immunized llamas to the hinge, CH2 and CH3 domains of human IgG1 (1, 2). To promote cytotoxic effector functions we introduced CDC (complement dependent cytotoxicity)-enhancing and ADCC (antibody-dependent cell-mediated cytotoxicity)-enhancing mutations into the CH2 and CH3 domains of human IgG1. As a second strategy to target CD38-overexpressing cells, we inserted CD38-specific nanobodies into the VP1 capsid protein of AAV2 (3). We analyzed the capacity of these constructs to target EGFR and CD38 in tumor cell lines and multiple myeloma (MM) patient bone marrow samples using proliferation, CDC, ADCC and AAV-transduction assays. ResultsEGFR-specific hcAbs effectively blocked the proliferation of tumor cell lines (HNSCC, head and neck squamous cell carcinoma and mCRC, metastatic colorectal cancer) expressing WT EGFR and cetuximab/panitumumab-escape variants of EGFR. EGFR- and CD38-specific hcAbs mediated effective ADCC towards tumor cell lines (HNSCC, mCRC and MM respectively). HcAbs carrying the hexabody mutation were more potent at inducing CDC than parental hcAbs. Display of CD38-specific nanobodies on the AAV capsid resulted in a 20- to 100-fold enhanced transduction of myeloma cells in patient bone marrow samples. Some of these results have recently been published (1, 2) or accepted for publication (3). We will present updated data on tumor cell lines and patient samples. ConclusionNanobody-based hcAbs and nanobody-displaying AAV hold promise as novel tools to target solid and hematological tumors. Legal entity responsible for the studyFriedrich Koch-Nolte. FundingDFG (German Research Foundation) and SFB (Collaborative Research Centres). DisclosureThe author has declared no conflicts of interest.

    更新日期:2019-12-17
  • 96P Clearance of HPV anal premalignant lesions and modulation of systemic immune responses to HPV oncogenes with low dose pomalidomide
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Polizzotto M, Van Bockel D, Law C, et al.

    BackgroundAnal high-grade intraepithelial lesions (HSIL) precede the development of HPV-associated anal cancer and so present a target for early intervention and cancer prevention. Spontaneous HSIL clearance is associated with systemic CD4 T-cell response to the HPV oncogene E6. Pomalidomide may enhance immune responses to HPV and be therapeutic in HSIL. MethodsThis phase II single centre study (NCT3113942) recruited participants with persistent (>12 months) biopsy-proven anal HSIL. Therapy was oral pomalidomide, 2mg for 21 of 28 days for up to 6 months. Primary outcome was response at end therapy (CR defined as histological clearance; PR as ≥ 50% reduction in area); secondary included response after 6 further months observation. Immune activation markers (CD38, HLA DR) were assessed with flow cytometry and antigen-specific CD4+ T-cell responses to HPV E6 and E7 with OX40 immunoassay. Results26 participants were enrolled, 24 were evaluable for response. All male; median age 54 (range 41-74). All AIN3 HSIL, median duration HSIL 37 months (15-86), median octants 2 (0.5-5); HPV16 in 55%; multiple high risk HPV types in 50%. Overall response (CR+PR) was 52% (CI: 31-73) at end therapy, increasing to 63% (95% CI 40-81) after 6 further months observation. Adverse events (AEs) were mild and self-limited, including cytopenias, constipation, and rash. Over 137 cycles (c), attributable grade 3/4 events were grade 3 neutropenia (4 c) and grade 3 angina (1 c). Systemic CD4 T-cell responses to HPV E6 but not E7 increased significantly during therapy, peaking day 14 of therapy: baseline 0.06%, (IQR 0.01 – 0.12%), median increase day 14 0.13% (IQR: 0.02 – 0.26%), p = 0.001. Activation of CD4 and CD8 cells increased significantly during therapy. Parameters returned to baseline after therapy. ConclusionLow dose oral pomalidomide was well tolerated and induced durable continuing clearance of anal HSIL of multiple genotypes in even in chronic extensive disease. Induction of HPV-specific CD4+ responses and immune activation support an immunological mechanism of action. Immunotherapy with pomalidomide is a promising approach to prevention of anal cancer and potentially other HPV cancers. Clinical trial identificationNCT3113942. Legal entity responsible for the studyKirby Institute, University of New South Wales, Sydney, Australia. FundingCancer Institute of New South Wales. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 53P Immune-related adverse events associated with immune-checkpoint inhibitors: A single center experience
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Samanci N, Oruc K, Bedir S, et al.

    BackgroundClinical trials have demonstrated the benefit of immune-checkpoint inhibitors (ICIs) for many cancer types. With the widespread use of ICIs, we are facing challenges in the management of immune-related adverse events(irAEs). It is extremely important for physicians to be aware of early recognition and immediate treatment of irAEs. In this study, we aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. MethodsBetween January 2015 and December 2018, patients who were treated with at least one ICIs in clinical trials, expanded access programs or in routine practice in Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine were included in this study. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, risk factors, and their association with treatment outcomes. All irAEs were graded using the CTCAE v4.0. ResultsA total of 255 patients were retrospectively evaluated. Of these 71 (27.8%) patients developed irAEs. 52(73.2%) of the patients were male, 19 (26.8%) were female. All patients have ECOG performance status 0 -1. More than 2 irAEs were detected in 16 (6.2%) patients. A total of 3177 doses were given with 93 episodes of any grade irAEs. There were 22 irAEs (23.7%) reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most common among them were pneumonitis (n:15), hepatitis (n:13), hypothyroidism (n:13) and dermatitis (n:12). 3 patients were reported to develop grade 4 pneumonitis, toxic epidermal necrolysis and thrombocytopenia. There were 9 immune related deaths in our study. In 4 patients same irAEs recurred upon rechallenge of the ICIs. 39 of irAEs (41.9%) occurred after anti PD1, 47 (50.5 %) occurred after anti PDL1, 7 (7.5%) occurred after combination of anti CTLA4+ anti PDL1. ConclusionWith the increased use of immunotherapeutic agents in oncology clinics, increased awareness and early recognition are required for effective management of irAEs and improved treatment outcomes. We believe that this study will have a significant impact on current and future service delivery in oncology units. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 2O Biomarkers of immune switch induced by a novel anti-macrophage antibody (anti-Clever-1 mAb; FP-1305) in MATINS trial patients with advanced solid tumours
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Hollmén M, Virtakoivu R, Jaakkola P, et al.

    BackgroundA scavenger receptor CLEVER-1 is highly expressed on tumor associated macrophages (TAMs) and mediates the clearance of “unwanted” self-components. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflammatory cytokine secretion and antigen presentation reactivating CD8+ T cell responses with robust anti-tumor activity (Viitala et al., 2019). Targeting CLEVER-1 could overcome the immunosuppressive tumor microenvironment and has led to the development of FP-1305, a humanized anti-CLEVER-1 IgG4-antibody. MethodsMATINS (Macrophage Antibody To INhibit immune Suppression) trial is a multicenter first-in-human phase I/II study (NCT03733990) to assess the tolerability, safety and preliminary efficacy of FP-1305 in patients with advanced, IO-refractory melanoma, cholangiocarcinoma, hepatocellular, colorectal, and pancreatic ductal adenocarcinoma. Biomarker analysis included CLEVER-1 determination, immune cell profiling by mass cytometry and analysis of cytokine production. Results11 patients (median age 57) were enrolled in four cohorts (0.3, 1.0, 3.0 or 10 mg/kg) and received 1-8 cycles (median 3) of FP-1305 every three weeks. FP-1305 has been well tolerated without dose-limiting toxicities and maximum tolerated dose (MTD) has not been reached. Promising early efficacy results have recently been reported (ESMO 2019, LBA19). FP-1305 dosing led to increased Th1 skewing (CXCR3+CCR6-) of CD4 and CD8 T cell populations with downregulation of several inhibitory immune checkpoint molecules. Increase in circulating IFN gamma was detected but it was most prominent in the patient showing durable partial response. ConclusionFP-1305 is the first macrophage checkpoint inhibitor candidate promoting immune switch with promising tolerability and clinical anti-tumor activity. FP-1305 represents a novel treatment option to provoke immune response against cold tumors. Clinical trial identificationNCT03733990. Legal entity responsible for the studyFaron Pharmaceuticals. FundingFinnish Academy, Finnish Cancer Foundations, Sigrid Juselius Foundation, Faron Pharmaceuticals. DisclosureM. Hollmén: Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. P. Jaakkola: Advisory / Consultancy: Faron Pharmaceuticals. A. Minchom: Advisory / Consultancy: Faron Pharmaceuticals. S. Jalkanen: Shareholder / Stockholder / Stock options: Faron Pharmaceuticals. M. Karvonen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Mandelin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Faron Pharmaceuticals. J. Koivunen: Advisory / Consultancy: Faron Pharmaceuticals; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: KaikuHealth. P. Bono: Advisory / Consultancy, Travel / Accommodation / Expenses, Spouse / Financial dependant: Faron Pharmaceuticals; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: OrionPharma. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 19P The prognostic nutritional index and neutrophil-to-lymphocyte ratio as prognostic factors in advanced non-small cell lung cancer patients treated with immunotherapy
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Cipriano É, Magalhães H, Estevinho F, et al.

    BackgroundThe immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) had shown to increase progression-free survival (PFS) and overall survival (OS). The prognostic nutritional index (PNI) and neutrophil-to-lymphocyte ratio (NLR) are biomarkers easy to measure by blood tests and they had been studied as possible prognostic predictors in patients (pts) with various types of cancer treated with ICI. This study intends to analyze the impact of the NLR and PNI in pts with NSCLC treated with ICI. MethodsThirty-four pts with stage IV NSCLC that had started ICI in 1st and subsequent lines between 03/2016 and 06/2019 were retrospectively analyzed. The pre-treatment NLR and PNI were calculated and the cut-off 5 and 50 were respectively considered. The Kaplan-Meier method and Log Rank test and the Cox regression were used in survival analysis. ResultsTwenty-seven (79%) were male, with a median age of 67 (34-79) years; ECOG 0-1 (n = 30; 88%); stage IVA (n = 14; 41%); PD-L1 ≥50% (n = 18; 53%); NLR ≥5 (n = 13; 38%); PNI ≥50 (n = 14; 41%). Eleven pts (32%) were submitted to ICI in 1st line. The median follow-up time was 19,3 months (mo.). The median PFS was 6,1 mo. (95%CI 1,94-10,26) and median OS was 9,3 mo. (95%CI 0,31-18,29) - 16,5 mo. in 1st line vs 8,6 mo. in subsequent lines. The median PFS was superior in patients with PNI ≥50 (7,0 vs 2,1 mo., p = 0,039), but there weren’t differences considering the NLR. The median OS was also superior when PNI ≥50 (16,8 vs 6,7 mo., p = 0,019). In multivariate analysis (sex, age, 1st line, PD-L1, stage, ECOG, NLR and PNI), the mortality probability was superior in pts with ≥70 years [HR 6,14 (95%CI 1,49-25,39)]. Moreover, PD-L1 ≥50% [HR 0,09 (95%CI 0,01-0,52)], male sex [HR 0,03 (95%CI 0,004-0,24)], stage IVA [HR 0,26 (95%CI 0,07-0,997)] and PNI ≥50 [HR 0,15 (95%CI 0,03-0,69)] were associated to a reduced mortality risk. ConclusionPNI ≥50 was predictive of a better PFS and OS and the NLR wasńt a predictor of survival. Regarding OS, PNI ≥50 was an independent survival prognostic factor. In order to understand the impact of this biomarker in NSCLC treated with ICI, it is important to evaluate it in more studies with a larger population and prolonged follow-up time. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 131P PD-1 and LAG-3 synergize to drive tumour-infiltration of T cytotoxic cells in NSCLC tumours
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Juncker-Jensen A, Nagy M, Kuo J, et al.

    BackgroundNon-small cell lung cancer (NSCLC) accounts for approximately 80-85% of all lung cancer cases, and is characterized by a poor response to chemotherapy and a low survival rate. Treatment targeting the immune checkpoint inhibitor pathway PD-1/PD-L1 has been found to be effective against NSCLC with manageable side effects, but with only 20-25% of patients showing a positive response there is an urgent need for additional immunotherapy options for this group of patients. LAG-3 and PD-1 are often co-expressed and upregulated on T cells leading to immune exhaustion and tumor growth, and co-blockade of the LAG-3 and PD-1 pathways has been shown to synergize to improve T cytotoxic cell responses. MethodsIn order to perform a comprehensive immunoprofiling of NSCLC tumors we used MultiOmyx™, an immunofluorescence (IF) multiplexing assay that utilize a pair of directly conjugated Cyanine dye-labeled (Cy3, Cy5) antibodies per round of staining. Using a 16-marker panel we have analyzed the proportion of B cells, T cell subtypes, M1/M2-type tumor-associated macrophages, as well as the expression of PD-1, PD-L1, LAG-3, and TIM-3 in 20 samples from patients with NSCLC. ResultsLAG-3 was found to be expressed mainly on T cytotoxic cells in both subtypes, but the overall density of LAG-3 was 59% higher in squamous cell carcinoma (SCC) tumors compared to adenocarcinoma tumors. In both SCC and adenocarcinoma subtypes TIM-3 was found primarily on tumor-associated macrophages (TAMs), followed by an equal distribution on helper and cytotoxic T cells. When analyzing the proportion of T cytotoxic cells infiltrating into the tumor area, we observed an apparent synergy between LAG-3 and PD-1, suggesting a therapeutic benefit of dual checkpoint blockade of LAG-3 and PD-1 in NSCLC. ConclusionIt is our hope that these data will help provide new insights into the biology of NSCLC that can ultimately be used to explore novel immunotherapeutic interventions for lung cancer treatment. Legal entity responsible for the studyNeoGenomics. FundingNeoGenomics. DisclosureA. Juncker-Jensen: Full / Part-time employment: NeoGenomics. M. Nagy: Full / Part-time employment: NeoGenomics. J. Kuo: Full / Part-time employment: NeoGenomics. E. Leones: Full / Part-time employment: NeoGenomics. F. Sahafi: Full / Part-time employment: NeoGenomics. K. Pham: Full / Part-time employment: NeoGenomics. E. Parnell: Full / Part-time employment: NeoGenomics.

    更新日期:2019-12-17
  • 36P First CAR-T cell immunotherapy against HLA-G: Targeting a unique ICP and TAA
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Loustau M.

    BackgroundCAR-T cells therapies turn out to be a breakthrough, particularly for B-cell malignancies. However, its application in solid tumor remains a challenge. The main limitations are: few highly specific tumor associated antigen (TAA), low T cell penetration and an immune-suppressive tumor microenvironment (TME). Thus, our aim was to develop a new immunotherapeutic strategy against HLA-G, an immune-tolerogenic molecule involved in tumor immune escape, frequently upregulated on tumor cells. HLA-G is a CMH-Ib molecule and exerts its immuno-inhibitory activity through specific binding with two inhibitory receptors, ILT2 and ILT4, leading to the inhibition of all immune cell subsets and the induction of suppressive immune cells. HLA-G was recently identified as an ICP molecule, could be highly neo-expressed in cancer, i.e.: ccRCC (98%) and associated with malignant transformation. HLA-G is found on tumor cells and is rarely observed in healthy tissues defining it as a remarkable TAA. RNAseq analyses show that HLA-G is a far better tumor specific antigen than PD-L1. However, no immunotherapy against HLA-G-expressing tumors has been developed. Indeed, neither stimulatory functions nor cellular responses directed against allogeneic HLA-G have been reported. MethodsHighly specific antibodies against HLA-G, generated by our team, strongly bind to multiple HLA-G isoforms and their scFv were used to develop 3rd generation chimeric antigen receptors (CARs). ResultsAnti-HLA-G CAR-T were specifically cytotoxic for HLA-G expressing target cells (K562-HLA-G1 and Jeg-3 cell lines), with resulting IFNg secretion and activation phenotype and also inducing a long-term T effector memory phenotype. Finally, in vivo assays demonstrated that anti-HLA-G CAR-T cells had strong anti-tumor activity controlling tumor progression up-to 50 days of experiment. ConclusionWe report here for the first time CAR-T cells specifically targeting HLA-G expected to disrupt the tumor micro-environment related to HLA-G and solid tumors. Legal entity responsible for the studyInvectys (Paris, France). FundingInvectys (Paris, France). DisclosureThe author has declared no conflicts of interest.

    更新日期:2019-12-17
  • 90TiP FRAIL-IMMUNE: A multicenter, prospective, single arm phase II of the combination of durvalumab with carboplatin and paclitaxel as first-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck not eligible to standard chemotherapy (GORTEC 2018-03)
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Fayette J.

    BackgroundOne third of patients with (R/M SCCHN) are not eligible to receive the standard first-line chemotherapy EXTREME (cisplatin, fluorouracile and cetuximab). In this population, the weekly scheme of carboplatin-paclitaxel demonstrated clinical efficacy an overall survival (OS) of 4.9-12.8 months and a response rate of 20-52%. In a study conducted in our center, patients ineligible to EXTREME due to performance status (PS) 2 or other reasons (excluding PS2) reached a median OS of 3.6 months and 11.5 months, respectively. Trial DesignA prospective, multicenter, single-arm phase II trial to study the efficacy and safety of durvalumab (anti-PD-L1) combined with carboplatin-paclitaxel in patients with R/M SCCHN ineligible to cisplatin. A first cohort of patients (n = 64) with PS0-1 will be accrued, then a cohort of patients with PS2 (n = 38) if results of the cohort PS0-1 are positive. Patients will receive four 28-day cycles (carboplatin AUC2 and paclitaxel 80mg/m², D1, D8, D15) with 4-weekly infusions of 1500mg durvalumab (pursued for a maximum of 12 months). An initial safety run-in step with predefined stopping rules is being conducted in the first 6 patients of the cohort PS0-1. The primary objective will be to determine the efficacy (12-month OS rate) of the combination. The treatment will be considered for further investigations, if at least 38 successes and 10 successes are observed in cohorts PS0-1 and PS2, respectively. Secondary endpoints will also be investigated: progression-free survival, time-to-treatment failure, OS, response rates, quality of life (QLQ-C30 and QLQ-H&N35) and tolerance profile of the combination. Radiological endpoints will be evaluated using the RECIST version 1.1. Translational objectives will be to study blood and tumor markers (expression of immune checkpoints, immune infiltrate and molecular alterations) as predictive and prognostic factors of efficacy. As of Oct 2nd 2019, a total of 5 patients has been accrued in the safety run-in step. Clinical trial identificationNCT0372967. Legal entity responsible for the studyCentre Léon Berard. FundingAstraZeneca. DisclosureJ. Fayette: Honoraria (self): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Innate Pharma; Honoraria (self): Merck; Honoraria (self): Rakuten; Honoraria (self): Biogen.

    更新日期:2019-12-17
  • 3O A pre-existing inflammatory immune microenvironment predicts the clinical and immunological response of vulvar high-grade squamous intraepithelial lesions to therapeutic HPV16 peptide vaccination
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Abdulrahman Z, de Miranda N, van Poelgeest M, et al.

    BackgroundVulvar High-grade Squamous Intraepithelial Lesion (vHSIL) is predominantly induced by high-risk Human Papilloma Virus type 16 (HPV16). In two independent trials, therapeutic vaccination against the oncoproteins of HPV16 with synthetic long peptides (SLP) resulted in vHSIL regression in about half of the patients after 12 months. Several studies have shown that the immune microenvironment influences therapy outcome. Therefore, a thorough investigation of the vHSIL immune microenvironment before and after SLP vaccination was performed, and its impact on clinical response was studied. MethodsTwo novel multiplex immunofluorescence panels were designed for formalin-fixed paraffin-embedded tissue, one for T cells (CD3, CD8, FoxP3, Tim3, Tbet, PD-1, DAPI) and one for myeloid cells (CD14, CD33, CD68, CD163, CD11c, PD-L1, DAPI). Pre- and 3 months post-vaccination biopsies of 29 patients and 27 healthy vulva excisions were stained, scanned with the Vectra multispectral imaging system, and automatically phenotyped and counted with inForm advanced image analysis software. ResultsA pre-existing pro-inflammatory TME, marked by high numbers of CD4 and CD8 T cells expressing Tbet and/or PD-1 as well as CD14+ inflammatory macrophages, is a strong predictor for good clinical response. A clear stepwise increase in pre-vaccination infiltrating Tbet+, CD4+, CD8+ T cells and CD14+ macrophages, and decrease in Foxp3+ Tregs was observed as response increased from non to partial to complete response. Moreover, the pre-vaccination immune microenvironment of complete responders resembled healthy vulva. Vaccination further increased infiltrating CD4+ and Tbet+ T cells and CD14+ macrophages and decreased FoxP3+ Tregs in the complete and partial responders, but not in the non responders. ConclusionClinical responsiveness to therapeutic HPV16 SLP vaccination requires a pre-existing inflamed type 1 immune contexture in vHSIL. Hence, only patients with an inflamed TME should be selected for monotherapy by therapeutic vaccination, since this strategy is incapable of creating an inflamed TME in patients where this is absent. Legal entity responsible for the studyThe authors. FundingLeiden University Medical Center. DisclosureS.H. van der Burg: Advisory / Consultancy: ISA Pharmaceuticals. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 54P Applicability of the LIPI score to metastatic microsatellite instability high cancer patients treated with immune checkpoint inhibitors
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Vuagnat P, Auclin E, Mezquita L, et al.

    BackgroundMicrosatellite instability high (MSI-H) is an approved tissue-agnostic predictive biomarker of benefit to immune checkpoint inhibitors (ICI). However not all patients (pts) respond to ICI and additional biomarker of response in this population is still required. The Lung-Immune Prognostic Index (LIPI), combining derived NLR (dNLR=neutrophils/[leucocytes-neutrophils]) and lactate dehydrogenase (LDH) demonstrated a strong correlation with ICI outcomes in NSCLC and other tumor types. We aimed to evaluate the value of pretreatment LIPI for predicting benefit to ICI in MSI-H population. MethodsWe performed a multicenter retrospective study of pts with metastatic MSI-H tumors treated with ICI from Apr 2014 to May 2019. Biological and clinical data were retrospectively collected and LIPI was calculated based as previously reported. LIPI groups were: good (dNLR≤3 + LDH≤upper limit of normality [ULN]), intermediate (dNLR>3 or LDH>ULN and poor (dNLR>3+LDH>ULN). The primary endpoint was progression-free survival (PFS) and secondary endpoints were overall survival (OS), overall response rate (ORR). ResultsPreliminary data is available for 111 pts, with the following characteristics: 43 (39%) male; median age of 62 (24-93), median number of previous lines 1 (range 0 – 6); most common tumor types were colorectal (43%) and endometrial cancer (15%). MSI was defined by immunochemistry and/or polymerase chain reaction (PCR) in 88% and 37 pts (38%) had a confirmed Lynch Syndrome. 98 pts (88%) were treated with a single agent-PD(L)1 inhibitor. The median (m) PFS was 14.1 months (m.) [95%CI, 8.38-not reached (NR)] and the mOS was NR [95%CI, 30-xx] with 44% of ORR. LIPI stratified the population in: good (51, 46%), intermediate (50, 45%) and poor groups (10, 9%). The good group had mPFS of 20.9m. vs. 32m. for intermediate vs. 1.8m. for poor groups (P = 0.0006). In the good group, the ORR was 55% vs. 38% for intermediate vs. 13% in poor group (P = 0.05). OS data are not mature yet. ConclusionPoor LIPI is correlated with worse ICI outcomes (PFS, ORR) in MSI-H pts, identifying potentially a MSI-H subset of pts with no benefit from ICI. This study is still ongoing for assessing the value of LIPI in a larger cohort. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureP. Vuagnat: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). E. Auclin: Travel / Accommodation / Expenses: MundiPharma; Speaker Bureau / Expert testimony: Sanofi Genzyme. L. Mezquita: Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Tecnofarma, Roche, AstraZeneca; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Roche, Chugai. M.R. Vidal Tocino: Advisory / Consultancy: Amgen, Celgene, Merck, Sanofi; Travel / Accommodation / Expenses: Amgen, Roche. P. Martin Romano: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). C. Baldini: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). A. Varga: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche: As part of the Drug Development Department (DITEP). B. Besse: Research grant / Funding (institution): Bristol-Myers Squibb, Roche, Chugai. C. Massard: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol-Myers Squibb, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, Novartis, Pfizer, Roche, Sanofi, Orion: Consultant/Advisory fees. A. Hollebecque: Research grant / Funding (institution), Full / Part-time employment, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP); Non-remunerated activity/ies, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi: As part of the Drug Development Department (DITEP). All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 115P Therapeutic efficacy of combining the tumour checkpoint controller BAL101553 (lisavanbulin) and immunomodulation in two mouse glioma models with different immunological status
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Genoud V, Marinari E, Bes V, et al.

    BackgroundGlioblastoma (GBM) is a highly malignant brain tumour with no curative treatments. Immunotherapies, including immune checkpoint inhibitors (ICI) are under clinical evaluation, but have not yet been proven to have major impact. The low immune infiltration and modest mutational load of most GBM suggest that combination therapies will be required to improve sensitivity to immunotherapies. MethodsTwo mouse GBM models were used, the immunogenic GL261 and the stringent, less mutated SB28. A novel, brain-penetrant, microtubule-targeting agent, BAL101553 (BAL) which induces tumour cell death through activation of the spindle assembly checkpoint, and an agonistic anti-CD40 antibody were combined with ICI (antibodies targeting PD-1 and CTLA-4) to evaluate potential therapeutic synergy. Tumours were analyzed molecularly (mutations, transcriptional profiling) and immunologically (immune infiltration, therapy response in T/B-cell deficient mice). ResultsWell-tolerated combination therapies that significantly enhanced survival were identified in both SB28 and GL261 GBM models. The aggressive SB28, most representative of untreated human GBM, was most responsive to BAL combined with anti-CD40 (median survival in days: vehicle=27, anti-CD40=29, BAL=42, BAL/CD40=49); this effect was found to be T-cell independent as a similar result was observed in SB28 glioma-bearing immunodeficient (RAG1 KO) mice. The immunogenic GL261 model was, as predicted, responsive to ICI; it was relatively insensitive to BAL and anti-CD40 monotherapies but responsive to a combination of these two treatments (median survival in days: vehicle=28, anti-CD40=30, BAL=33, BAL/CD40=40). ConclusionCombination GBM therapies that include immunomodulation will likely require selection of patients according to immunological characteristics. Most clinical exploration of immunomodulators focusses on enhancing T-cell mediated anti-tumour immunity but our data suggest that synergistic combination of a tumour checkpoint controller and immunostimulation can be appropriate for poorly immunogenic GBM that is refractory to T-cell control. Legal entity responsible for the studyThe authors. FundingBasilea Pharmaceutica Ltd. DisclosureP. McSheehy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. F. Bachmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. H. Lane: Shareholder / Stockholder / Stock options, Full / Part-time employment: Basilea Pharmaceutica Ltd.. P.R. Walker: Advisory / Consultancy, Research grant / Funding (self): Basilea Pharmaceutica Int. Ltdtd. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 97P Impact of prior lines of systemic therapy (PST) on the efficacy of cemiplimab, a human monoclonal anti–PD-1, in patients (pts) with advanced cutaneous squamous cell carcinoma (CSCC)
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Rischin D, Khushalani N, Schmults C, et al.

    BackgroundCemiplimab demonstrated antitumour activity and an acceptable safety profile in a phase II study of pts with CSCC (NCT02760498). Here, we report efficacy by PST. MethodsThe primary objective of the study is to evaluate the objective response rate (ORR) by independent central review (ICR). Pts with metastatic CSCC (mCSCC; Group 1) and locally advanced CSCC (Group 2) received 3 mg/kg Q2W for 96 weeks, and mCSCC received 350 mg Q3W for 54 weeks (Group 3). Data cutoff dates were 20 September 2018 (Groups 1 and 3) and 10 October 2018 (Group 2). ResultsOf the 193 pts enrolled, 128 had cemiplimab as first-line therapy (1LT) and 65 had PST (table). Median follow-up was 9.4 months. The ORR per ICR was 46.9% (95% CI: 38.0–55.9; 17 complete responses [CR] and 43 partial responses [PR]) in pts with cemiplimab as 1LT and 38.5% (95% CI: 26.7–51.4; five CRs and 20 PRs) in pts with PST. The disease control rate per ICR was 75.8% (95% CI: 67.4–82.9) in pts with cemiplimab as 1LT and 64.6% (95% CI: 51.8–76.1) in pts with PST. Estimated 12-month duration of response (DOR) was 88.3% (95% CI: 73.9–95.0) among all 60-responding pts with cemiplimab as 1LT and 90.9% (95% CI: 68.1–97.6) among all 25-responding pts with PST. Estimated Kaplan–Meier 12-month progression-free survival was 56.9% (95% CI: 46.4–66.2) in pts with cemiplimab as 1LT and 46.7% (95% CI: 33.4–58.9) in pts with PST. 12-month overall survival was 90.7% (95% CI: 83.7–94.8) in pts with cemiplimab as 1LT and 76.3% (95% CI: 63.7–85.0) in pts with PST. The most common treatment-related adverse events in all pts were fatigue (n = 37, 19.2%), pruritus (n = 25, 13.0%) and diarrhoea (n = 24, 12.4%) and rash and maculopapular rash (both n = 21, 10.9%). ConclusionAs demonstrated by the numerically higher ORR, 12-month PFS, and OS, the efficacy of cemiplimab in advanced CSCC may be greater when used as 1LT, supporting its early use for patients with advanced CSCC. Table: 97P Therapeutic setting, number of regimens and type of systemic therapies in pts with PSTPts with PST (N = 65)Therapeutic setting, n (%)Metastatic disease22 (33.8)Adjuvant10 (15.4)Neoadjuvant4 (6.2)Chemotherapy with concurrent radiation35 (53.8)Other8 (12.3)Number of regimens at baseline, median (range)1 (1–4)Type of PST, n (%)Antineoplastic agents65 (100.0)Platinum compounds46 (70.8)Monoclonal antibodies18 (27.7)Pyrimidine analogues15 (23.1)Taxanes15 (23.1)Protein kinase inhibitors4 (6.2)Combinations of antineoplastic agents3 (4.6)Folic acid analogues1 (1.5)Other antineoplastic agents1 (1.5)Corticosteroids for systemic use1 (1.5)Glucocorticoids1 (1.5) Clinical trial identificationNCT02760498. Editorial acknowledgementMedical writing support under the direction of the authors was provided by Kate Carolan, PhD, of Prime (Knutsford, UK) and funded by Regeneron Pharmaceuticals, Inc. and Sanofi according to Good Publication Practice guidelines. Legal entity responsible for the studyRegeneron Pharmaceutical, Inc. and Sanofi. FundingRegeneron Pharmaceutical, Inc. and Sanofi. DisclosureD. Rischin: Research grant / Funding (institution), Non-remunerated activity/ies: Regeneron Pharmaceuticals, Inc.; Research grant / Funding (institution): Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses, Non-remunerated activity/ies: Merck Sharp & Dohme; Research grant / Funding (institution), Non-remunerated activity/ies: Bristol-Myers Squibb; Research grant / Funding (institution), Non-remunerated activity/ies: GSK. N.I. Khushalani: Advisory / Consultancy, Research grant / Funding (self): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): HUYA Bioscience International; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy, Data safety monitoring committee: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: ARRAY Biopharma; Advisory / Consultancy: Immunocore; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self): GlaxoSmithKline; Research grant / Funding (self): Cellgene; Research grant / Funding (self): Amgen; Honoraria (self): Sanofi; Shareholder / Stockholder / Stock options: Bellicum Pharmaceuticals; Shareholder / Stockholder / Stock options: Mazor Robotics; Shareholder / Stockholder / Stock options: Amarin; Shareholder / Stockholder / Stock options: Transenetrix. C.D. Schmults: Advisory / Consultancy, Research grant / Funding (self), Steering committee member: Castle Biosciences; Advisory / Consultancy, Research grant / Funding (self), Steering committee member: Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Sanofi; Research grant / Funding (self): Novartis; Research grant / Funding (self): Genentech; Research grant / Funding (self): Merck; Advisory / Consultancy, Chair for NCCN: NCCN. A. Guminski: Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies: Sun Pharma; Advisory / Consultancy: Merck KGaA; Advisory / Consultancy: Eisai; Advisory / Consultancy: Pfizer; Non-remunerated activity/ies: Astellas; Research grant / Funding (institution), Clinical trial unit support: PPD Australia. A.L.S. Chang: Advisory / Consultancy, Research grant / Funding (self): Regeneron Pharmaceuticals, Inc.; Research grant / Funding (self): Novartis; Research grant / Funding (self): Galderma; Advisory / Consultancy, Research grant / Funding (self): Merck. K.D. Lewis: Research grant / Funding (self), Grants and personal fees: Regeneron Pharmaceuticals, Inc.. A.M. Lim: Non-remunerated activity/ies: Merck Sharp & Dohme; Travel / Accommodation / Expenses: Bristol-Myers Squibb. L. Hernandez-Aya: Advisory / Consultancy: Massive Bio; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Regeneron Pharmaceuticals, Inc.; Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (self): Immunocore; Research grant / Funding (self): Merck Sharp & Dohme; Research grant / Funding (self): Polynoma; Research grant / Funding (self): Corvus Pharmaceuticals; Research grant / Funding (self): Roche; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): Amgen; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Takeda. B.G.M. Hughes: Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Advisory / Consultancy: Eisai; Advisory / Consultancy: Merck; Research grant / Funding (institution): Amgen. D. Schadendorf: Research grant / Funding (institution): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: Amgen; Advisory / Consultancy: Leo Pharma; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Patients’ fees: Merck-EMD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Incyte; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution), Patients’ fees: MSD; Advisory / Consultancy, Steering committee honorarium: 4SC; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array; Advisory / Consultancy, Research grant / Funding (institution), Patients’ fees: Philiogen. A. Hauschild: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD/Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Provectus; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Philogen; Advisory / Consultancy, Research grant / Funding (institution): Regeneron Pharmaceuticals, Inc.; Advisory / Consultancy: OncoSec. E. Stankevich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. J. Booth: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. S. Li: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. Z. Chen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. J. Desai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. I. Lowy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. M.G. Fury: Shareholder / Stockholder / Stock options, Full / Part-time employment: Regeneron Pharmaceuticals, Inc.. M.R. Migden: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Regeneron Pharmaceuticals, Inc.; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eli Lilly; Honoraria (self), Travel / Accommodation / Expenses: Sun Pharma.

    更新日期:2019-12-17
  • 72P Evaluation of the correlation between diverticulosis and the onset of diarrhea in patients with lung cancer treated with immune checkpoint inhibitors
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Negrini G, Ghilardi L, Bonomi L, et al.

    BackgroundImmune checkpoint inhibitors anti-PD-1 (Nivolumab and Pembrolizumab) represent a remarkable advance in non-small-cell lung cancer (NSCLC) treatment with impressive clinical activity and durable responses in some patients. However, immunotherapies generate new toxicity profiles called immune-related adverse events (irAEs) that require specific management. Gastrointestinal (GI) irAEs (diarrhea and colitis) are among the most common and if they are left unrecognised or untreated, they can become life threatening. Therefore, the identification of the risk factors for the development of diarrhea could be helpful for the prevention and management of GI irAEs. Among these, the presence of diverticulosis could affect the onset of diarrhea. MethodsThis retrospective analysis was conducted in 94 patients with metastatic NSCLC who received Nivolumab at the Papa Giovanni XXIII Hospital in Bergamo between 2015 and 2017. We evaluated the presence of diverticulosis before the start of immunotherapy, the degree and management of diarrhea during therapy and the correlation between the presence of diverticulosis and GI irAEs. ResultsAll patients had previously been treated with chemotherapy. 90 patients received Nivolumab at a dose of 3mg/kg while 4 patients received Nivolumab flat dose of 240mg. The RR was 14% and the DCR was 45%. The median PFS has not yet been reached. 19 of 94 patients had a radiological diagnosis of diverticulosis before the start of treatment and 11 of 94 patients developed diarrhea during the therapy. While of the 75 patients without diverticulosis only 7% developed diarrhea, 32% of patients with diverticulosis developed diarrhea. The chi-square test was used for statistical analysis. GI irAEs were in most cases of grade 2 and were treated with steroid therapy without having to resort to other types of immunosuppressive therapy. No patient discontinued treatment due to adverse event. ConclusionIn our population, the presence of diverticulosis increases the risk of gastrointestinal irAEs. However, these patients can be treated with immunotherapy but they represent a risk class for the onset of diarrhea. Further studies are needed to confirm our findings. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 20P The immune profiles in young, adult and elderly of advanced stage colorectal cancer patients
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Budhi I, Bagus M, Ayu S, et al.

    BackgroundThe incidence of colorectal cancer cases is high and increases each year. Colorectal cancer is the 3rd most common cancer in both sexes. The five-year survival rate has not increased significantly for several decades. Usually our patients come to the hospital already in advanced stage and the elderly patients seem to have a better clinical outcome than young and adult patients. One factor that could be suggest for those cases is different immune profiles between them. We evaluated the difference of immune profiles between those groups in advanced stage colorectal cancer. MethodsThis was a cross sectional analytic study on colorectal cancer patients in advanced stage, to evaluate whether any difference in immunity profiles between 3 age groups (young: <40 y.o; adult: 40 – 60 y.o; elderly: >60 y.o). We evaluated the level of CRP, IL-1β, IL-6, IL-10 IFNγ, TNFα, CD-8, IG G and IG M from blood specimens of those colorectal cancer patients. MANOVA test was done to evaluate the level of significance of those differences between each age group. Results62 colorectal cancer patients were evaluated on this study. We found significant differences in the levels of CRP, IL-6, IFNγ, CB-8, IG G and IG M between the young, adult and elderly patients, rp < 0.05. Whereas the difference between the young and adult patients, in the levels of IL-6, IFNγ, CD-8, IG G and IG M were found to be significant (p < 0.05), while between the young and elderly group, the signifant differences were in the levels of CRP, IL-6, IFNγ, CB-8, IG G and IG M (p < 0.05). The level of IL-6 was only significantly different between the adult and elderly group (p < 0.05) ConclusionThere were significant differences in immune profile between young, adult and elderly colorectal cancer patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 132P Correlation between tumour infiltration lymphocyte and PDL-1 expression in laryngeal cancer and its prognostic significance: A prospective, non-interventional trial
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Ismail M, Wakiel H, Ghany D, et al.

    BackgroundImmune system plays an important role in cancer evolution. However, cancer cells affect the immune system and use it for its growth and survival. Tumour infiltration lymphocytes and PDL-1 expression proved to play an important prognostic role in different malignancies. We aimed at evaluating this role in laryngeal cancer. MethodsWe prospectively analyzed the pre-treatment paraffin blocks for laryngeal cancer patients, whether on the laryngoscopy or operative specimens, to identify the CD8-positive cells in the tumour epithelium or stroma and the PDL-1 expression on the tumour cells. Appropriate tissue was used as positive control; placenta for PDL-1 and tonsil for CD8. A total score formed of the sum of percentage and intensity of PDL-1. A final comprehensive rate was considered as low expression when combined percentage and intensity score from 0 to 4, and high expression when score from 5-7. According to the distribution, the CD8+T cell invasion was divided into strong infiltration (> 10/100 of epithelial cells; >20/100 stromal cell infiltration) and weak infiltration (< 10/100 epithelial cells; < 20/100 stromal cell infiltration). Results40 patients were included in our study; 12 patients had early stage disease (I or II) and 28 with advanced stage (III or IV). PDL-1 expression was positive in 92.5%. Neither the PDL-1 nor CD-8 were found significantly correlated to OS in the whole population, however patients with advanced stage, median OS was significantly low for negative or low compared to high PDL-1 expression (11.7 vs 25.2 months (p = 0.036)), a trend of better OS in high CD8 Epithelial expression (25.1 versus 15.9, P = 0.514) and again trend of higher OS in high CD8 Stromal expression (25.3 versus 15.6 months, p = 0.375). Also there were significant correlation between the CD8 expression in the tumour epithelium and stroma with the PDL-1 expression with p-value of 0.001 and < 0.0001 respectively. ConclusionThere is a positive correlation between tumour infiltration lymphocytes and PDL-1 expression in laryngeal squamous carcinoma and the higher PDL-1 expression in advanced stage laryngeal cancer is associated with better OS. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 148P NKG2E comprises an immunogenic peptide, derived from an alu-retrotransposon: An attractive novel target for immunotherapeutic approaches
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Papamichos S.

    BackgroundEndogenous retroelements are a main source of targetable tumor-specific antigens that have the potential to augment host adaptive antitumor responses. KLRC3 gene encodes for the NKG2E and NKG2H isoforms of NKG2 family of transmembrane receptors. Current data support that NKG2E represents the main protein isoform. MethodsGenome, mobilome and molecular evolutionarily analysis were performed through the corresponding tracks of UCSC Genome Browser Database. NKG2E protein expression data were downloaded from the Human Protein Atlas. NetMHCII 2.3 was used to predict MHC class II binding scores. ResultsIn normal tissues, NKG2E protein is scarcely expressed in a rare subset of immune cells in the intestinal tract and lymphoid tissue. Vice versa, in tumor tissues NKG2E expression is detected in > 75% of tumor cells in cases of liver, breast and ovarian cancer as well as in 25-75% of tumor cells in cases of thyroid, stomach and prostate cancer. NKG2E protein is encoded by the long isoform of KLRC3 gene. The last exon of this mRNA is derived via an Alu-element exonization, which provides the last 14 aa of the coding region. Previous analysis showed that the 14 aa Alu-peptide is hydrophobic and impels the intracellular retention of NKG2E protein thereby impeding its function as a transmembrane receptor. A previous study revealed the presence of highly-specific IgG autoantibodies against the Alu-peptide in a disease known to stimulate Alu RNAs overexpression, but not in healthy individuals. The latter signifies not only a high immunogenicity but also that the host is mostly immunologically ignorant rather than tolerant of the Alu-peptide. Accordingly NetMHCII analysis identifies the Alu-peptide as a HLA-DRB1_0103 and -DRB1_1101 high binder. ConclusionNKG2E protein represents an aberrant molecule that is misexpressed in multiple cancers, including immunologically “cold” tumor types. Characterization of the rare immune cells producing the aberrant NKG2E molecule in normal tissues warrants further research. Subsequent studies could inquire into a TCD4-specific TCR usage that would allow for the inoculation of cancer patients with autologous CD4-T cells reactive against the Alu-peptide. Legal entity responsible for the studySpyros I. Papamichos. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

    更新日期:2019-12-17
  • 5P Differential expression patterns of immune checkpoint markers in tumour-stromal microenvironment of primary and chemoreduced retinoblastoma
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Singh L, Singh M, Rizvi M, et al.

    BackgroundThe goal of this study is to identify the pathological findings and expression of immune checkpoint marker (PD-1, PD-L1, and CTLA-4) in the tumor microenvironment of both primary and chemoreduced retinoblastoma and correlate with clinicopathological parameters and patient outcome. MethodsTotal of 262 prospective cases was included prospectively in which 144 cases underwent primary enucleation and 118 cases received chemotherapy/radiotherapy before enucleation (chemoreduced retinoblastoma). Immunohistochemistry, qRT-PCR and western blotting were performed to evaluate the expression pattern of immune checkpoint markers in primary and chemoreduced retinoblastoma. ResultsTumor microenvironment was different for both primary and chemoreduced retinoblastoma. Expression of PD-1 was found in 29/144 (20.13%) and 48/118 (40.67%) in primary and chemoreduced retinoblastoma respectively, whereas PD-L1 was expressed in 46/144 (31.94%) and 22/118 (18.64%) in cases of primary and chemoreduced retinoblastoma respectively. Expression pattern of CTLA-4 protein was similar in both groups of retinoblastoma. On multivariate analysis, massive choroidal invasion, bilaterality and PD-L1 expression (p = 0.034) were found to be statistically significant factors in primary retinoblastoma whereas PD-1 expression (p = 0.015) and foamy macrophages were significant factors in chemoreduced retinoblastoma. Overall survival reduced in cases of PD-L1 (80.76%) expressed primary retinoblastoma, and PD-1 (63.28%) expressed chemoreduced retinoblastoma. ConclusionThis is the first of its kind study predicting a relevant role of the immune checkpoint markers in primary and chemoreduced retinoblastoma with prognostic significance. Differential expression of these markers in both group of retinoblastoma is a novel finding and might be an interesting and beneficial target for chemoresistant tumors. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 116P Development of advanced human immune system mouse models for pre-clinical research in immuno-oncology
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Mossu A, Tschumi B.

    BackgroundThe reconstitution of a fully functional human immune system in the NCG mouse (hu-NCG) provides a unique opportunity to assess the efficacy of new drug candidates acting on human immune cells such as T cells, myeloid cells and NK cells. Enhanced NCG mice have been further developed to boost the differentiation of myeloid and NK cells, allowing scientists to efficiently test new antibodies or small molecules targeting these immune cell populations. MethodsA fully functional human immune system has been reconstituted in NCG mice after the transplantation of CD34+ human stem cells (hu-NCG model). Then, cell-line derived xenografts (CDX) and patient derived xenografts (PDX) have been engrafted in the hu-NCG model. The tumor growth has been monitored and the immune response assessed by flow cytometry. ResultsWe observed infiltration of human immune cells in the tumors. Furthermore, checkpoint inhibitors such as anti-PD1 strongly reduced tumor growth in hu-NCG demonstrating the potency of this model in onco-immunology. Alternatively, we demonstrated that hu-NCG, immunized against cancer antigens elicits strong T cell response as well as IgG production. ConclusionCollectively, the huNCG mouse model demonstrats its relevance for the preclinical testing (Mono and Combo therapies) of drugs in immuno-oncology. Legal entity responsible for the studyThe authors. FundingTranscure Bioservices. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 73P Real-world experience of immune-mediated hepatitis in Danish lung cancer patient using PD1 inhibitors
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Lauritsen L, Persson G, Poehl M, et al.

    BackgroundThere is limited information about the response to steroids in treatment of immune-mediated hepatitis (IMH) in patients treated with immune checkpoint inhibitors (ICI). We investigated the incidents of IMH in 307 Danish lung cancer patients with advanced non-small cell lung cancer (NSCLC) and reviewed the efficacy of the IMH treatment. MethodsData from NSCLC patients medical records were retrospectively registered when treated with ICI between July 2016 and December 2018 at University Hospital Herlev and Rigshospitalet, Copenhagen, Denmark. ResultsIn all 307 patients were treated with ICI – 85 patients received nivolumab and 222 pembrolizumab. Age ranged from 21 to 87 years, median 69. IMH was more common with pembrolizumab than with nivolumab (13% vs. 5%). There were 32 patients with grade 1-4 immune-related adverse events (irAEs) IMH (10 %), here off grade 1, 18 (56 %), grade 2, 6 (19 %), grade 3, 7 (22 %) and grade 4, 1 patient (3 %). Onset of raised transaminases ranged from 1-54 weeks, median 8. Time to normalization ranged from 2-464 days, median 24. In 24 patients with grade 1-2 the range was 2-256 days, median 24, until normalization; for grade 3-4 the range was 10-464, median 24. Half of the patients with grade 2 irAEs initiated treatment with steroids and 7 of 8 patients with grade 3-4 irAEs received immediately treatment with steroids. Steroid dose was on average 32 mg/day over a period of 1 year (range 1-32 months). The single patient with grade 4 irAEs also received treatment with mycophenolate mofetil however the transaminases never normalized. One patient with grad 3 irAEs received treatment with ursodeoxycholic acid and tacrolimus due to lack of improvement with steroids. Over a year passed before the transaminases normalized. This patient exclusively underwent liver biopsy which was diagnosed as autoimmune hepatitis. All patients with grade 3-4 had PD-L1 expression above 50% and all permanently discontinued ICI treatment. ConclusionLiver toxicity frequency correlates to findings in clinical trials (KEYNOTE-024 and KEYNOTE-042) and are mainly of grade 1. There was no correlation, in this dataset, between dose of steroids and time to normalizing of transaminases in patients treated with immunosuppressants. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 98P Results from a phase I study of MK-1308 (anti–CTLA-4) plus pembrolizumab in previously treated advanced small cell lung cancer
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Cho B, Yoh K, Bar J, et al.

    BackgroundAn ongoing open-label, multiarm, multicenter, phase I study of the anti–CTLA-4 antibody MK-1308 in combination with pembrolizumab in advanced solid tumors (NCT03179436) revealed manageable safety and promising efficacy in patients (pts) with advanced non-small cell lung cancer receiving first-line therapy [Perets et al. J Clin Oncol. 2019;37(suppl):2558]. Here we report data from the small cell lung cancer (SCLC) cohort of this study. MethodsIn the dose confirmation phase, pts with advanced SCLC received MK-1308 at 75 mg Q6W + pembrolizumab 200 mg Q3W (up to 35 cycles). The primary end point was safety, and the secondary end point was ORR based on blinded independent central review (BICR) per RECIST v1.1. PFS based on BICR per RECIST v1.1 and OS were exploratory end points. The database cutoff date for this analysis was June 3, 2019. ResultsForty pts with previously treated advanced SCLC (second-line or beyond) were enrolled and dosed; median duration of follow-up was 11 mo. At data cutoff, 32 pts (80%) discontinued study treatment—23 (58%) due to progressive disease, 4 (10%) due to AE, 2 (5.0%) due to clinical progression—and 3 (7.5%) withdrew consent. Median age was 66 years; 60% of pts were male and 65% had ECOG PS 1 at baseline. Seven pts achieved partial response according to BICR assessment, for an ORR of 18% (95% CI, 7.3-33). Eight pts (20%) had a best overall response of stable disease and 21 (53%) had progressive disease. Response duration ranged from 2.9 to 8.4+ mo. At the time of the data cutoff, 5 of 7 responses (71%) were ongoing. Median time to response was 2.1 mo (range, 1.1-12). Median PFS was 2.0 mo (95% CI, 1.9-3.9), and the 6-mo PFS rate was 26%. Median OS was 11 mo (95% CI, 5.9-not reached), and the 6-mo OS rate was 66%. Treatment-related adverse events (TRAEs) as determined by the investigator occurred in 32 pts (80%). Grade 3 TRAEs were reported in 11 pts (28%); no grade 4-5 events were reported. Three pts (7.5%) discontinued treatment due to TRAEs. ConclusionIn heavily pretreated pts with SCLC, MK-1308 + pembrolizumab was generally well tolerated with encouraging antitumor activity. Clinical trial identificationNCT03179436. Editorial acknowledgementMedical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA) and funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the studyMerck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. FundingMerck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. DisclosureB.C. Cho: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): MOGAM Institute; Honoraria (self), Research grant / Funding (self): Dong-A ST; Honoraria (self), Research grant / Funding (self), Licensing / Royalties: Champions Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Yuhan; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ono; Honoraria (self), Research grant / Funding (self): Dizal Pharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Advisory / Consultancy: Boehringer-Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Takeda; Shareholder / Stockholder / Stock options: TheraCanVac Inc; Shareholder / Stockholder / Stock options: Bridgebio Therapeutics; Shareholder / Stockholder / Stock options: Gencurix Inc. K. Yoh: Research grant / Funding (institution): MSD. J. Bar: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Advisory / Consultancy: OncoHost; Advisory / Consultancy: VBL; Research grant / Funding (institution): Pfizer. A. Nagrial: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Incyte. D.R. Spigel: Leadership role: Centennial Medical Center; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Boehringer-Ingelheim; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Genentech; Travel / Accommodation / Expenses: Genzyme; Travel / Accommodation / Expenses: Intuitive Surgical; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Purdue Pharma; Travel / Accommodation / Expenses: Spectrum Pharmaceuticals; Travel / Accommodation / Expenses: Sysmex. M. Gutierrez: Shareholder / Stockholder / Stock options: COTA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Esanex; Advisory / Consultancy: Guardant 360; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Foundation Medicine. D-W. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/Medimmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceutical; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. D. Rasco: Research grant / Funding (institution): Merck; Research grant / Funding (institution): Regeneron. M. Satouchi: Honoraria (self), Research grant / Funding (institution): MSD. M-J. Ahn: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: ONO; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Takeda; Advisory / Consultancy: Lilly; Advisory / Consultancy: Alpha Pharm. D.H. Lee: Honoraria (self): AbbVie; Honoraria (self): AstraZeneca; Honoraria (self): Boehringer-Ingelheim; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): ChongKunDang; Honoraria (self): CJ Healthcare; Honoraria (self): Eli Lilly; Honoraria (self): Janssen; Honoraria (self): Menarini; Honoraria (self): Merck; Honoraria (self): MSD; Honoraria (self): Mundipharma; Honoraria (self): Novartis; Honoraria (self): Ono; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Samyang Biopharm; Honoraria (self), Advisory / Consultancy: ST Cube; Honoraria (self): Takeda. C. Maurice-Dror: Travel / Accommodation / Expenses: Janssen; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Roche. S. Siddiqi: Full / Part-time employment: Merck & Co., Inc.. X. Li: Full / Part-time employment: Merck & Co., Inc.. J. Cyrus: Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R.A. Altura: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. R. Perets: Advisory / Consultancy: Karyopharm; Advisory / Consultancy: BiolineRx. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 55P Incidence and clinical implications of late immune-related adverse events in long responders to PD-1/PD-L1 checkpoint inhibitors: A multicenter study
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Nigro O, Cortellini A, Giusti R, et al.

    BackgroundImmunotherapy has become a standard of care for an increasing number of tumors. Patients have a chance of developing immune-related adverse events (irAEs). In general, irAEs occur quite early, mostly within weeks to 3 months after initiation of treatment. Being drugs relatively innovative, “late” irAEs are still unknown. MethodsWe conducted a multicenter retrospective study of advanced cancer patients (any histology, regardless of treatment line) treated with anti-PD-1/PD-L1 (mono)immunotherapy, with a minimum time to treatment failure (TTF) of 12 months. IrAEs were categorized into “early” (<12 months of treatment) and “late”. An explorative analysis of clinical outcomes (TTF and Overall Survival – OS) was performed. ResultsWe evaluated 318 consecutive patients treated with immunotherapy from September 2013 to August 2018. Median age was 68.6 years (32-90). 175 patients (55.5%) experienced any grade early-irAEs, while 110 (34.6%) experienced any grade late-irAEs (p = 0.0013); 13 patients (4.1%) experienced G3/G4 early-irAEs, while 12 (3.8%) G3/G4 late-irAEs (p = 0.8446). There was a significant association between the occurrence of any grade early-irAEs and late-irAEs (p = 0.0452), as well as between G3/G4 early-irAEs and late-irAEs (p = 0.0251). Among patients who experienced early-irAEs, 63 (36%) experienced “multiple-site” irAEs (multiple sites/organs), while 17 patients (15.4%) experienced multiple-site late-irAEs (p = 0.0040). The median period of follow-up was 22.2 months. The median time to irAEs onset were 3.1 and 16.1 months for early- and late-irAEs, respectively. Late irAEs were not significantly related to TTF; on the other hand, were significantly related to a prolonged OS. When adjusted for primary tumor, late-irAEs were confirmed to be significantly related to a prolonged OS (HR = 0.25 [95%CI:0.11-0.55]; p = 0.0006). ConclusionLate-irAEs among long responders seem to have a mild/moderate incidence. They are mostly non-serious and clinical manageable, with a low rate of treatment discontinuation. In this positive-selected population, the occurrence of any grade late-irAEs seems to be furtherly related to a prolonged OS. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 46O Impact of early introduction of steroid on immune-checkpoint inhibitors (ICI) in patients with advanced non-small cell lung cancer treated
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    De Giglio A, Mezquita L, Auclin E, et al.

    BackgroundThe use of steroids at baseline before ICI initiation has been associated with poor outcomes, particularly when their indication is related to cancer symptoms. It is poorly known if the initiation of steroids during the course of ICI impacts the outcomes. MethodsRetrospective analysis of advanced NSCLC patients treated with ICI at Institute Gustave Roussy. Eligible: steroids-naïve at baseline, initiating steroids therapy (≥10 mg of prednisone-equivalent) within the first 8 weeks of ICI. We correlated steroid use with outcomes, including progression-free survival (PFS) and overall survival (OS). ResultsIn an overall population of 424 patients treated with ICI, 250 were steroids-naïve at baseline. The median age was 63 years (range 30–92), most of them were male (65.5%), current or former smoker (90.6%), with non-squamous histology (76.1%) and ECOG PS 0/1 (76.8%). A total of 49 patients received early steroids: 39 patients for cancer-related indications [dyspnea (50%), brain metastasis (15.8%), pain (7.9%), superior vena cava syndrome (7.9%), fatigue (5.3%) and others (13.1%)]. For the 10 others indications were: immune-related adverse events (54.6%), COPD exacerbation (27.1%) and others (18.2%). Median (m) PFS and OS were 1.9 months (mo.) [95% CI, (1.77-2.40)] and 10 mo. [95% CI, (8.11-12.91)], respectively. Early introduction of steroids under ICI was associated with a shorter median (m) PFS (1.3 mo., P < 0.0001), and mOS (2.3 mo., P < 0.0001). Patients receiving steroids for cancer-related symptoms had significantly poorer outcomes with mPFS of 1.1 mo. [95% CI, 0.85-1.51] and mOS of 1.9 mo. [95% CI, (1.54-2.4)]. No differences were observed between the group of patients that started steroids for other indications [mPFS 2.7 mo. (1.21-NR); mOS 13.4 mo., (4.30-NR)] and the group without steroids [mPFS 2.6 mo. (2.20-3.94); mOS 13.8 mo. (11.4-18)]. Early steroids introduction for cancer-related symptoms was an independent prognostic factor for both poor PFS [HR 3.04; 95% CI, (1.38-6.66); P = 0.006] and OS [HR 1.21; 95%CI, (0.53-2.8); P < 0.0001]. ConclusionIntroduction of steroids within the first 8 weeks of ICI has no detrimental impact on prognosis if the indication is not related to cancer symptoms. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureL. Mezquita: Advisory / Consultancy: Roche Diagnostics; Speaker Bureau / Expert testimony: Bristol-Myers; Speaker Bureau / Expert testimony: Squibb; Speaker Bureau / Expert testimony: Tecnofarma; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Bristol-Myers; Travel / Accommodation / Expenses: Squibb; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Chugai; Research grant / Funding (institution), Mentorship Program: AstraZeneca. E. Auclin: Travel / Accommodation / Expenses: Mundipharma. C. Caramella: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Amgen. L. Hendriks: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Non-remunerated activity/ies, Mentorship Program: AstraZeneca; Non-remunerated activity/ies, Webinars: Quadia. R. Ferrara: Advisory / Consultancy: MSD; Travel / Accommodation / Expenses: Pfizer. P. Lavaud: Travel / Accommodation / Expenses: Astellas-Pharma; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Janssen Oncology; Travel / Accommodation / Expenses: Mundi Pharma. A. Gazzah: Research grant / Funding (institution), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Aduro Biotech; Research grant / Funding (institution): Agios Pharmaceuticals; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Argen-X Bvba; Research grant / Funding (institution): Arno Therapeutics; Research grant / Funding (institution): Astex Pharmaceuticals; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Aveo; Research grant / Funding (institution): Bayer Healthcare Ag; Research grant / Funding (institution): Bbb Technologies Bv; Research grant / Funding (institution): Beigene; Research grant / Funding (institution): Bioalliance Pharma; Research grant / Funding (institution): Biontech Ag; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Bristol Myers Squibb; Research grant / Funding (institution): Celgene Corporation; Research grant / Funding (institution): Chugai Pharmaceutical Co.; Research grant / Funding (institution): Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Iris Servie; Research grant / Funding (self): Janssen Cilag; Non-remunerated activity/ies, Drug Supplied: AstraZeneca, Bayer, Bristol-Myers Squibb, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. J. Adam: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Honoraria (self): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Takeda; Honoraria (self): Chugai. D. Planchard: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: prIME Oncology; Advisory / Consultancy: Peer CME; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Medimmun; Research grant / Funding (institution): Sanofi-Aventis; Research grant / Funding (institution): Taiho Pharma; Research grant / Funding (institution): Novocure. N. Chaput: Research grant / Funding (institution): Cytune Pharma, GSK, Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi. B. Besse: Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Biogen; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): IPSEN; Research grant / Funding (institution): Merck KGaA; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Onxeo; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Pharma Mar; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Spectrum Pharmaceuticals; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tiziana Pharma. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 21P Prognostic biomarkers in lung cancer patients treated with immunotherapy
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Ferreira S, Esteves S, Almodovar M.

    BackgroundImmunotherapy modified advanced lung cancer treatment. Unfortunately, not all patients respond to it and little is known about predictive markers of response. Recently, a lung immune prognostic index (LIPI) was developed to predict outcomes. Neutrophil-lymphocyte ratio (NLR) has also been shown as possible marker of response to immune checkpoint inhibitors. The aim of this study is to evaluate the prognostic value of both LIPI and NLR in patients with advanced lung cancer treated with anti-PD1 drugs, pembrolizumab and nivolumab. MethodsData from patients diagnosed with lung cancer (stage III-IV) treated with pembrolizumab and nivolumab, from a Portuguese tertiary cancer centre were reviewed retrospectively (July’15 to July’19). LIPI and NLR were calculated before the beginning of immune checkpoints inhibitors. NLR was calculated as the ratio between neutrophils and lymphocytes. NLR was categorized into low (≤ median NLR in our cohort) and high NLR (>median). LIPI score results from NLR and LDH level and has 3 different risk categories: low, intermediate and high. Univariate analysis and multivariable analysis (Cox model adjusted for age, EGFR status, PD-L1 expression and previous treatment) were done to evaluate the association between LIPI and NLR with time to progression (TTP) and overall survival (OS). ResultsIn our cohort, 120 patients were treated, according to PD-L1 expression, with pembrolizumab (83) and nivolumab (37). Median follow-up in living patients was 13 months, having occurred 60 deaths and 54 disease progression. In both univariate (p = 0.019) and multivariable (p = 0.001) analysis, LIPI score was an independent prognostic factor for OS but not for TTP. HR for intermediate vs low LIPI score was 3.1 (95%CI 1.1-8.8) and HR for high vs low LIPI score was 7.5 (95% CI = 2.5-22.8). Similarly, in univariate (p = 0.007) and multivariable (p = 0.006) analysis, NLR was an independent prognostic factor for OS but not for TTP. HR for high NLR was 2.9 (95% CI = 1.3-6.4). ConclusionIn our cohort of patients, both LIPI score and NLR are prognostic factors for overall survival in advanced lung cancer patients treated with pembrolizumab and nivolumab. Prospective studies are needed to validate the value of these biomarkers in immunotherapy. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 133P Tumour immune infiltrate characterization in luminal breast cancer in three distinct age categories and its correlation with frailty
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Berben L, Wildiers H, Kenis C, et al.

    BackgroundImmunosenescence, the age-related decrease in immune competence, is characterized by decreased adaptive immunity and increased low-grade inflammation. This may lead to altered anti-tumor immune responses and thus affect tumor immune infiltrate in older patients with cancer. However, detailed tumor infiltrate characterization in breast cancer (BC) has not yet been performed in the context of aging. MethodsThis exploratory study investigated age-related changes in the tumor microenvironment of patients with early BC (grade I-III, ER+, HER2-). Patients were subdivided into three age categories: 35-45 years (y) (N = 15), 55-65y (N = 19), ≥70y (N = 31). Stromal tumor infiltrating lymphocytes (sTILs) percentage was assessed following published guidelines. Immune infiltrate characterization was established by determining CD68 grade and scoring additional immune markers (CD3, CD4, CD5, CD8, CD20 and FOXP3) with a newly developed analysis pipeline using the QuPath software. In the oldest group, the geriatric 8 (G8) score was obtained as a correlate for clinical frailty level. ResultsWith increasing age, sTILs percentage significantly decreased, concomitant with significantly lower Tcells (CD3+ and CD5+), cytotoxic Tcells (CD8+) and Bcells (CD20+) densities in the whole tumor area. When assessing tumor regions separately, significant age-related decreases in immune cell density in invasive front (CD3+, CD5+, CD8+, CD20+ cells) and tumor center (CD3+, CD5+, CD8+ cells) were observed. No age-related changes were seen for CD4+ and FOXP3+ cell infiltration nor for CD68 grade in the tumor. G8 score showed a significant inverse correlation with regulatory Tcells (FOXP3+) density in tumor center. However, spatial distribution of the immune cell populations did not depend on age nor frailty level. ConclusionIn conclusion, sTILs percentage and density of several immune markers in the tumor significantly differed between young and older patients with BC. Moreover, density of regulatory T-cells was higher in frailer patients (lower G8 score). This may indicate that tumor immune responses in these patients may be less effective, and approaches for immunotherapy may vary depending on patients’ age/frailty level. Legal entity responsible for the studyHans Wildiers. FundingFWO. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 37P Chemokine receptor CCR2b expressing anti-Tn-MUC1 CAR-T cells enhanced anti-breast cancer activity
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Lin Y, Yin H, An H, et al.

    BackgroundEnhanced anti-tumour activity is required for eradication of solid tumours by CART cells. One possibility of enhancing anti-tumour activity is by programming CART cells to express chemokine receptors that match chemokines produced either by the tumours or tumour-associated cells, thereby improving the infiltrating capacity of the CART cells. In this study, we engineered CCR2b expressing anti-Tn-MUC1 CAR T cells for the treatment of breast cancer. MethodsAnti-Tn-MUC1-CARs were constructed using the SM3 scFv. Following lenti-MUC1 CAR retroviral transduction, efficiency of transgenic expression was assessed by flow cytometry. CCR2b expressing anti-Tn-MUC1 CAR T cells were prepared using PLV-CAR-5E5-CCR2b lentivirus. The susceptibility of MCF-7 cells to either anti-MUC1 CART or CCR2b expressing anti-MUC1 CART cell-mediated lysis was assessed using in vitro killing assays. For cytolytic analysis, CART-cells were cocultured 10:1 (effector:target) ratio with MCF-7 cells. The effects of CCR2b expressing CART cells on anti-tumour activity and infiltration were also assessed in an in vivo murine xenograft model. ResultsActivated T cells co-modified with both CCR2b and anti-MUC1-CAR had greater anti-tumour activity both in vivo and in vitro. When the effector / target cell ratio was 10, the killing rates of CART and CART-CCR2b were 56.9% and 83.9%, respectively. Tumour size was significantly smaller (P < 0.001) in the CAR-CCR2b group compared to the CAR alone group. At day 7 post-injection of CART cells, the infiltrated T cells was significantly increased (∼2 folds) in the CAR-CCR2b group compared with the CART only group. ConclusionOur data demonstrated that the anti-tumour activity of the CCR2b expressing anti-Tn-MUC1 CART cells is 1.5 times more potent than CART cells without CCR2b. Augmentation of tumour suppression was also demonstrated in vivo in a murine xenograft model. These pre-clinical results show translational potential to the clinic for treatment of solid breast tumours. Legal entity responsible for the studyGuangzhou Anjie Biomedical Technology Co. Ltd. FundingGuangzhou Anjie Biomedical Technology Co. Ltd. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 6P Prognostic significance of tumour-infiltrating lymphocytes on survival outcomes of patients with resected pancreatic ductal adenocarcinoma: A systematic review and meta-analysis
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Tan H, Catedral L, San Juan M.

    BackgroundPancreatic cancer remains a leading cause of cancer-related mortality worldwide. Tumor-infiltrating lymphocytes (TILs) play an important role in mediating tumor progression and treatment resistance in pancreatic cancer. However, the prognostic value of TILs in pancreatic cancer remains uncertain. This meta-analysis evaluated the prognostic significance of TIL subsets (CD3+, CD4+, CD8+, FoxP3+ T cells) on overall survival (OS) and disease-free survival (DFS) of patients with resected pancreatic ductal adenocarcinoma. MethodsPertinent studies were gathered through systematic search of PubMed, Google Scholar and Cochrane Library databases up to August 1, 2019. Using Review Manager version 5.3, pooled hazard ratios and 95% confidence intervals were calculated using random or fixed effects models, depending on the heterogeneity of studies. ResultsA total of 11 studies comprising 1760 patients were included. Pooled analysis revealed that high levels of CD8+ TILs were associated with improved OS (HR = 0.59, 95% CI = 0.51-0.69, p < 0.00001) and DFS (HR = 0.60, 95% CI = 0.50-0.73, p < 0.00001). Similarly, high levels of CD3+ TILs correlated with better OS (HR = 0.64, 95% CI = 0.54-0.75, p < 0.00001) and DFS (HR = 0.53, 95% CI = 0.31-0.92, p < 0.0001). In contrast, high FoxP3+ TILs associated with worse OS (HR = 1.37, 95% CI = 1.00-1.87, p = 0.05), with no significant difference in DFS (HR = 1.21, 95% CI = 0.88-1.67, p = 0.23). While high CD4+ TILs showed significant improvement in OS (HR = 0.74, 95% CI = 0.63-0.86, p = 0.0001), there was no significant disparity in DFS (HR = 0.79, 95% CI = 0.47-1.35, p = 0.39). ConclusionTILs are a promising prognostic biomarker in pancreatic cancer. High levels of CD8+ TILs correlated with favorable OS and DFS, while high levels of FoxP3+ TILs associated with poor OS. Nonetheless, results of this meta-analysis should be approached with caution due to the lack of established standards in assessment of TILs and the small number of available studies. Prospective studies that assess TILs in a more comprehensive and standardized manner are needed. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 99P A platform for extracellular interactome discovery identifies novel functional binding partners for the immune receptors B7-H3/CD276 and PVR/CD155
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Husain B, Martinez-Martin N.

    BackgroundAnti-tumor immunity is critically regulated by immune checkpoints such as TIM-3, PD-1 or TIGIT. Notwithstanding the remarkable success of the antibody-mediated immune checkpoint blockade in the clinics, many key immune receptors remain orphan or poorly characterized, hindering the development of novel therapeutics. This is partially due to technical challenges associated with the study of membrane-expressed proteins and identification of receptor binding partners. Here, we present a new technology for receptor-ligand discovery, which we apply to investigate interactions established by key inhibitory immune receptors. MethodsA new platform was developed for high sensitivity receptor-ligand discovery in high throughput, the Conditioned Media Alpha Screen. Using this method, prominent immune receptors were screened for binding to a library consisting of ≈1,200 single transmembrane proteins in the human genome. The new interactions were confirmed using biophysical and cell-based methods for functional characterization of select receptor-ligand pairs. ResultsUsing this technology Interleukin-20 receptor subunit alpha (IL20RA) was identified as the first counter-receptor for B7-H3. Furthermore, the natural killer cell receptor KIR2DL5A is identified as a new binding partner for PVR, an interaction that is fully validated using orthogonal methods and cellular assays. Here we show that KIR2DL5A engagement by PVR expressed on tumor cells results in reduced natural killer cell cytotoxicity. PVR deletion or treatment with an anti-KIR2DL5A antibody restored NK-mediated cytolysis of tumor cells. Additionally, competition assays show that PVR interacts with both TIGIT and KIR2DL5A on the cell surface, suggesting a previously unrecognized mechanism of action. ConclusionHere we developed a new platform for elucidation of secreted or membrane protein interactomes. The power of this technology is demonstrated by identification of new interactors for emerging therapeutic targets such as PVR or B7-H3. These results provide insights into immune receptor biology and highlight potential new cellular targets, ultimately serving as a unique tool to inform therapeutic development. Legal entity responsible for the studyThe authors. FundingGenentech Inc. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 74P Cost of adverse events (AEs) with second-line (2L) immuno-oncology agents (IO) and chemotherapy (CHEMO) in advanced non-small cell lung cancer (aNSCLC) in the real-world
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Wang C, Gupte-Singh K, Belli A, et al.

    BackgroundRandomized clinical trials in aNSCLC demonstrated that 2L IO prolonged overall survival and lowered AE rates compared with 2L CHEMO. However, real-world (RW) evidence from clinical practice is limited, and the potential cost benefits of lower AE rates have not been examined. Here, we report average costs per patient (pt) associated with grade 3-4 AEs during 2L treatment with IO and CHEMO in aNSCLC from a US payer perspective. MethodsAEs in pts treated with 2L IO or CHEMO for aNSCLC (Mar 2015-Dec 2017) were abstracted from US electronic health records in COTA’s database. Hospitalization costs for each ICD-10 code associated with the management of a grade 3-4 AE during treatment were estimated using the Healthcare Cost and Utilization Project (HCUP) National Inpatient Sample 2017 dataset. ResultsOf 596 pts in the analysis, 276 received IO (199 nivolumab) and 320 received CHEMO. The proportion of IO- vs CHEMO-treated pts was higher for pts aged <75 years (79% vs 71%), men (54% vs 47%), and current/former smokers (92% vs 83%); proportions in the IO and CHEMO groups were similar for non-squamous histology (84% vs 83%) and history of brain metastases (37% vs 37%). Overall, 40 (14.5%) IO-treated pts and 68 (21.3%) CHEMO-treated pts had grade 3-4 AEs, resulting in average costs per pt of $9,421 and $15,677, respectively. The main cost and event drivers in both treatment groups were alanine aminotransferase elevation (IO: 36% of total costs [32% of grade 3-4 AEs], CHEMO: 25% [21%]) and leukocytosis, indicative of infection (IO: 22% [28%], CHEMO: 33% [41%]). Table shows average cost per pt in selected subgroups. Table: 74P Average cost of grade 3-4 AEs per patient (Pt)IO (n = 276)CHEMO (n = 320)nAverage Cost per PtnAverage Cost per Pt<65 y107$6,877114$17,203≥65 y169$11,033206$14,832Male150$4,417150$10,460Female126$15,379170$20,279White176$9,265233$17,547Former/current smoker255$7,973265$17,292History of brain metastasis101$9,760117$20,219No history of brain metastasis175$9,226203$13,059Squamous43$3,09653$18,749Nonsquamous233$10,634267$15,181 ConclusionIn this RW analysis in pts with aNSCLC, 2L IO was associated with lower costs for the management of grade 3-4 AEs than 2L CHEMO. Editorial acknowledgementWriting assistance was provided by Roland Tacke, PhD, of Evidence Scientific Solutions Inc, funded by Bristol-Myers Squibb. Legal entity responsible for the studyBristol-Myers Squibb. FundingBristol-Myers Squibb. DisclosureC.K. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. K. Gupte-Singh: Full / Part-time employment: Bristol-Myers Squibb. A.J. Belli: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. D.C. Lane: Shareholder / Stockholder / Stock options, Was an employee at Bristol-Myers Squibb while this work was done and recently joined COTA: Bristol-Myers Squibb. A. Lakshmanan: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA. A.D. Norden: Shareholder / Stockholder / Stock options, Full / Part-time employment: COTA.

    更新日期:2019-12-17
  • 117P Immune checkpoint inhibitors (ICI) in combination with chemotherapy as first-line (1L) treatment for non-small cell lung cancer (NSCLC): A pair-wise meta-analysis (MA)
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Afonso-Afonso F, Gancedo M, Manrique M, et al.

    BackgroundICI has revolutionized the treatment of lung cancer, with new approaches in 1L NSCLC. The aim of this study is to compare the efficacy of treatments that combine chemotherapy (CH) plus a PD1/L1 inhibitor in clinical trials (CT) and the benefits in the different subgroups of patients. MethodsWe performed a searching in Pubmed to identify CT. Key words were: NSCLC, PD1/L1 and CH. All phase III trials that combined CH with an antiPD1/L1 were selected. The results were combined in MA with the corresponding forest plots and presented as Hazard Ratios (HR) and Odds Ratio (OR), with 95% CI. DerSimonian-Laird random effects models for main and subgroup analyses has been implemented. ResultsA total of 86 publications were reviewed, 6 of them met the inclusion criteria with 3,807 patients. 6 pair wise MA was performed. Control arm in all studies was platinum doublet CH. Bevacizumab was added in 1 trial in the control and experimental arm. 4 studies tested an antiPD-1, and 2 antiPD-L1. 2 studies included EGFR/ALK mutated patients (EGFR/ALK+). PFS final data was reported in all the studies and overall survival (OS) in 4. The addition of PD-1/L1 inhibitors was associated with significantly prolonged progression-free survival (PFS) (HR: 0.59, 95% CI: 0.55-0.64, p < 0.001) and OS (HR: 0.75, 95CI: 0.64-0.87; p < 0.001). Women, ≤65 years old, PS 0, never smokers, liver metastasis (mx) and PD-L1 ≥50% were the subgroups with better benefit (table). Just one trial showed PFS and OS improvement in EGFR/ALK+. Numerically better ORR was obtained in the IMpower150 (56.4%) trial for non-squamous (sq) NSCLC and KEYNOTE407 for sq NSCLC (57.9%). ConclusionThe association of immunotherapy plus CH is a better treatment option for all patients in 1L NSCLC. Standard subgroups are the most benefited, except liver mx patients and EGFR/ALK+ especially benefited for the combination of an antiPD-L1 and an antiVEGF. Table:117P OS by subgroupsHR (CI 95%)Women0.51 [0.32-0.84]Men0.75 [0.64-0.87]<650.62 [0.46-0.84]≥650.74 [0.63-0.87]PS 00.65 [0.49-0.88]PS 10.72 [0.60-0.87]Never smoker0.47 [0.26-0.85]Smoker0.71 [0.56-0.91]No liver mx0.61 [0.55-0.67]Liver mx0.69 [0.46-1.0]PD-L1 H0.66 [0.52-0.82] Legal entity responsible for the studyThe authors. FundingRoche Farma S.A. DisclosureF.J. Afonso-Afonso: Advisory / Consultancy: Roche; Advisory / Consultancy: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Janssen; Advisory / Consultancy, Travel / Accommodation / Expenses: IPSEN; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy: Takeda; Advisory / Consultancy: Sanofi. M. Amenedo Gancedo: Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: PharmaMar; Speaker Bureau / Expert testimony: Roche. M.C. Areses Manrique: Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Boehringer. B. Campos Balea: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer. N. Fernández-Núñez: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehinrger; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Sanofi. J.L. Firvida Perez: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. J. García González: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer. M. Lázaro Quintela: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Pfizer; Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: GSK; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer; Advisory / Consultancy, Travel / Accommodation / Expenses: Takeda; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Tesaro. L. León-Mateos: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer. J. Ruíz-Bañobre: Advisory / Consultancy: Boehringer; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: IPSEN; Travel / Accommodation / Expenses: PharmaMar; Speaker Bureau / Expert testimony: Roche. D. Pérez Parente: Full / Part-time employment: Roche. L. Crama: Full / Part-time employment: Roche. P. Ruiz Gracia: Full / Part-time employment: Roche. L. Santomé Couto: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Bristol-Myers Squibb; Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy: Boehringer. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 56P Predictive factors of intensive care outcomes of patients admitted with immune-related adverse events
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Paiva R, Cojocaru E, Grover V.

    BackgroundThere are fewer adverse events with immune checkpoint inhibitors (ICPI) than with chemotherapy, however, some patients receiving ICPI may require intensive care treatment in case of severe immune-related adverse events (IRAE’s), which should be immediately recognized to permit an appropriate treatment. We present data of patients admitted to The Royal Marsden Cancer Critical Care Unit (CCU) with IRAE’s. Our objective was also to determine if baseline inflammatory biomarkers (IB), such as LDH, neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR) and systemic inflammatory response index (SIRI) at admission could correlate with patient outcomes. Methods17 patients were identified between January 2012 and July 2019. Survival analysis was performed using Kaplan-Meier curves and Cox regression, using SPSS v24. All ratios were calculated with absolute counts of neutrophils, lymphocytes and monocytes. Best cut-off ratios were obtained using ROC curves. ResultsMost patients (88.2%; n = 15) had the diagnosis of metastatic melanoma. 6 patients were treated with ipilimumab, 3 with nivolumab, 7 with the combination of both and 1 patient with pembrolizumab. Median length of stay in the CCU was 4 days. The most common reason for admission was colitis in 47.1% (n = 8) of patients. Median overall survival (OS) from date of admission was 8.7 months. Outcome from CCU (stable discharge or long-term rehab) correlates with survival (R2=0.61). In the group of patients with LDH ≥ 189, OS was 1.4 months and in the group with LDH<189, OS was not yet reached (HR 0.28; p = 0.05). In the group with NLR ≥ 6.8, OS was 1.5 months and in the group of NLR<6.8, the median OS was 27.6 months (HR 0.34; p = 0.11). ConclusionIt is likely that the number of critical care admissions may increase with more patients receiving ICPI. These events can be responsible for great morbidity which might be associated with increased mortality. IB such as high LDH, high NLR and high SIRI might correlate to poor outcome and worse survival and could be used to develop awareness of these events and a more effective approach. However, some of these results were not statistically significant and further studies are needed with a larger data to validate them. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 22P Early changes in plasma cell-free DNA (cfDNA) as a predictive biomarker of immune checkpoint inhibitors (ICIs) efficacy
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Garcia I, Moreno A, Arenillas C, et al.

    BackgroundThe role of cfDNA-based analyses in the management of patients (pts) receiving ICIs is still poorly understood. We have implemented a translational program to systematically obtain blood samples of pts receiving ICIs in phase I clinical trials for cfDNA monitoring. MethodsSince August 2018, 92 pts were prospectively included and baseline blood samples and prior to every cycle were collected. Plasma cfDNA was isolated using QIAamp Circulating Nucleic Acid Kit and measured using Qubit fluorometer. DNA fragments length and profile were assessed using Agilent 2100 Bioanalyzer. Pts with baseline and prior to cycle 2(preC2) blood samples and at least 1 tumor assessment have been included in the analysis. We established 2 groups based on variations of cfDNA levels on preC2 related to baseline: 1) cfDNA progression group as increase (>0% cfDNA change) 2) cfDNA response group as decrease (<0% cfDNA change). We analysed the correlation between longitudinal changes in cfDNA with progression free survival (PFS) and clinical benefit (partial response or stable disease as best response). PFS was calculated using Kaplan-Meier method, long rank test was used for statistical comparison and chi-square for categorical variables. Results92 pts with different advanced tumor types were included. Median number of previous lines was 2.38. Median time from baseline cfDNA to preC2 was 22.82 days and from preC2 to first tumor assessment was 32.18 days. PFS in the cfDNA response group (38 pts) was higher compared with cfDNA progression group (54 pts); median 4.87 m (3.11 – 6.62) and 3.0 m (2.24-3.76), respectively (HR = 0.49 [0.28-0.86] p < 0.001). Clinical benefit was higher in the cfDNA response group (66%) as compared to cfDNA progression group (44%), chi‐square p < 0.04 No difference was observed in median baseline cfDNA levels between pts with PD as best response (28.12 ng/ml) and pts with clinical benefit (19.76 ng/ml) p = 0.28. ConclusionThe monitoring of early changes of cfDNA levels is a fast approach to predict response to ICI therapy in our cohort. Further validation of these results and correlation with circulating tumor DNA is ongoing. Legal entity responsible for the studyThe authors. FundingThis research has been partially funded by the Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI), supported by the Banco Bilbao Vizcaya Argentaria Foundation (BBVA Foundation) - Grant 9/2017. DisclosureC. Hierro Carbo: Research grant / Funding (self): Bayer; Honoraria (self): Ignyta; Honoraria (self), Travel / Accommodation / Expenses: Lilly; Honoraria (self), Travel / Accommodation / Expenses: Roche. J. Martin-Liberal: Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Ipsen; Travel / Accommodation / Expenses: Pierre Fabre; Honoraria (self): Bristol-Myers Squibb; Travel / Accommodation / Expenses: Astellas. I. Braña: Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Regeneron; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Incyte; Speaker Bureau / Expert testimony, Research grant / Funding (self): Orion Pharma; Research grant / Funding (institution): Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Janssen; Research grant / Funding (self): Kura; Research grant / Funding (institution): Pfizer. M. Vieito Villar: Travel / Accommodation / Expenses: Roche. E. Elez: Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Sanofi; Speaker Bureau / Expert testimony, Research grant / Funding (self): Merck Serono; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Speaker Bureau / Expert testimony: Servier. E. Felip: Speaker Bureau / Expert testimony: ABBVIE; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Blueprint; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy: Guardant; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: Janssen. R. Dienstmann: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Research grant / Funding (self): Merck Serono; Advisory / Consultancy: Symphogen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Sanofi; Advisory / Consultancy: IPSEN; Advisory / Consultancy: Astellas. A. Gros: Research grant / Funding (institution): Novartis. J. Tabernero: Advisory / Consultancy: Array; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Advisory / Consultancy: Beigene; Advisory / Consultancy: Boehringer; Advisory / Consultancy: Chugai; Advisory / Consultancy: Genetech; Advisory / Consultancy: Genmab; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Roche; Advisory / Consultancy: Inflection Bioscience; Advisory / Consultancy: IPSEN; Advisory / Consultancy: Kura; Advisory / Consultancy: Lilly; Advisory / Consultancy: Menarini; Advisory / Consultancy: MSD; Advisory / Consultancy: Merck; Advisory / Consultancy: Merrimarck; Advisory / Consultancy: Merus; Advisory / Consultancy: Molecular Partners. E. Garralda: Advisory / Consultancy: ROCHE; Advisory / Consultancy: Ellipses; Advisory / Consultancy: Neomed; Advisory / Consultancy: Janssen; Advisory / Consultancy: Boehringer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): MSD; Advisory / Consultancy: Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 164P Combined detection of CD137 and type 1 functions improves identification and characterization of the activated T lymphocyte repertoire
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Draghi A, Gokuldass A, Chamberlain C, et al.

    BackgroundCD137 (4-1BB) is widely considered a comprehensive marker of T cell activation, and it is largely used in cancer immunology to determine the proportion of tumor-reactive T cells. However, CD137 detection does not provide specific information regarding the functions of activated T cells. Hence, in this study we tried to determine whether the simultaneous detection of CD137 plus common antitumor immune functions (type 1 functions such as production of cytokines TNFα and IFN-γ, or upregulation of CD107a) was feasible and provided advantages over using both methods separately. MethodsThe influence of common protein transport inhibitors used to allow cytokine detection, such as Brefeldin A (BFA) or Monensin (MN), on surface and intracellular expression of CD137 was tested in vitro. Activation of tumor infiltrating lymphocytes (TILs) was achieved with unspecific stimuli (PMA and Ionomycin) or naturally presented tumor-antigens (autologous tumor cells). TIL activation was defined as the proportion of CD4+ or CD8+ TILs staining for either CD137 (CD137+ TILs) and/or at least one of TNFα, IFNγ and CD107a (Type 1 function+ TILs) via flow cytometry. ResultsOur results showed that MN had minimal impact on the ability to detect surface CD137, whereas BFA had a much larger effect regardless of the stimulus employed. Nonetheless, robust results could be obtained when type 1 functions detection was combined with intracellular staining of CD137 in the presence of both BFA and MN. Using this method, we identified three tumor-antigen specific T cell subpopulations, characterized by combined expression of CD137 and type 1 functions or CD137 without type 1 functions and vice-versa. The combined method allowed the identification of a much larger proportion of tumor-reactive T cells, over either of the two methods used alone. Indeed, CD137 alone identified 46% of the total tumor-reactive CD8+ TILs, while 86% of the total tumor-reactive CD8+ TILs were positive for type 1 functions. ConclusionCombined detection of CD137 and common type 1 functions represents a more comprehensive method to identify and characterize the total repertoire of tumor-antigen specific, activated T lymphocytes, regardless of the antigen recognized. Legal entity responsible for the studyHerlev and Gentofte Hospital. FundingResearch grant A11806 and A12535, The Danish Cancer Society; Research grant R233-2016-3728 and R286-2018-991 Lundbeck Foundation; Clinician-Scientist Grant from the Herlev and Gentofte Hospital Research Council. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 134P Comprehensive assessment of anti-tumour PDL1 blockade effect in a sarcoma mouse model
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Nafia I, Chaibi A, Bortolotto D, et al.

    BackgroundDevelopment of novel immunotherapeutics in oncology is of crucial interest and their good testing at preclinical stage relies on i) the features of the animal model used and ii) the application of an appropriate comprehensive strategy for the deep delineation of mechanisms underlying resistance/sensitivity to a drug. MethodsUsing a syngeneic sarcoma mouse model, treated with anti-PDL1, we investigated by intratumoral microdialysis and flow cytometry the immunometabolic profile and immune landscape of the tumour, respectively. The anti-tumor effect of PDL1 blockade was assessed through tumour growth monitoring and tumoral biopsies were also collected for gene expression analysis. Finally, involvement of CD8 T cells in the anti-tumour PDL1 blockade-mediated activity was addressed using a specific depleting antibody -based strategy. ResultsWhen compared to a non-tumour area, data obtained from tumour microdialysates highlighted i) a slight Kynurenine pathway activation, ii) a strong Arginase activity, and iii) a high Adenosine production. Interestingly, anti-PDL1 effect was associated with a decrease of the tumoral Adenosine level thus arguing for an important role of the Adenosine axis in the control of the anti-tumour immune response. In addition, PDL1 blockade led to an intratumoral CD45+ leukocytes enrichment, with a higher abundance of lymphocytes also displaying increased level of IFNgamma. In contrast, macrophages – CD11b+/F4:80+ - were limited upon treatment, especially the immunosuppressive CD11b/Gr1Low/Int cellsubsets, in favor of an increase of the M1/M2 macrophages ratio. Interestingly, CD8 depletion fully abrogated anti-PDL1 anti-tumour effect thus showing the unequivocal role of this population. Finally, gene expression analysis revealed, in addition to an interferon signature, changes in genes from the myeloid / neutrophil subsets including Arg1 and key chemokines. ConclusionAltogether, this multiparametric dataset gives i) a better understanding of intrinsic features of the preclinical model and deeper insights into the mechanism of action of an effective drug, and ii) might serve as a platform combination-based strategy for comprehensive explorations of novel candidates. Legal entity responsible for the studyAlban Bessede. FundingExplicyte Immuno-Oncology. DisclosureA. Bessede: Shareholder / Stockholder / Stock options, Full / Part-time employment: Explicyte. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 7P Multispectral immunofluorescence and computational imaging analysis define the prognostic role of T-cell infiltrates in gastric cancer
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Challoner B, von Loga K, Woolston A, et al.

    BackgroundGastric cancer (GC) is the 3rd commonest cause of cancer mortality. T cells infiltrates are prognostic in other cancer types (Pagès 2018) but most studies in GC have used manual counting, lacked a validation cohort and were performed in Asian patients with often better outcomes than Western patients. The prognostic role of T cells hence remains poorly established in Western GCs. MethodsTissue microarrays from 474 therapy naïve GCs resected in Leeds, UK, were split into discovery and validation cohorts and stained using multispectral immunofluorescence for CD8 (cytotoxic-), CD45RO (memory-), FOXP3 (regulatory-T cells), cytokeratin and DAPI. T cell densities were measured by computational image analysis. GCs were assigned to 5 equal sized density classes (C1 low to C5 high) for each marker and cancer specific survival (CSS) was assessed. ResultsCD45RO (p = 0.000) and FOXP3 (p = 0.001) densities were significantly associated with CSS in the discovery cohort (n = 327). For both markers, C1 (low) and C5 (high) were associated with the shortest and longest CSS, respectively, C2 to C4 all showed similar CSS and were consolidated into an intermediate group. Reanalysis using low, intermediate and high groups showed significant associations of CD45RO (p = 0.024) and FOXP3 (p = 0.003) densities with CSS in the validation cohort (n = 147). TNM stage, CD45RO and FOXP3 densities were independent predictors of CSS in multivariate analysis of both cohorts. EBV positive (EBV+) and MMR deficient (dMMR) GCs are considered highly immunogenic GC subtypes. 20/475 GCs were EBV+ and 70% of these showed high CD45RO or FOXP3 densities. 51/488 were dMMR but only 38% were CD45RO or FOXP3 high, perhaps indicating the frequent acquisition of immune evasion mechanisms by dMMR GCs (von Loga 2019). ConclusionThis study identified and validated CD45RO and FOXP3 T cell infiltrates as independent prognostic markers in Western GC patients. This may enable personalized follow up or (neo)adjuvant treatment strategies. Whether high infiltrates are predictive of immunotherapy benefit should be assessed. Unexpectedly, high FOXP3 densities were associated with longer CSS, warranting studies into the role regulatory T cells in GC. Legal entity responsible for the studyMarco Gerlinger. FundingNational Institute for Health Research and Biomedical Research Council - Royal Marsden Hospital, Cancer Research UK, Schottlander Foundation. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 149P Revamping the ovarian tumour microenvironment with an oncolytic adenovirus yields enhanced tumour-infiltrating lymphocyte anti-tumour activity
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Santos J, Heiniö C, Cervera-Carrascon V, et al.

    BackgroundThe ovarian tumour microenvironment is an abundant source of tumour-infiltrating lymphocytes (TILs) which can be readily harnessed for infusion in the context of adoptive TIL therapy. This strategy has been proven feasible, but it appears clinically ineffective in ovarian cancer patients due to the absence of tumour-reactive TILs and the presence of immunosuppression. Hence, we hypothesized that an oncolytic adenovirus expressing Tumour Necrosis Factor (TNF)-alpha(a) and Interleukin (IL)-2 (Ad5/3-E2F-D24-hIL-2-IRES-TNFa; TILT-123) could overcome this by generating a proinflammatory microenvironment and reinvigorating TIL anti-tumour activity. MethodsFresh explants from metastatic or primary tumour sites were obtained from stage III-IV ovarian cancer patients and short-term cultures were established in the absence or presence of oncolytic adenovirus. The remainder of the tumour explant was used to generate clinically relevant TILs which were co-cultured with autologous T cell-depleted single cell suspensions pre-treated with or without oncolytic adenoviruses. Cytokine content changes and TIL reactivity was assessed during culture by flow cytometry or interferon (IFN) gamma(g) enzyme-linked immune sorbent assay. ResultsTreatment of short-term cultures with oncolytic adenovirus coding for TNFa and IL-2 introduced profound changes within the microenvironment, which were characterized by an increase in proinflammatory cytokines and decrease in suppressive cytokines. Further benefits were seen in T-cell depleted ovarian cancer single-cell suspensions infected with cytokine-coding oncolytic adenovirus, which enabled significant production of IFNg by autologous TILs. Such levels were not seen in co-cultures where no virus or the backbone oncolytic adenovirus (no cytokine transgenes) was added. ConclusionThese data illustrate the potential of oncolytic adenovirus coding for TNFa and IL-2 to rewire the ovarian tumour microenvironment for effective TIL anti-tumour reactivity. This approach may improve the efficacy of adoptive TIL therapy in ovarian cancer patients, thus warranting further clinical investigation. Legal entity responsible for the studyTILT Biotherapeutics Ltd. FundingTILT Biotherapeutics Ltd. DisclosureJ.M. Santos: Full / Part-time employment: TILT Biotherapeutics Ltd. V. Cervera-Carrascon: Full / Part-time employment: TILT Biotherapeutics Ltd. M. Siurala: Full / Part-time employment: TILT Biotherapeutics Ltd. T. de Gruijl: Advisory / Consultancy: TILT Biotherapeutics Ltd. A. Hemminki: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: TILT Biotherapeutics Ltd. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 118P The role of asunercept as a selective CD95L inhibitor in cutaneous melanoma: Rationale and results from an enhanced TiRP model
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Krendyukov A, Kneisel N, Zhu J, et al.

    BackgroundCD95/CD95L signalling plays an important role in cancer cells resistant to CD95-mediated apoptosis and CD95L inhibition can overcome this mechanism. Several mechanisms related to apoptosis induction or dysfunction of effector T-cells via CD95L in the tumour microenvironment (TME) have also been investigated, with supporting evidence from preclinical melanoma models. MethodsAn autochthonous mouse model of melanoma (TiRP), genetically engineered to express P1A (defined MAGE-type antigen) mimics the T-cell suppressive effects of the TME through CD95L, which normal transplantation models cannot replicate. An advanced version of this murine melanoma TiRP model has been recently developed. This model can generate synchronized tumours in multiple mice in which treatments can be compared simultaneously while maintaining the advantages of the previous model regarding the role of CD95L in the TME interaction. This enhanced TiRP model was used to verify the effect of CD95L inhibition on apoptosis of tumour specific TILs using asunercept. ResultsIn this novel synchronized in vivo melanoma model, asunercept decreased intra-tumour apoptosis among tumour-specific T cells by 67% vs controls (9% vs 28%, p = 0.04). This validates the immune-suppressive interaction between the TME and infiltrating tumour-specific T cells in this model. Furthermore, cross-species specific asunercept prevents T cell apoptosis triggered by the tumour microenvironment, highlighting a rationale for potential application of CD95L inhibition in immuno-oncology for other solid tumours. ConclusionSelective CD95L inhibition by asunercept might have potential clinical implications in different tumours beyond recurrent glioblastoma, including cutaneous melanoma. To date, asunercept has demonstrated clinical efficacy and safety in patients with recurrent glioblastoma and myelodysplastic syndromesand may warrant further investigation in clinical trials. Legal entity responsible for the studyThe authors. FundingApogenix AG. DisclosureA. Krendyukov: Full / Part-time employment: Apogenix AG. N. Kneisel: Full / Part-time employment: Apogenix AG. J. Zhu: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research. C. Merz: Full / Part-time employment: Apogenix AG. D. Richards: Full / Part-time employment: Apogenix AG. C. Gieffers: Full / Part-time employment: Apogenix AG. B. van den Eynde: Research grant / Funding (self), Full / Part-time employment: Ludwig Institute for Cancer Research; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: iTeos Therapeutics.

    更新日期:2019-12-17
  • 57P Immune-related adverse events: The experience of a community hospital
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    de Almeida S, Honório M, Guerra N, et al.

    BackgroundTreatment with immune checkpoint inhibitors (ICPi) has revolutionized cancer treatment over the past few years. Despite the clinical benefits, there is a wide range of toxicities related to the mechanism of action of such group of therapies. Almost every system of organs may be affected. Although rare, fulminant and even fatal toxicities may occur and so, high level of suspicion is the key element to detect and treat them. The purpose of this analysis was to present real world data of programmed death-1 receptor (PD-1) and its ligand (PD-L1) blockade immune-related toxicities in a population of patients treated in a Community Hospital. MethodsA descriptive retrospective analysis of 65 consecutive patients with advanced non-small cell lung cancer (NSCLC), thymoma, head and neck cancer, urothelial and clear cell kidney cancer treated between February 2016 and December 2018 with anti-PD-1/PD-L1 checkpoint inhibitors, was performed. The variables analyzed were the prevalence of toxicities, evaluated according to the system of organs affected and the drug used, their severity according to the Common Terminology Criteria for Adverse Events (CTCAE) classification (v 5.0) and timing of onset. Analyses were performed with use of SPSS v.18 software. ResultsOn our population, 94% received treatment with anti-PD-1 checkpoint inhibitor and 89% had NSCLC. Treatment-related adverse events (AE) were observed in 40% of the patients, for any AE. Grade 3-4 toxicities were reported in 6,2% of the patients. Rheumatologic and cutaneous AE were the most frequent ones. They were all reported amongst patients treated with anti-PD-1 checkpoint inhibitors. The reported treatment-related AEs for the nivolumab and pembrolizumab-treated groups were 42,9% and 30,4% (any AE) and grade 3-4 AEs were 7,1% and 4,3%, respectively. No deaths related to toxicity were documented. Rheumatologic and cutaneous AEs were the earliest ones to appear, median time of onset 4 and 6 weeks respectively. Pneumonitis was the latest toxicity, with a median time to appearance of 45 weeks. ConclusionThe data we present here represents an heterogeneous population in real world settings and it similar to the literature. Implementing careful follow-up for immune related events contributes to promptly diagnose and treat. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 100P Combination of intratumoural double-stranded RNA (dsRNA) BO-112 with systemic anti-PD-1 in patients with anti-PD-1 refractory cancer
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Marquez-Rodas I, Longo F, Aix S, et al.

    BackgroundBO-112 is a dsRNA (poly I:C) formulated with polyethylenimine, that upon Intratumoral (IT) injection acts by activating TLR3, RIG-1 and MDA-5. This induces immunogenic cell death and potentiate systemic therapy with checkpoint inhibitors in animal models. In patients (pts), single-agent BO-112 IT increases necrosis, apoptosis and expression of pro-immune genes in solid cancers, with a manageable safety. 1 mg was the dose combined with anti-PD-1 in the current clinical trial (NCT02828098). MethodsBO-112 was combined with anti PD-1 in 28 pts with solid tumors primarily resistant to anti PD-1 (nivolumab or pembrolizumab). A lesion >1 cm amenable to IT injection was required. 28 pts were treated with 1 mg IT BO-112 qw x 2 or 3 doses before continuing the previous anti PD-1 combined with BO-112, until progression, limiting toxicity or up to 1y. Pre & post BO-112 biopsies from injected lesion were analysed. Response was first assessed by RECIST 1.1 at week 8-12. ResultsBO-112 related AEs and biological effects at interim analysis are summarized in the table. The combination was well tolerated. No deaths were associated with BO-112. Of 18 evaluable pts for response, at first assessment: 2 have achieved an objective partial response (PR) (1 melanoma and 1 renal carcinoma), with 1 of them continuing treatment; 11 patients had stable disease (SD); 5 patients progressed (PD). Additionally 6 patients progressed prior to the first evaluation, 3 died before efficacy assessments and 1 received palliative radiotherapy and was considered not evaluable. Table: 100PAll G3-5 TEAEs (%)G3-4 BO-112 related TEAEs (%)Necrosis (D > 5%) (%)*CD8+ T cell infiltrate (D > 5%) (%)* *evaluableAll N = 2818 (64)1 (4)10 (50)7 (35)Melanoma N = 107 (70)05 (56)4 (44)Non-Small lung cancer N = 138 (62)1 (8)3 (38)1 (13)Other N = 53 (60)02 (67)2 (67) ConclusionBO-112 combined with anti PD-1 shows a manageable safety profile, direct antitumor effects and innate and adaptive immune system activation. Efficacy analyses suggest potential to reverse primary resistance to anti-PD1 treatment. Studies in other indications, including combination with radiotherapy, are planned. Clinical trial identificationNCT02828098. Legal entity responsible for the studyBioncotech Therapeutics. FundingBioncotech Therapeutics. DisclosureI. Marquez-Rodas: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pierre Fabre; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bioncotech; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Regeneron; Advisory / Consultancy, Research grant / Funding (institution): Incyte; Non-remunerated activity/ies: Biosequence; Research grant / Funding (institution): Idera. P. Lopez-Casas: Full / Part-time employment: Bioncotech. M. Martin: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Puma; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Tahio; Advisory / Consultancy: Pharmamar; Advisory / Consultancy: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Daiichi. D. Tersago: Full / Part-time employment: Bioncotech. M. Quintero: Full / Part-time employment, Officer / Board of Directors: Bioncotech. I. Melero: Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Alligator; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Genentech; Advisory / Consultancy: Genmab; Advisory / Consultancy: Incyte; Advisory / Consultancy: Tusk; Advisory / Consultancy: Numab; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: F Star; Advisory / Consultancy: Bayer; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 75P Immune-related toxicities in NSCLC: Real-world experience from a tertiary cancer center
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    d'Arienzo P, Olsson-Brown A, Sallam M, et al.

    BackgroundImmune checkpoint inhibitors (ICIs) are key in the treatment of advanced non-small cell lung cancer (NSCLC). However, there is a paucity of large real-world case series on timing and severity of immune-related adverse events (irAEs) that could inform treatment service provision. MethodsA retrospective study of patients with advanced NSCLC treated with ICIs at The Clatterbridge Cancer Centre between 2016 and 2018 was conducted to review irAEs in the context of therapeutic efficacy. Kaplan Meier analysis, Mann-Whitney and chi-squared tests were used. Results303 patients were identified. Median age was 68 years; 83 patients (27%) had a performance status (PS) of 0; 85 (28%) had an ACE-27 comorbidity score ≥2. 277 (91%) had pembrolizumab (107 (35%) first line), 21 (7%) nivolumab and 5 (2%) atezolizumab. Median number of cycles was 6 (range 1-29). Median progression-free and overall survival (PFS/OS) were 5.0 and 10.0 months. IrAEs were reported in 40% of patients and 13% experienced multiple irAEs; 11% were ≥G3. The most common irAEs were dermatitis (12%), dysthyroidism (9%), colitis (6%), hepatitis (5%), arthralgia (5%), pneumonitis (5%); the most common ≥G3 irAEs were pneumonitis (3%), hepatitis (2%) and colitis (2%). Treatment was discontinued due to irAEs in 12% of patients. Median time to irAEs onset by system involved varied between 46 days (hyperthyroidism) and 122 days (arthralgia). There was no association between irAEs and age (p = 0.16), PS (p = 0.46), or ACE-27 score (p = 0.68). 83% of irAEs occurred within 6 months of initiating ICIs; no clear correlation between irAEs incidence and time on treatment was found. Patients with irAEs within 6 months of treatment had longer PFS (7.1 vs. 3.9 months, HR 0.70, p = 0.014) and OS (15.6 vs. 7.7 months, HR 0.48, p < 0.001) than those without irAEs. Notably, patients experiencing irAEs ≥G2 within the first 21 days of treatment had poorer clinical outcomes than those with later irAEs (median PFS 2.9 vs 10.3 months, p < 0.001; median OS 5.9 vs. 20.3 months, p = 0.001). ConclusionIn our large real-world retrospective cohort study the incidence of irAEs reflected that seen in clinical trials. There appears to be a toxicity-efficacy relationship with irAEs; however, larger studies are required to validate this. Legal entity responsible for the studyThe Clatterbridge Cancer Centre NHS Foundation Trust. FundingHas not received any funding. DisclosureA.C. Olsson-Brown: Honoraria (self): MSD; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): Eli Lily; Research grant / Funding (self): Novartis. C. Escriu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Boeringher Ingelheim; Speaker Bureau / Expert testimony: Pfizer. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 23P Immunological signature meta-analysis across lung cancer cohorts within the NanoString Clinical Transcriptional Atlas Group (CTAG) associated with patient outcome and history
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Radosevic-Robin N, Reeves J, Leroy K, et al.

    BackgroundWith the approval of anti-PD1 blocking antibodies in a growing number of indications, understanding the mechanisms responsible for potentiating response to these agents has been a critical avenue of research. However, most studies rely on the use of single cohorts and are relatively limited in their scope, thus limited their utility. MethodsWe created a consortium of investigators who share clinical and accompanying transcriptional data collected on the NanoString® nCounter® platform from patients treated with single agent immunotherapy to facilitate biomarker research. In this study, we apply a meta-analysis to a combined cohort of 4 lung cancer studies (n = 150) to identify transcriptional correlates of response to identify patients who are likely to experience clinical benefit. ResultsRNA was profiled with the NanoString IO360 and IO360 beta gene expression panels, and 43 signatures that describe facets of the immune response, tumor biology, and the tumor microenvironment were calculated. Included in these signatures is the Tumor Inflammation Signature (TIS), an investigational 18 gene signature of a suppressed adaptive immune response which enriches for clinical response to pembrolizumab. These signatures, as well as genes of interest identified in a given cohort, were compared to objective response, overall survival, or progression free survival across the cohorts. We confirm previously reported association of TIS with patient outcome and identify immune cell subsets that are also associated with response. In addition, we examine differences between patients with distinct mutational backgrounds, smoking histories, or histological classifications, as well as differences attributable to biopsy location. ConclusionThis multi-cohort study allows for the development of multi-variate predictors of response to anti-PD1 monotherapy using a single research assay to transcriptionally profile the tumors. We can generate robust predictions from real-world cohorts, which may lead to the development of improved diagnostic assays to guide treatment decisions. Legal entity responsible for the studyNanoString Technologies. FundingNanoString Technologies. DisclosureN. Radosevic-Robin: Research grant / Funding (institution): NanoString Technologies. J. Reeves: Full / Part-time employment: NanoString Technologies. K. Leroy: Research grant / Funding (self): NanoString Technologies. M. Duruisseaux: Research grant / Funding (self): NanoString Technologies. P. Morel: Full / Part-time employment: NanoString Technologies. M. Bhagat: Research grant / Funding (institution): NanoString Technologies. F. Penault-Llorca: Advisory / Consultancy, Research grant / Funding (institution): NanoString Technologies. D. Damotte: Research grant / Funding (institution): NanoString Technologies. F. Goldwasser: Research grant / Funding (institution): NanoString Technologies. A. Brindel: Research grant / Funding (institution): NanoString Technologies. M. Cumberbatch: Research grant / Funding (institution): NanoString Technologies. S. Ong: Full / Part-time employment: NanoString Technologies. J. Lopez: Research grant / Funding (institution): NanoString Technologies. S. Warren: Full / Part-time employment: NanoString Technologies.

    更新日期:2019-12-17
  • 165P Pre-therapeutic evaluation of patient-specific responses to immune-checkpoint inhibition in colorectal cancer
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Sturmheit T, Konczalla L, Temovski T, et al.

    BackgroundCancer immunotherapy has revolutionized treatment options for patients suffering from immunogenic tumors, among them melanoma, bladder and lung cancer. In the context of colorectal cancer (CRC), the administration of checkpoint inhibitors (CPIs) was shown to induce durable clinical responses in patients with mismatch repair deficient and microsatellite instable tumors, a though very small fraction of all CRC subtypes. To ameliorate response rates in metastatic CRC, various therapeutic strategies are currently being investigated to increase the immunogenicity of mismatch repair proficient (pMMR)/ microsatellite stable (MSS) CRC tumors and to set the ground for immunotherapy. Several conventional therapies approved for treating CRC patients are classified as immunogenic cell death inducers and may aid in priming cytotoxic T cells to the patient’s tumor. MethodsAt 2cureX, we aim to pre-therapeutically measure the potential responsiveness of a CRC patient to various drug therapy options to support the oncologists in identifying the best suitable treatment regimen. Our functional IndiTreat® assay system allows for testing of chemotherapeutic agents, targeted therapies and combinations thereof against micro-tumors (tumoroids), which we derive from CRC tissue or liver metastases. To broaden the applicability of the IndiTreat® test, the present study aims to adapt the assay system to functional testing of checkpoint inhibitors in the context of pMMR/MSS CRC, subsequent to standard of care therapy. ResultsTo assess the potential efficacy of IO interventions for individual patients, we co-culture tumoroids and (in vitro expanded) autologous PBMCs and monitor immune-mediated killing of tumoroids in the presence of CPIs. Tumoroids recapitulate the highly individual disease of cancer patients and constitute a valuable platform for evaluating different aspects of immune-mediated tumor cell recognition and killing. ConclusionIn vitro testing of individual responses to CPIs will be of key relevance for stratifying pre-treated pMMR/MSS CRC patients according to their likelihood to benefit from IO therapy and holds the potential to make these powerful drugs available to more patients suffering from CRC. Legal entity responsible for the studyThe authors. Funding2cureX, BMBF KMU-innovativ. DisclosureT. Sturmheit: Full / Part-time employment: 2cureX. T. Sutus Temovski: Full / Part-time employment: 2cureX. J. Thastrup: Full / Part-time employment: 2cureX. W. Fiedler: Advisory / Consultancy, Research grant / Funding (self), Licensing / Royalties: Amgen; Advisory / Consultancy: ARIAD/ Incyte; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Jazz Pharmaceuticals; Research grant / Funding (self): Pfizer. J. Wellbrock: Licensing / Royalties: Amgen. J. Kupper: Full / Part-time employment: 2cureX. A. Block: Research grant / Funding (self): 2cureX . All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 135P Analysis of the immune microenvironment in pre-treatment non-small cell lung cancer (NSCLC) patients with follow-up response data to second-line immunotherapy
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Bhagat M, Warren S, Elliott N, et al.

    BackgroundPatients selected based on PD-L1 expression for second-line immune checkpoint inhibitor (ICI) treatment are often identified using archival specimens collected months or years prior to starting immunotherapy. Such patients may have received and failed multiple lines of standard of care (SOC) treatments with subsequent potential impact on PD-L1 expression and immune microenvironment. MethodsWe have analysed formalin fixed paraffin embedded (FFPE) tissues in a cohort of NSCLC patients (n = 16) taken during resection performed as first-line surgical treatment for which radiotherapy, SOC chemotherapy, and second-line immunotherapy clinical follow-up data are available. The immune microenvironment was evaluated by immunohistochemistry (IHC) plus digital image analysis for CD3, CD8, PD-L1, CD68 and CD163, and by Nanostring using the IO360TM gene expression panel, with the aim of exploring whether immune signatures predictive of response to ICI therapy may be identified in such samples. ResultsClinical follow-up data indicated objective response to ICI therapy for 4/16 patients (n = 2 Nivolumab, n = 1 Pembrolizumab, n = 1 Durvalumab) with time from first diagnosis to receiving second-line ICI treatment ranging from 5 to 102 (mean 33.6) months. During this time these patients received various lines of radiotherapy and SOC chemotherapy prior to receiving immunotherapy. While the Tumor Inflammation Signature was not predictive of response, gene expression analysis did identify several signatures associated significantly with response, including increased abundance of CD8 T cells, cytotoxic cells, cytotoxicity, MHC class II antigen presentation and Melanoma-Associated Antigens (MAGE). These data were supported by a significant elevation of CD8 T cells by IHC in the responder versus non-responder populations, from a mean of 329 to 961 CD8+ T cells/mm2. ConclusionTaken together these data demonstrate that despite various lines of previous radiotherapy and chemotherapy spanning several years, immune profiles associated with response to second-line immunotherapy can be detected in surgical first-line resection samples. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureM. Bhagat: Shareholder / Stockholder / Stock options, Officer / Board of Directors: TriStar Technolgoy Group. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 8P The prognostic value of tumour-infiltrating lymphocytes (TILs) in pancreatic cancer: A systematic review and meta-analysis
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Orhan A, Vogelsang R, Andersen M, et al.

    BackgroundPancreatic cancer (PC) contributes to over 7 % of all cancer related deaths worldwide with a relative 5-year survival of less than 8 %. High levels of tumor-infiltrating lymphocytes (TILs) are associated with improved survival in many cancer types. Examining the impact of TILs on survival in PC could provide better prognostication and help clinicians tailor therapy for patients. MethodsA systematic search based on the PICO-process was conducted on PubMed, Embase, The Cochrane Library and Web of Science. Outcome of interest was overall survival (OS). Studies examining high vs. low levels of TILs in pancreatic tumor tissue and its impact on OS was included. Following data extraction a random-effects model meta-analysis was conducted on the reported outcome with corresponding lymphocyte subset. The Newcastle-Ottowa Scale was used for study quality assessment. ResultsIn total, 43 studies were included in the systematic review and 40 were eligible for meta-analysis. A time-to-event meta-analysis on the different lymphocyte subtypes revealed, that high vs. low infiltration of CD3+ T and CD8+ T cells was significantly associated with improved OS (HR = 0.59, 95 % CI: 0.51 - 0.68, I2: 0 % and HR = 0.61, 95 % CI: 0.57 – 0.67, I2: 0 %, respectively). High infiltration of FoxP3+ T cells was associated with decreased OS (HR = 1.41, 95 % CI: 1.15 – 1.73, I2: 85 %). The prevalence of CD4+ and CD20+ lymphocytes in pancreatic tumor tissue was not significantly associated with increased OS (HR = 0.87, 95 % CI: 0.65 - 1.17, I2: 80 % and HR = 0.86, 95 % CI: 0.54 – 1.35, I2: 66 %, correspondingly). ConclusionHigh infiltration of CD3+ and CD8+ lymphocytes is associated with improved OS among patients with resected PC, whereas high infiltration of FoxP3+ T cells is associated with decreased OS. CD4+ and CD20+ lymphocytes did not have a significant impact on OS. Based on these findings, staining for TILs, especially CD3+, CD8+ and FoxP3+ T cells, might be an important tool for future assessment of patient survival and prognosis, as well as for tailored oncological therapy. Clinical trial identificationCRD42019134744. Legal entity responsible for the studyThe authors. FundingCenter for Surgical Science. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 119P Final results of phase II trial (MIRACULUM) of the novel PD-1 inhibitor prolgolimab in patients with advanced melanoma
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Tjulandin S, Fedyanin M, Demidov L, et al.

    BackgroundMIRACULUM (NCT03269565) is a multicenter open-label parallel-arm phase II study investigating the antitumor activity of prolgolimab, an IgG1 anti-PD-1 monoclonal antibody with Fc silencing “LALA” mutation, in patients with advanced melanoma. Final analysis after ≥12 months of follow-up is presented. MethodsPatients (pts) with unresectable or metastatic melanoma, without autoimmune disease, no prior BRAF/MEK inhibitors, and anti-PD-1 or anti-CTLA-4 therapy were eligible. Pts received prolgolimab 1 mg/kg Q2W (arm 1) or 3 mg/kg Q3W (arm 2) until disease progression or intolerable toxicity. A statistical hypothesis that prolgolimab has significant anti-tumor effect (ORR more than 28%) was tested for each study arm. Results126 pts (63 in each arm) received at least one dose of prolgolimab (mITT population). Baseline pt characteristics were generally balanced between the arms. Prior systemic therapy was administered in 17 (27%) and 16 (25%) pts in arm 1 and 2, respectively. Stage II-III unresectable disease was observed in 4 (6.4%) pts in arm 1 and in 2 (3.2%) pts in arm 2. As of Feb 22, 2019, median follow-up was 13.8 mo (95%CI, 13.2-14.7) in arm 1 and 14.5 mo (95%CI, 13.9-15.2) in arm 2. The study met its primary endpoint in both study arms. In arm 1, 38% ORR was achieved, including 5 CR and 19 PR, and the disease control rate (DCR) was 64%. In arm 2, 29% ORR was achieved, including 2 CR and 16 PR, and the DCR was 46%. 12-mo OS rates were 74.6% for 1 mg/kg Q2W and 54.0% for 3 mg/kg Q3W. 12-mo PFS rates were 41.3% for 1 mg/kg Q2W and 34.9 for 3 mg/kg Q3W. Median response duration was not reached; 83% of all responses were ongoing at data cutoff. Treatment-related AEs (TRAEs) occurred in 55.6% and 54.0% of pts, including 12.7% and 3.2% with grade 3-4 TRAEs in arm 1 and 2, respectively. Immune-related AEs (irAEs) occurred in 36.5% of pts in arm 1 and 34.9% of pts in arm 2, including 7.4% and 1.6% of pts with grade 3/4 irAEs in each arm. ConclusionBoth dosing regimens of prolgolimab (1 mg/kg Q2W and 3 mg/kg Q3W) have durable antitumor activity and a manageable safety profile in patients with advanced melanoma. Clinical trial identificationNCT03269565. Legal entity responsible for the studyBIOCAD. FundingBIOCAD. DisclosureS. Tjulandin: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. M. Fedyanin: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. L. Demidov: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. V. Moiseyenko: Research grant / Funding (institution): BIOCAD. S. Protsenko: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. S. Odintsova: Speaker Bureau / Expert testimony: BIOCAD. T.Y. Semiglazova: Advisory / Consultancy, Speaker Bureau / Expert testimony: BIOCAD. M. Nechaeva: Speaker Bureau / Expert testimony: BIOCAD. O. Kozlova: Full / Part-time employment: BIOCAD. M. Shustova: Full / Part-time employment: BIOCAD. A. Garipov: Full / Part-time employment: BIOCAD. R. Ivanov: Full / Part-time employment: BIOCAD. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 58P Risk factors for immune related adverse events: A retrospective study
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Parmanande A, Barreira J, Spencer A, et al.

    BackgroundImmunotherapy with checkpoint inhibition has gained high importance for oncological treatments with benefits in overall survival (OS). However these drugs are not harmless, and immune related adverse events (irAE) have been reported. We pretend to evaluate which patients (pts) are in risk for developing these. MethodsRetrospective evaluation of all pts treated with PD-1 and PD-L1 inhibitors for solid tumors in our center, during January 2015 and October 2018. A multivariate regression was made to determine potential risk factors for irAE. Significance was stablished at p < 0,05. Statistical analysis was made with STATA. Results75 pts were included. Median age as 66 years (28-88y). 47 pts (62%) were male. 67 pts (90%) had metastatic disease. 48 pts (64%) were treated with nivolumab, 17 (22%) with pembrolizumab, 8 (10%) with durvalumab and 2 pts with atezolizumab. The most common diagnosis was non small cell lung cancer, with 53 pts (70%), of which 38 were adenocarcinomas. Urothelial cancer, hepatocellular carcinoma e renal cell cancer had 12%, 6% and 5% of the sample respectively. 31 (42%) pts had irAE. 20 (65%) had grade 2 or lower events, and 5pts had multiple irAE. The most common irAE were endocrine dysfunction, skin toxicity and pneumonitis, with 29%, 25% and 19% respectively. Of the 11 serious irAE (grade 3 or higher), the most common cause was pneumonitis with 5 cases. Median time of occurence was 3 weeks after the first treatment (0-52w). The multivariate regression showed higher likelihood of irAE in patients that were female, odds ratio (OR) of 3,72 (p = 0,037, 95% confidence interval (CI95%) 1,15 - 12,83); Lung adenocarcinoma, OR 3,94 (p = 0,032, CI95% 1,12 - 13,79), history of allergies, OR 17,04 (p = 0,022; CI95%) 1,57 - 191,55); history of autoimmune disease, OR 16,88 (p = 0,002; CI95% 2,75 - 103,48). There was no correlation between drug used, previous thoracic radiotherapy or previous steroid treatment. ConclusionThis study helped distinguish potential risk factors for irAE, like the female gender and history of allergies. Autoimmune disorders are already reported as risk factores. However the small sample isn't enough for us to draw accurate conclusions. More prospective trials are waranted in this setting. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 38P Obtaining tumour-specific T cells in a mouse melanoma model
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Yuzhakova D, Izosimova A, Barbashova L, et al.

    BackgroundOne of most promising strategies for cancer immunotherapy is adoptive T cell therapy (ACT). In the frame of this approach, tumor-specific lymphocytes (TSL) are infused into patients to recognize and destroy tumor cells. The key step of ACT is identification of TSL within the tumor-infiltrating lymphocytes (TILs). However, current procedures of obtaining TSL are very labor-intensive and expensive or have not demonstrated the sufficient clinical benefits. The purpose of this study was to develop an effective and simple method for TSL identification in a mouse melanoma model. MethodsThe experiments were carried out on C57BL/6 mice bearing B16F0 mouse melanoma model. TILs were obtained by disaggregation of tumor nodules, and mouse spleen T-cells were harvested by magnetic separation. Tumor reactivity of T-lymphocytes was assessed by IFNγ secretion assay or intracellular staining. IFNγ+ T-cells were collected by BD FACSAria III cell sorter (BD Biosciences, USA). ResultsTo obtain melanoma specific T-cells we isolated TILs from tumor nodules and sorted live activated IFNγ+ T-cells. We identified 1-6% CD4+ and 3-8% CD8+ IFNγ+ activated T-lymphocytes. With bioinformatic analysis of T-cell receptor repertoires we detected the clusters of cells that recognize the same antigens and are enriched in IFNγ+ cell fraction compared to IFNγ- cells. This fact is an additional evidence of tumor specify of these cells. To check tumor specificity of bioinformatically identified T-cells we have used one of the common approaches for TSL identification – in vitro stimulation of T-cells by APCs loaded with tumor antigen. First, we established mice with stable immunity against B16F0 and harvested T-cells from spleen. Then T-cells were cocultured with B16F0-loaded APCs. To improve the efficiency, we have optimized several parameters, such as additional immunization of the mice and co-cultivation conditions. As a result, we registered 1% of B16F0-specific CD4+ T-lymphocytes against the background of non specifically activated cells. ConclusionWe have developed a new method to obtain potential TSL from tumor nodules. Future experiments will be directed to compare their repertoires with B16F0-specific T-cells. Legal entity responsible for the studyThe authors. FundingMinistry of Education and Science of the Russian Federation (grant No 14.W03.31.0005). DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 101P Results of the NLG2105 phase I trial using the IDO pathway inhibitor indoximod, in combination with radiation and chemotherapy, for children with newly diagnosed DIPG
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Johnson T, Aguilera D, Al-Basheer A, et al.

    BackgroundWe conducted a phase Ib dose-confirmation study of indoximod with radiation, followed by indoximod with cyclic temozolomide therapy, to evaluate safety and overall survival (OS) in children with newly diagnosed DIPG (diffuse intrinsic pontine glioma). Indoximod is a small-molecule inhibitor of the IDO pathway that reverses immune suppression imposed by tumor microenvironments. DIPG is a uniformly fatal orphan disease with no curative treatment options. MethodsChildren age 3 to 21 years, with newly diagnosed DIPG were eligible for treatment with oral indoximod (38.4 mg/kg/day divided BID, throughout) combined with fractionated conformal radiation therapy (54 Gy in 30 fractions), followed by cyclic oral chemo-immunotherapy using indoximod combined with temozolomide (200 mg/m2/day, days 1-5 of each 28-day cycle). The indoximod dose was the previously determined recommended phase-II dose (RP2D), and the study design called for phase I monitoring to confirm safety of this dose in DIPG patients. ResultsThirteen children (median age 9 years, range 5 to 20 years) with newly diagnosed DIPG were treated using this indoximod-based radio-chemo-immunotherapy regimen. The 12-month OS was 62% (8/13) and estimated median OS was 14.5 months (follow-up range 4.8 to 22 months) with 4 patients remaining in follow-up. This compares favorably to the expected 12-month OS of approximately 45% and median OS of approximately 10.8 months from published historical controls (Kilburn, et al; 2017). Two patients experienced near-complete responses until showing relapse at 7.6 months and 13.3 months of study therapy. Patients were followed with quantitative volumetric analyses of MRIs and serial measurements of peripheral blood inflammatory monocytes, T cell activation, and pro-inflammatory cytokines. The most common adverse events attributed to indoximod were thrombocytopenia, diarrhea, nausea, vomiting, and fatigue. ConclusionAdding indoximod-based immunotherapy to conventional radiation and chemotherapy for up-front therapy of children with DIPG appears to be well tolerated with improved outcomes. Clinical trial identificationNLG2105, NCT02502708. Legal entity responsible for the studyNewLink Genetics Corporation. FundingNewLink Genetics Corporation, Alex's Lemonade Stand Foundation, Cannonball Kids cancer Foundation, Beloco Foundation, Eli’s Block Party Foundation, Hyundai Hope on Wheels Foundation, Northern Nevada Children’s Cancer Research Foundation, CAM Fund, Press On Foundation. DisclosureT.S. Johnson: Research grant / Funding (institution): NewLink Genetics Corporation. E.P. Kennedy: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. N. Vahanian: Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: NewLink Genetics Corporation. D.H. Munn: Advisory / Consultancy, Shareholder / Stockholder / Stock options, Licensing / Royalties: NewLink Genetics Corporation. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 76P Real-world data analysis of PD-L1 expression and overall survival (OS) in advanced non-small cell lung cancer (aNSCLC)
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Staib J, Sudarsanam S, Byfield S, et al.

    BackgroundClinical trials show favorable OS for patients (pts) with incident aNSCLC and programmed death ligand 1 (PD-L1) expression treated with PD-L1 immune checkpoint inhibitor (ICI) pembrolizumab (PEM) or PEM-chemotherapy compared to no ICI. We use real world data to examine OS in pts with PEM-based regimens vs NoICI as initial aNSCLC treatment by PD-L1 expression. MethodsThis retrospective study used de-identified administrative claims, including month of death (MoD) from regular operations, spanning 1/2017-12/2018 from a large, national US insurer. Claims were linked with biomarker test data from a CLIA-certified cancer diagnostics lab. During 2018, Medicare Advantage pts having ≥1 claim with diagnosis (dx) of lung cancer (ICD-10 C34), advanced disease (C77-C79), a PD-L1 test (CPT 88360) and test result, Tumor Proportion Score (TPS), were included. Pts were newly diagnosed (no C34 in 2017) and continuously enrolled in 2017 & 2018 or until death in 2018. Cohorts were based on initial therapy as PEM-based or NoICI and TPS result. Pts were followed from dx to MoD or 12/2018. OS was MoD, minus month of dx; otherwise censored at 12/2018. Multivariable Cox proportional hazard regressions compared OS across cohorts. Results457 pts met study criteria: 126 PEM-based and 331 NoICI. Median age was 76 years in both cohorts. PEM-based had more males (63% vs 51%; p = 0.02) Median months followed was 6 (PEM-based) and 4 (NoICI). For PEM-based , 23 (18%) had TPS 0, 36 (29%) had TPS 1- 49 and 67 (53%) had TPS 50+. For NoICI, 118 (36%) had TPS 0, 120 (36%) had TPS 1- 49, and 93 (28%) had TPS 50+. 20% (n = 25) of PEM-based and 31% (n = 104) of NoICI died during the study period. Mortality hazard ratios for PEM-based vs NoICI by TPS score were: TPS 0, 0.46 (CI 95% 0.16 – 1.30); TPS 1 to 49, 0.73 (CI 95% 0.35 – 1.52); and TPS 50+,0.35 (CI 95% 0.18 – 0.68). OS was more favorable for the PEM-based cohort for all TPS groups, though only TPS 50+ was significant. ConclusionThis study used administrative claims and lab test data allowing examination of effectiveness of PEM-based vs. NoICI therapy for aNSCLC. As in clinical trials, this analysis suggests OS benefit for PEM-based vs NoICI. Further analysis with longer follow-up will better assess OS benefit by TPS score. Legal entity responsible for the studyUnitedHealth Group. FundingHas not received any funding. DisclosureJ. Staib: Shareholder / Stockholder / Stock options, Full / Part-time employment: UnitedHealth Group; Shareholder / Stockholder / Stock options: Bristol Myers Squibb; Shareholder / Stockholder / Stock options: Merck; Shareholder / Stockholder / Stock options: Natera; Shareholder / Stockholder / Stock options: NeoGenomics. S. Sudarsanam: Shareholder / Stockholder / Stock options, Full / Part-time employment: NeoGenomics Laboratories. S. Dacosta Byfield: Shareholder / Stockholder / Stock options, Full / Part-time employment: UnitedHealth Group. C. Kennedy: Shareholder / Stockholder / Stock options, Full / Part-time employment: UnitedHealth Group. L. Weiss: Shareholder / Stockholder / Stock options, Full / Part-time employment: NeoGenomics Laboratories.

    更新日期:2019-12-17
  • 24P Multiple KRAS mutations detected by cancer related DNA in patients with resected pancreas adenocarcinoma during treatment with TG01/GM-CSF and gemcitabine (CT TG01-01)
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Palmer D, Møller A, Greenhalf B, et al.

    BackgroundTG01/GM-CSF is an injectable antigen-specific cancer immunotherapy targeted to treat patients (pts) with KRAS mutations, found in > 90% of pancreatic adenocarcinomas (PAC). TG01 consists of a mixture of 7 synthetic peptides representing 7 of the most common codon 12 and 13 mutations associated with PAC. Pancreatic cancer is a heterogeneous and genetically unstable disease, meaning that more than one KRAS mutation may be present in a single tumor. We investigated if cancer-related DNA from pts with resected PAC had more than one KRAS mutation and if the mutation status changed during treatment with TG01/GM-CSF. MethodsPts were eligible after an R0 or R1 PAC resection. TG01 (0.7 mg intradermal injection id) together with GM-CSF (0.03 mg id) was given on day 1, 3, 5, 8, 15, 22 and 2-weekly until end of chemotherapy, 4-weekly up to 1 year and 12-weekly up to 2 yrs. Within 12 weeks after resection, pts were expected to receive gemcitabine for 6 cycles. Plasma samples (up to 9) from 21 pts were collected and cancer related KRAS DNA were analyzed using ARMS (real time qPCR) for the 6 most common mutations: 12D, 12V, 12A, 12R, 12S and 12C. Results21 pts from UK, median age 65 (46-77) enrolled between Jan-2014 and Apr-2016. Previous results from tumor specimen showed that 16 out of 21 pts had a KRAS mutation (single mutation). However, when analyzing mutations using ARMS 20 out of 21 pts had ≥1 KRAS mutations; 19 out of 21 pts (90%) had between 1-6 mutations throughout the study. 12D and 12V mutations co-occurred in 17 out of 21 (81%) of the pts. In one pt all 6 assessed KRAS mutations were detected throughout the study. In 5 pts mutations disappeared during the treatment while in 10 pts the mutations changed either revealing new mutations or shift of mutations over time, possibly indicating selection pressure. ConclusionThe great majority of patients with PAC have multiple KRAS mutations; in addition, mutations changed during the course of the study. Single mutation vaccines and small molecules targeting single mutations are therefore unlikely to be effective while therapies targeting a mix of KRAS mutations (TG01) may be more beneficial. Clinical trial identificationCT TG01-01; EudraCT: 2012-002400-40. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 166P Insights in the mode of action of a T cell bispecific antibody in tumour bearing mice
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Giusti A, Sam J, Karagianni M, et al.

    BackgroundCD3 bispecific antibodies are a very potent means to re-activate the immune system against tumour cells targeting cancer-associated antigens and CD3 on T cells and acting as direct immune activators. The aim of this study was to investigate the early changes occurring in the tumour and peripheral blood in tumour bearing mice treated with a T cell Bispecific (TCB) antibody designed to elicit T cell activation upon simultaneously binding to T cells and to a tumour-specific target. MethodsC57Bl/6 mice bearing a B16 metastatic lung murine melanoma were treated with a single dose iv of a TCB targeting murine CD3 and an antigen highly expressed in the B16 tumour. At 2h, 4h, 7h, 24h, 48h after treatment blood was collected for hematology, serum chemistry, cytokines, flow cytometry and pharmacokinetic analysis and the tumour-bearing lung was collected and analyzed for cytokines, flow cytometry and histopathology. ResultsTreatment with the targeted TCB induced, starting from two hours post single dose administration, a transient marked drop in lymphocytes, an increase in neutrophils and monocytes and an increase in acute phase proteins (haptoglobin, SAA1, a1-AGP and SAP) in the peripheral blood, correlating with the histopathological changes at the tumour site. Histopathology, immunohistochemistry and flow cytometry of the tumour showed that acute inflammation was already present at two to four hours after treatment in the form of neutrophilic infiltrate, while CD3+ T lymphocytes started to accumulate in the tumour 24h after treatment. These changes were accompanied by an increase of some cytokines in the tumour (e.g. IL-6, MCP1, IL-1b) and in the peripheral blood. ConclusionChanges observed in tumour bearing mice upon treatment with a tumour-targeted TCB suggest an early engagement of tumour resident T cells resulting in cytokine release locally and systemically within 2h after treatment, with homing and extravasation of inflammatory cells into the tumour progressively increasing 24h to 48h after treatment. This course of events is believed to be translatable to patients treated with TCBs. Legal entity responsible for the studyRoche Glycart AG. FundingRoche Glycart AG. DisclosureA.M. Giusti: Full / Part-time employment: Roche Glycart AG. J. Sam: Full / Part-time employment: Roche Glycart AG. M. Karagianni: Full / Part-time employment: Roche Glycart AG. A. Schneider: Full / Part-time employment: Roche Glycart AG.

    更新日期:2019-12-17
  • 59P Checkpoint inhibitors and conventional therapy for central nervous system lymphoma
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Shmidt D, Gavrilenko A, Polushin A, et al.

    BackgroundPrimary (PCNSL) and secondary (SCNSL) central nervous system lymphoma still carry a poor prognosis. Treatment of relapsed/refractory (r/r) CNS lymphoma remains a challenge. Biological features of CNS lymphoma determine the opportunity to use checkpoint inhibitors in r/r CNS lymphoma. MethodsAnalysis included 35 patients with CNS lymphoma treated at the First Pavlov Saint Petersburg state medical University between 2010 and 2019. SCNSL comprised 54% of patients (n = 19), PCNSL - 40% (n = 14), and 6% (n = 2) had CNS involvement in primary testicular lymphoma (PTL). Latter would further be analysed together with PCNSL. Median age at a diagnosis was 56 (30-65) in pts with PCNSL and 48 (20-65) in pts with SCNSL. Tumor histology was diffuse large B-cell lymphoma in 83% of cases. Relapsed or refractory CNS lymphoma was the case in 21 pts (60%): PCNSL – 81% (n = 13/16), SCNSL – 42% (n = 8/19). Nivolumab (nivo) was used in 12 pts: PCNSL – 44% (n = 7/16), SCNSL – 26% (n = 5/19). Median follow-up was 16 months (mo) (0-99): 24,5 mo (0-99) for PCNSL, 12 mo (1-34) for SCNSL pts. One patient had been infected with HIV. ResultsTreatment related mortality was 11% (n = 4/35). 1-year overall survival (OS) was 74% in PCNSL and 69% in SCNSL group. 6-months OS of r/r disease was 75% for PCNSL and 33% for SCNSL. Patients received nivo at dose 3 mg/kg (n = 3), 1 mg/kg (n = 6), 100 mg (n = 3) и 200 mg (n = 1). Median follow-up in pts receiving nivo was 7 mo (0-31). Objective response rate was 58% (n = 7). Complete response was seen in 6 pts (3 PCNSL, 3 SCNSL), partial response – in 1 PCNSL patient, 4 pts had stable disease (2 PCNSL, 2 SCNSL), disease progression was the case in 1 patient with PCNSL. Adverse events (AE) were grade 2 immune arthritis and maculopapular rash. The was no grade 3-4 AE. Eight patients who received nivo are alive at the moment of analysis. Tumor resection was performed in 8 (23%) pts (6 with PCNSL and 2 SCNSL). Consolidation took place in 11 (31%) pts (4 PCNSL, 7 SCNSL). Radiotherapy was performed in 11 pts (31%): 5 PCNSL, 4 SCNSL. Autologous hematopoietic stem cell transplant was performed in 1 patient with PCNSL and 5 pts with SCNSL. ConclusionNivo is a safe and efficient option in some pts with CNS lymphoma. Appropriateness, timing and optimal regimen of nivo therapy should be determined in prospective trials. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 120P Combination of triptorelin with nivolumab in ICI resistant advanced melanoma
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Robert C, Lejeune F, Lebbé C, et al.

    BackgroundIt has been shown that androgens are immunosuppressive. Androgen deprivation with GnRH agonists regenerates the thymus and its functions in adults, leading to increase in blood and lymphoid organ lymphocytes, in naive lymphocytes with expansion of TCR Vbeta repertoire, and in Tumour Infiltrating Lymphocytes (TILs) in prostate tumours. This phase I study evaluated the safety of triptorelin in combination with nivolumab, as well as its potential to reverse resistance to PD-1 inhibitors in male melanoma patients. MethodsTreatment consisted of triptorelin 3.75 mg i.m. every 4 weeks and nivolumab 3 mg/kg i.v. every 2 weeks. Bicalutamide 50 mg p.o. QD was added for the first 28 days. Evaluation of response was performed after 3 months. Triptorelin PK was assessed and various PDy markers were measured in blood and tumour samples. Planned treatment duration was 48 weeks. ResultsFourteen male patients were included, of whom 11 were white and 3 were black, with mean age 65 years (range 45-82). At screening 4 were locally advanced while 10 had distant metastases (2 with M1a, 1 with M1b, 6 with M1c and 1 with M1d). Ten patients had cutaneous melanoma, 2 patients had mucosal melanoma, and 2 had an unknown primary. Safety: No grade 4 AEs were reported. Five grade 3 AEs were reported in 4 patients, of which one (abdominal pain) was attributed to triptorelin and resolved after 39 days (causing no treatment interruption as it started on the day treatment was discontinued due to progression), and one (neutropenia) was considered related to nivolumab and resolved following treatment interruption for 14 days. Efficacy: BOR (RECIST 1.1) was assessed as 2 PR, 5 SD, and 7 PD. The two patients with PR showed reductions from baseline in Target Lesions of 76% (one pancreas metastasis) and32% (two inguinal lymph nodes), following an initial pseudoprogression. ConclusionThe association of triptorelin to nivolumab was well tolerated and yielded partial response in two patients. Legal entity responsible for the studyDebiopharm International S.A. FundingDebiopharm International S.A. DisclosureC. Robert: Advisory / Consultancy: Novartis, Bristol-Myers Squibb, MSD, Roche, Sanofi, Amgen, Pierre Fabre. F.J. Lejeune: Honoraria (self): Debiopharm International SA. C. Lebbé: Honoraria (self): Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen, Pierre Fabre, Pfizer, Incyte; Advisory / Consultancy: Roche, Bristol-Myers Squibb, Novartis, MSD, Amgen; Travel / Accommodation / Expenses: Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Roche, Bristol-Myers Squibb, Novartis ,Amgen; Advisory / Consultancy: Aventis. T. Lesimple: Research grant / Funding (self): Roche; Advisory / Consultancy: MSD, Novartis, Pierre Fabre. E. Lundström: Full / Part-time employment: Debiopharm International SA. V. Nicolas: Full / Part-time employment: Debiopharm International SA. B. Gavillet: Full / Part-time employment: Debiopharm International SA. V. Grégoire: Full / Part-time employment: Debiopharm International SA. P. Crompton: Full / Part-time employment: Debiopharm International SA.

    更新日期:2019-12-17
  • 9P Overall assessment of tumour-infiltrating lymphocytes in early-stage nasopharyngeal carcinoma
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Almangush A.

    BackgroundNasopharyngeal carcinoma (NPC) has distinct histopathology and associated with high mortality rate. Identification of NPC cases that have aggressive behavior at an early-stage can aid in improvement of the survival. Assessment of tumor-infiltrating lymphocytes (TILs) has shown a promising prognostic value in many epithelial cancers. MethodsThis study included a multicenter cohort of 44 cases treated for early-stage (I-II) NPC at the five Finnish university hospitals (Helsinki, Turku, Tampere, Kuopio and Oulu). Hematoxylin and eosin-stained cancer sections were used to evaluate TILs. We followed the guidelines that recently introduced by International Immuno-Oncology Biomarkers Working Group for assessment of TILs in different tumors including head and neck cancer. ResultsThe score of intra-tumoral TILs showed a promising prognostic value for predicting survival in early NPC. A hazard ratio of 2.45 and 95% confidence interval of 1.07 to 5.62 (P = 0.03) was reported, indicates that tumors with low TILs have a higher risk of mortality. ConclusionIn early-stage of NPC, assessment of TILs has a significant prognostic value that can be useful to identify cases with aggressive behavior. Further studies are necessary to validate the importance of TILs in larger cohorts of early NPC. Legal entity responsible for the studyAlhadi Almangush. FundingHas not received any funding. DisclosureThe author has declared no conflicts of interest.

    更新日期:2019-12-17
  • 102P Results from a phase II trial of pembrolizumab (P) plus gemcitabine (Gem) in patients (pts) with HER2-negative advanced breast cancer (ABC): GEICAM/2015-04 (PANGEA-Breast) study
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Merino L, Cruz J, Alonso J, et al.

    BackgroundThis trial is based on a combination strategy with two immunostimulatory agents in the search of synergism that may induce responses with long-term clinical benefit in ABC pts. Safety data from the run-in-phase were published in ESMO IO 2018. Here, we report the results from the phase II part of the study. MethodsHER2-negative ABC pts previously treated with anthracyclines and taxanes (unless contraindicated), ≤ 4 chemotherapy lines and/or ≥ 2 hormone therapy lines, and irrespective of PD-L1 status, were eligible. Study treatment consisted of 21-day cycles (cy) of P 200mg on day 1 and Gem 1250mg/m2 on days 1 and 8 until progressive disease (PD) or unacceptable toxicity, whatever occurred first. Primary objective was Objective Response Rate (ORR). ResultsThirty-six pts were included in the first stage of a Simon’s design. Recruitment was stopped as only 5 pts presented an objective response (partial) (≥ 7 responses needed to continue recruiting pts). Median age was 52 years (range 31-77), 21 pts had triple negative disease, the majority of pts had an ECOG performance status ≤ 1 (n = 35), visceral involvement (n = 28) and ≥ 2 metastatic locations (n = 27). Median number of prior lines (any therapy) for ABC was 4 (range 0-11). Pts received a median of 4.5 cy of Gem and 4 cy of P (same range for both drugs, 1-24). The median relative dose intensity of P and Gem was 100% and 80%, respectively. Treatment discontinuation due to PD was reported on 29 pts. The ORR was 15.2% (95% confidence interval (CI) 5.1-31.9) and the Clinical Benefit Rate was 17% (95% CI 33.5-69.2); median duration of objective response was 4.3 months (mo) (95% CI 2.3-7.4), median Progression-Free Survival was 3.1 mo (95% CI, 2-4.3), and median Overall Survival was 7.9 mo (95% CI 6.5-10.3). Eight pts were on treatment ≥ 6 mo before PD (2 pts on 11.4 and 16.1 mo). Grade (G) ≥ 3 AEs related to the study treatment were reported on 14 pts (39%), being neutropenia the most common G3 (22.2%) and G4 (5.6%) AE. ConclusionP can be safely combined with Gem, the combination did not meet the efficacy objective in terms of ORR but 22.2% pts were on treatment ≥ 6 mo. Clinical trial identificationNCT03025880. Legal entity responsible for the studyGEICAM Spanish Breast Cancer Group. FundingMSD. DisclosureJ. Cruz: Honoraria (self), Advisory / Consultancy: Glaxo; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pharmamar; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Pfizer. M. Ramos Vazquez: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer. J. Cortés: Honoraria (self), Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Celgene; Advisory / Consultancy: Cellestia; Honoraria (institution), Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Biothera Pharmaceutical; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Advisory / Consultancy: Polyphor; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (institution), Advisory / Consultancy: Servier; Honoraria (self), Honoraria (institution), Advisory / Consultancy: MSD; Advisory / Consultancy: GSK; Honoraria (self): Novartis; Honoraria (self), Honoraria (institution): Eisai; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (institution), MedSIR (Stock, patent and intellectual property): Ariad Pharmaceuticals. Baxalta GMBH/Servier Affaires. Bayer Healthcare. Guardanth Health. Piqur Therapeutics. Puma C. Queen Mary University of London. Seagen. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 136P Profiling the tumour immune microenvironment in pleomorphic dermal sarcomas suggests its potential effectiveness for immunotherapy
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Noh K, Klein S, Mauch C, et al.

    BackgroundImmune-checkpoint inhibitors have shown high objective response rates and long-lasting clinical benefits in several studies, thus revolutionized cancer treatment. Pleomorphic dermal sarcoma (PDS) is a rare cutaneous tumour with local recurrences and distant metastases occurring up to 20% of the cases. With only limited treatment options in advanced stages, there is a strong rationale to explore novel treatments in PDS. In order to achieve this, the profiling of the immune environment in PDS needs to be first explored. MethodsWe collected 14 PDS cases that underwent primary surgical resection at University Hospital Cologne. With formalin-fixed paraffin-embedded (FFPE) materials, we performed a comprehensive immune-phenotype analysis using immunohistochemistry and multiplex gene expression analysis, as well as quantitative assessment of immune cells through quantitative image-analysis. Based on these findings and our preliminary studies, two patients with advanced PDS were enrolled in programmed cell death protein 1 (PD-1) inhibitor therapy. ResultsEight out of fourteen PDS cases (57%) showed abundance of CD8-positive T-lymphocyte infiltration. Three cases that had above median level of infiltration (hereinafter referred to as CD8-high) displayed high expression levels of immune-related cytokines, immunotherapy response markers, MHC-I expression, and infiltration by PD-L1-, PD-1- and LAG-3-expressing immune cells. The multivariate analysis revealed that CD8-high group highly expressed CD74, LYZ and HLA-B while the CD8-low cases overexpressed CXCL14. In addition, M2 tumor-associated macrophages (TAMs) were localized at the tumor invasion front. Likewise, both patients showed good response to anti-PD-1 therapy in combination with or without radiotherapy and remain in complete remission until now. ConclusionWe provide the initial comprehensive immune-phenotype profiling of PDS and two representative cases that were successfully treated with immune-checkpoint inhibitor for the first time. These results will aid in further assessment of PDS cases and formulate the qualification criteria for immunotherapy in individuals presenting this rare skin malignancy. Legal entity responsible for the studyUniversity Hospital Cologne. FundingEFRE 2018 (ImmunePredict). DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 150P Intratumoural MDSC recruitment by chemotherapeutic agent, 5-FU offsets the anti-tumor activity of immune-checkpoint inhibitor in HCC
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Kwong T, Wong C, Zhou J, et al.

    BackgroundCurrent hepatocellular carcinoma (HCC) immunotherapy trials only yield modest outcome, suggesting that possibly strong intrinsic immunosuppressive network needed to be tackled. Conventional chemotherapies are found to exert immunomodulatory effect on the tumor microenvironment (TME). Our study investigated anti-tumor activity of 5-FU in combination with anti-PD-L1, using pre-clinical HCC mouse model, and evaluated the immunomodulation in TME after drug treatments. MethodsFor the orthotopic HCC in vivo experiment, 6-8-week-old male C57BL/6 mice were injected intrahepatically with 5x10^5 RIL-175 luc+ cells. In order to assess its immunomodulatory effect on HCC TME rather than on direct tumor-killing effect, 5-FU was administrated (i.p.) 3 times per week at a relative low dose—20mg/kg. Whilst, anti-PD-L1(10mg/kg) was delivered (i.p.) every 5 days. Tumor growth was monitored via in vivo imaging. Tumor, liver, spleen and blood was collected afterwards, followed by immune profiling analysis via flow cytometry. ResultsIn terms of in vivo imaging results, mice with single anti-PD-L1 treatment showed significant response in tumor growth amongst other groups. Meanwhile 5-FU monotherapy and combined treatment group showed no difference with vehicle group. We found an increased amounts of T lymphocytes and NK cells in the tumor site after anti-PD-L1 single treatment, suggesting that these immune active cells contributed to the anti-tumor effect. Tumor-infiltrating myeloid cells, particularly P-MDSC, elevated upon 5-FU treatment in both single and combined group, suggesting that they may play a role in mediating immunosuppression. ConclusionThis study illustrated that anti-PD-L1 monotherapy enriched tumor-infiltrating T lymphocytes and NK cells, possibly accounting for the deferred tumor growth. However, the accumulation of myeloid cells in 5-FU treated mice hinders the anti-tumor activity of anti-PD-L1 from this orthotopic HCC mouse model. Therefore, low dose of 5-FU may initiate immunosuppressive mechanism to alter the effectiveness of anti-PD-L1 in HCC. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 25P Analysis of NGS-based blood immune cell RNA signatures for colorectal cancer detection
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Morgenthaler S, Lindsay H, Ciarloni L, et al.

    BackgroundColorectal Cancer (CRC) is the second leading cause of cancer mortality worldwide. Effective and non-invasive biomarkers are needed to improve early diagnosis and disease management. Immune cells play a key role in tumor progression. Circulating immune cell count is a potential cancer biomarker, as indicated by the association of high blood neutrophil-to-lymphocyte ratio with poor prognosis in patients with cancer. The study goal was to determine the correlation between circulating immune cell counts and immune cell-specific RNA signatures and to evaluate the signature potential for CRC detection. MethodsThe transcriptome profiles of peripheral blood mononuclear cells from 561 Asian and Caucasian subjects (189 CRC, 115 advanced adenomas, 39 other cancers, 218 controls without colorectal lesions (CON)) were generated by RNA-seq on the Illumina platform. Neutrophils, lymphocytes and monocytes counts were obtained by standard hematology testing. Specific RNA signatures for neutrophils, monocyte/macrophages, T cells, CD4, CD8, B cells, NK cells were compiled from literature. The mean expression level of all genes in each Immune cell signature was calculated and used for statistical analyses. ResultsThe main immune cell type RNA signatures showed correlation with the relative cell counts (r: 0.4-0.6), indicating the validity of the RNA signatures. Myeloid cell (monocyte/macrophage and neutrophil) RNA signatures were the most significantly upregulated in CRC compared to CON (p < 0.01), whereas the T-cell signature was the most significantly downregulated. Interestingly, the NK cell RNA signature was strongly upregulated in the Asian compared to Caucasian patients, which was mirrored by a higher lymphocyte cell count, in line with a previous study. ConclusionThis study shows that measuring specific immune cell type by RNA signatures correlate with traditional cell counting methods, enabling the extraction of valuable clinical information from blood transcriptomic data. This data suggests that both blood myeloid and T cells RNA signatures are promising biomarkers for CRC detection. Further biomarker development would require the optimization of the RNA signatures to validate and increase their diagnostic power. Legal entity responsible for the studyNovigenix. FundingNovigenix. DisclosureS. Morgenthaler: Advisory / Consultancy: Novigenix. L. Ciarloni: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novigenix. G. Dorta: Advisory / Consultancy: Novigenix. S. Hosseinian Ehrensberger: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novigenix. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
  • 77P The characteristics of long-lasting responders to PD-1 inhibitor in advanced non-small cell lung cancer patients
    Ann. Oncol. (IF 14.196) Pub Date : 2019-12-15
    Jo H, Yoshida T, Yagishita S, et al.

    BackgroundWe often experience long-lasting response of PD-1 inhibitor in advanced NSCLC patients. However, the characteristics associated with long-lasting response to PD-1 inhibitor is still unknown. In this study, we investigated the characteristics of patients who showed long-lasting (≥2 years) response to anti-PD-1 antibodies. MethodsWe reviewed consecutive advanced NSCLC patients who received a PD-1 inhibitor monotherapy (nivolumab, or pembrolizumab) between December 22, 2015 and May 31, 2017 at National Cancer Center Hospital in Japan. The cut-off date was June 1, 2019. We defined patients who obtained clinical benefit for more than 6 months as “Responders”. Among them, those who had a durable response for more than 2 years were defined as “Long-term responders” (LTR), and those who responded or shorter than 2 years as “Non-LTR”. We investigated the patient baseline characteristics and clinical outcomes of anti-PD-1 monotherapy including objective response rate (ORR) and maximal tumor shrinkage. Tumor response was assessed by RECIST version 1.1. The PD-L1 expression on tumor cells was assessed by using 22C3 antibody. ResultsA total of 232 patients were included in this analysis. Responders accounted for 37.9 % (88 out of 232). Of these patients, 31 (35.2%) were LTR group and 57 (64.8 %) were non-LTR group. At the time of data cut off, 22 (71.0%) of 31 patients in LTR group showed lasting response of PD-1 inhibitor. There were no significant differences in the baseline characteristics such as age, sex, performance status, driver mutation, clinical stage, and smoking status. Regarding histological distribution, non-squamous cell histology was more common in the LTR group (68% vs. 90%, P = 0.021). The ORR in the LTR group was significantly higher than non-LTR group (80.6% vs. 32.0%, P <0.0001). The median tumor shrinkage (range) in the LTR group was also significantly higher than that in the non-LTR group [72.8 (range: 6.8-100)% vs 48.7(range: 3.9-100)% (P=0.0002)]. In contrast, no difference was found in the PD-L1 expression between two groups (P = 0.213). ConclusionLong-lasting response of PD-1 inhibitor was particularly characterized by high tumor shrinkage in patients who had response to PD-1 inhibitors. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureY. Okuma: Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Chugai. Y. Goto: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Chugai; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Shionogi; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Glaxo Smith Kline; Advisory / Consultancy: Guardant Hearlth; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Dai-ichi Sankyo; Research grant / Funding (institution): Kyorin. H. Horinouchi: Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZaneca; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Taiho; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol Myers Squibb; Speaker Bureau / Expert testimony: Kyowa-kirin; Research grant / Funding (institution): Abbvie; Speaker Bureau / Expert testimony: Dai-ichi Sankyo; Research grant / Funding (institution): Kyorin; Research grant / Funding (institution): Genomic Health. N. Yamamoto: Advisory / Consultancy, Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy: Cimic; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Daiichi-Sankyo; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Kyowa-Hakko Kirin; Research grant / Funding (institution): JansenPharma; Research grant / Funding (institution): MSD. Y. Ohe: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): ONO; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristrol-Myers Squibb; Honoraria (self): Boehringer lngelheim; Honoraria (self): Bayer; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self): MSD; Honoraria (self), Research grant / Funding (institution): Taiho; Advisory / Consultancy, Research grant / Funding (institution): Kyorin; Advisory / Consultancy: Celltrion; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Dainippon Sumitomo; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Daiichi-Sankyo. All other authors have declared no conflicts of interest.

    更新日期:2019-12-17
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