Cost-effectiveness of web-based patient-reported outcome surveillance in lung cancer patients J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-15 Thibaut Lizée, Ethan Basch, Pierre Trémolières, Eric Voog, Julien Domont, Guillaume Peyraga, Thierry Urban, Jaafar Bennouna, Anne-Lise Septans, Magali Balavoine, Bruno Detournay, Fabrice Denis
BackgroundA multicenter randomized clinical trial in France found an overall survival benefit of web-based patient-reported outcome (PRO)-based surveillance following initial treatment for lung cancer compared with conventional surveillance. The aim of this study was to assess the cost-effectiveness of this PRO-based surveillance in lung cancer patients.MethodsThis medico-economic analysis employed data from the clinical trial, augmented by abstracted chart data and costs of consultations, imaging, transportations, information technology, and treatments. Costs were calculated based on actual reimbursement rates in France, and health utilities were estimated based on scientific literature review. Willingness-to-pay thresholds of €30 000 per quality-adjusted life year (QALY) and €90 000/QALY were used to define a very cost-effective and cost-effective strategy, respectively. Average annual costs of experimental and control surveillance approaches were calculated. The incremental cost-effectiveness ratio (ICER) was expressed as cost per life-year gained (LYG) and QALY gained, from the health insurance payer perspective. One-way and multivariate probabilistic sensitivity analyses were performed.ResultsAverage annual cost of surveillance follow-up was €362 lower per patient in the PRO arm (€941/year/patient) compared to control (€1 304/year/patient). The PRO approach presented an ICER of €12 127 per LYG and €20 912 per QALY gained. The probabilities that the experimental strategy is very cost-effective and cost-effective were 97% and 100%, respectively.ConclusionSurveillance of lung cancer patients using web-based PRO reduced the follow-up costs. Compared to conventional monitoring, this surveillance modality represents a cost-effective strategy and should be considered in cancer care delivery.
Chk1 inhibition enhances cisplatin cytotoxicity and overcomes cisplatin resistance in small cell lung cancer by promoting mitotic cell death J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-14 Wei-Hsun Hsu, Xiaoliang Zhao, Jianquan Zhu, In-Kyu Kim, Guanhua Rao, Justine McCutcheon, Shuo-Tse Hsu, Beverly Teicher, Bhaskar Kallakury, Afshin Dowlati, Yu-Wen Zhang, Giuseppe Giaccone
Introduction Platinum-based chemotherapy remains the standard treatment for patients with small cell lung cancer (SCLC), but the benefit of the treatment is often hampered by rapid development of drug resistance. Thus far, there is no targeted therapy available for SCLC. Over 90% of SCLC tumors harbor mutations in the tumor suppressor gene p53, an important DNA damage checkpoint regulator, and these tumor cells rely predominantly on the checkpoint kinases to control DNA damage response. Methods We examined whether and how inhibition of checkpoint kinase 1 (Chk1) affects cisplatin cytotoxicity in SCLC cells with and without p53 mutations, and evaluated the effect of Chk1 inhibitor and cisplatin combination in cisplatin-sensitive and –resistant preclinical models. Results Inhibition of Chk1 synergized with cisplatin to induce mitotic cell death in the p53-deficeint SCLC cells. The effect was regulated in part through activation of caspase-2 and downregulation of E2F1. Furthermore, Chk1 inhibitors prexasertib and AZD7762 enhanced cisplatin antitumor activity and overcame cisplatin resistance in SCLC preclinical models in vitro an in vivo. We also observed that higher expression of Chk1 was associated with poorer overall survival of patients with SCLC. Conclusion Our data account Chk1 as a potential therapeutic target in SCLC, and rationalize clinical development of CHK1 inhibitor and cisplatin combinational strategy for the treatment of SCLC.
Outcomes of Long-term Interval Rescreening with Low-Dose CT for Lung Cancer in Different Risk Cohorts J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-13 Reenika Aggarwal, Andrew CL. Lam, Maureen McGregor, Ravi Menezes, Katrina Hueniken, Hannah Tateishi, Grainne M. O’Kane, Ming Sound Tsao, Frances A. Shepherd, Wei Xu, Micheal McInnis, Heidi Schmidt, Geoffrey Liu, John Kavanagh
Hypothesis We hypothesize that the incidence of screen-detected lung cancer (LC), in participants with previously negative scans, will be highest in the cohort with the highest baseline risk score. Methods Individuals with negative baseline screening results from the Princess Margaret International Early Lung Cancer Action Program prior to 2009 underwent low-dose CT rescreening from 2015 to 2018. Individuals were contacted in order of descending risk, as determined by the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial's PLCOM2012 6-year LC risk-prediction model, and then categorized into three risk cohorts according to their baseline risks. The incidence of LC in each risk cohort was determined and compared. Chi-square testing was used for categorical variables and one-way ANOVA on ranks was used for continuous variables. Results Of the 1261 participants we attempted to recontact, 359 participants returned for a rescreening scan (mean of 7.6 years between scans). Participants were divided into low (<2%), moderate (≥2%–<3.5%), and high baseline risk (≥3.5%) cohorts. On average, those in the high-risk cohort compared to the moderate and low-risk cohorts were older (66 vs 62 and 59 years) and had a greater smoking history (54 vs 47 and 29 pack-years). The incidence of cancer in the high-risk cohort was significantly higher than in the moderate-risk cohort (11% vs 1.7%, p=0.002). Conclusions There was a significantly higher incidence of LC in the high-risk cohort than in the moderate-risk cohort. The cut-point between the high and moderate-risk was determined to be ≥3.5% 6-year baseline risk.
The Combination of MEK inhibitor with Immunomodulatory Antibodies Targeting PD-1 and PD-L1 Results in Prolonged Survival in Kras/p53-Driven Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-13 Jong Woo Lee, Yu Zhang, Kyung Jin Eoh, Roshan Sharma, Miguel F. Sanmamed, Jenny Wu, Justin Choi, Hee Sun Park, Akiko Iwasaki, Edward Kaftan, Lieping Chen, Vali Papadimitrakopoulou, Roy S. Herbst, Ja Seok Koo
Purpose To characterize the tumor-infiltrating immune cells population in Kras/p53-driven lung tumors and to evaluate the combinatorial anti-tumor effect with MEK inhibitor (MEKi), trametinib, and immunomodulatory monoclonal antibodies (mAbs) targeting either programmed cell death protein-1 (PD-1) or programmed cell death protein ligand 1 (PD-L1) in vivo. Experimental Design Trp53FloxFlox;KrasG12D/+;Rosa26LSL-Luciferase/LSL-Luciferase (PKL) genetically engineered mice were utilized to develop autochthonous lung tumors with intratracheal delivery of adenoviral Cre recombinase. Using these tumor-bearing lungs, tumor-infiltrating immune cells were characterized by both mass cytometry and flow cytometry. PKL-mediated immunocompetent syngeneic and transgenic lung cancer mouse models were treated with MEKi alone as well as in combination with either anti-PD-1 or anti-PD-L1 mAbs. Tumor growth and survival outcome were assessed. Finally, immune cell populations within spleens and tumors were evaluated by flow cytometry and immunohistochemistry. Results Myeloid-derived suppressor cells (MDSCs) were significantly augmented in PKL-driven lung tumors compared to normal lungs of tumor-free mice. PD-L1 expression appeared to be highly positive in both lung tumor cells and, particularly MDSCs. The combinatory administration of MEKi with either anti-PD1 or anti-PD-L1 mAbs synergistically increased anti-tumor response and survival outcome compared with single-agent therapy in both the PKL-mediated syngeneic and transgenic lung cancer models. Theses combinational treatments resulted in significant increases of tumor-infiltrating CD8+ and CD4+ T cells, whereas attenuation of CD11b+/Gr-1high MDSCs, in particular, Ly6Ghigh polymorphonuclear-MDSCs in the syngeneic model. Conclusion These findings suggest a potential therapeutic approach for untargetable Kras/p53-driven lung cancers with synergy between targeted therapy using MEKi and immunotherapies.
Characterization, prognosis, and treatment of patients with metastatic lung carcinoid tumors J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-13 Patrick Robelin, Julien Hadoux, Julien Forestier, David Planchard, Valérie Hervieu, Amandine Berdelou, Jean-Yves Scoazec, Pierre-Jean Valette, Sophie Leboulleux, Michel Ducreux, Catherine Lombard-Bohas, Eric Baudin, Thomas Walter
Introduction Metastatic lung carcinoids (MLC) remain poorly characterized and no prognostic stratification exists. Methods We conducted a retrospective study including patients with MLC in two European expert centers. The aims were to characterize these, identify prognostic factors of survival, and effectiveness of their treatments. Results A total of 162 patients with MLC were included: 50% were women, and median age was 61 years. Half of patients had synchronous metastases, mainly located in the liver (75%), bone (42%), and lung (25%). According to WHO classification, MLC were typical (28%), atypical (60%), or unspecified (12%). A functioning syndrome was observed in 43% of cases and an uptake at somatostatin receptor scintigraphy (SRS) in 76% of cases. The 5-year overall survival was 60% and at 10 years this was 25%. In multivariate analysis, ECOG performance status (PS) 0-1 (HR=5.81, 95%CI[2.10;16.11]), uptake on SRS (HR=0.38, 95%CI[0.22;0.66]), low serum chromogranin A (CgA; HR=2.27, 95%CI[1.36;3.81]) and typical carcinoid (HR=1.87, 95%CI[1.26;2.78]) were associated with better survival. According to RECIST 1.0, the highest objective response rates were obtained after radiofrequency ablation of metastases (86%), liver embolization (56%), peptide receptor radionuclide therapy (PRRT; 27%), and oxaliplatin-based chemotherapy (18%). Conclusions MLC are characterized by a high frequency of atypical carcinoids, functioning syndrome, and liver/bone metastases. WHO classification, PS, SRS, and CgA were associated with longer survival. Partial response was more frequent with locoregional therapies, PRRT or oxaliplatin-based chemotherapy.
Impaired Cytolytic Activity and Loss of Clonal Neoantigens in Elderly Patients with Lung Adenocarcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-12 Zhihua Gong, Qingzhu Jia, Junying Chen, Xinwei Diao, Jianbao Gao, Xinxin Wang, Bo Zhu
IntroductionWhether the efficacy of PD-1/PD-L1 inhibitors declines with senescence remains controversial for lung adenocarcinoma (LUAD). Responsiveness to anti-PD-1/PD-L1 therapy is thought to rely on neoantigen exposure and immune elements in the tumor microenvironment. In this study, we explored the features of the tumor immune microenvironment in elderly patients with treatment-naïve LUAD.MethodsTranscriptome profiles and clinical characteristics of patients with LUAD were retrieved from TCGA as a discovery cohort. Immune cell infiltration (quantified by a single-sample gene set enrichment analysis), immunoregulatory molecule expression, and mutational patterns (from TCIA) were compared between young and elderly patients. Immune cell infiltration was verified by immunohistochemistry using a validation cohort including 105 treatment-naïve patients with LUAD. A tissue microarray consists of 120 LUAD patients were used in IHC validation.ResultsActivated CD8+ T-cell numbers increased slightly with age, but cytolytic molecules in T-cells (GZMB, PRF1, GZMA, GZMM, and GNLY) gradually declined. PD-L1 expression was not associated with age; however, a number of immunosuppressive elements beyond PD-L1 were up regulated in aging patients, including regulatory T-cells and co-inhibitory molecules, e.g., TIM-3, TIGIT, and HHLA2. Finally, senescence was accompanied by a loss of clonal neoantigens, which is believed to be correlated with responsiveness to immune checkpoint inhibitors.ConclusionsElderly patients were characterized by increased numbers of CD8+ T-cells and impaired cytolytic molecule expression. The observed immune signature was also associated with a loss of clonal neoantigens and the accumulation of immunosuppressive elements. These findings demonstrate a unique immune microenvironment in senescence and support biomarker-guided candidate identification for anti-PD-1/PD-L1 therapeutic strategies for elderly patients with LUAD.
2017-2018 Scientific Advances in Thoracic Oncology: Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-11 Stefan Zimmerman, Arundhati Das, Shuhang Wang, Ricklie Julian, Leena Gandhi, Juergen Wolf
Small cell lung cancer remains an aggressive, deadly cancer with only modest effect on survival from standard chemotherapy. However, with the advent of immunotherapy and comprehensive genomic and transcriptomic profiling, multiple new targets are showing promise in the clinical arena, and just recently PD-L1 inhibition has been shown to improve the efficacy of standard chemotherapy in extended disease SCLC. Our increasing understanding of the interactions between different pathways will enable more tailored immuno- as well as targeted therapies based on specific biomarkers and rational combinations. Here we discuss the pre-clinical and clinical strides of 2017 and 2018 that put us on the threshold of a new era in therapeutics that will hopefully translate into significant improvements in survival.
Osimertinib plus durvalumab versus osimertinib monotherapy in EGFR T790M-positive NSCLC following previous EGFR-TKI therapy: CAURAL brief report J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-11 James Chih-Hsin Yang, Frances A. Shepherd, Dong-Wan Kim, Gyeong-Won Lee, Jong Seok Lee, Gee-Chen Chang, Sung Sook Lee, Yu-Feng Wei, Yun Gyoo Lee, Gianluca Laus, Barbara Collins, Francesca Pisetzky, Leora Horn
IntroductionOsimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Durvalumab is an anti-PD-L1 monoclonal antibody. The Phase III open-label CAURAL trial (NCT02454933) investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and T790M mutation-positive advanced non-small cell lung cancer (NSCLC) and disease progression following EGFR-TKI therapy.MethodsPatients were randomly assigned 1:1 to receive oral osimertinib (80 mg once daily) with/without durvalumab (10 mg/kg intravenously every two weeks), until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by investigator). The amended primary objective was to assess safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.ResultsCAURAL recruitment terminated early due to increased interstitial lung disease (ILD)-like events incidence in the osimertinib plus durvalumab arm from the separate Phase Ib TATTON trial (NCT02143466). At CAURAL recruitment termination, 15 patients had been randomly assigned to osimertinib and 14 to osimertinib plus durvalumab. Most common AEs (% [Grade ≥3]): diarrhea (53% [6%]) in the osimertinib arm; rash (67% ) in the combination arm. One patient randomized to the combination arm reported Grade 2 ILD while receiving osimertinib monotherapy (after discontinuing durvalumab following one dose). Objective response rates: 80% in the osimertinib arm; 64% in the combination arm.ConclusionLimited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of PD-1/PD-L1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but requires a careful approach if considered in the future.
Brief report: efficacy of immune checkpoint inhibitors in KRAS-mutant Non-small cell lung cancer (NSCLC) J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-06 Arnaud Jeanson, Pascale Tomasini, Maxime Souquet-Bressand, Nicolas Brandone, Mohamed Boucekine, Mathieu Grangeon, Solène Chaleat, Natalyia Khobta, Julie Milia, Laurent Mhanna, Laurent Greillier, Julie Biemar, Isabelle Nanni, L’houcine Ouafik, Stéphane Garcia, Julien Mazières, Fabrice Barlesi, Céline Mascaux
Introduction KRAS mutation (KRASm) is the most frequent molecular alteration found in advanced non-small cell lung cancer (NSCLC), is associated with a poor prognosis, without available targeted therapy. Treatment options for NSCLC have been recently enriched by the development of immune checkpoint inhibitors (ICI), and data about its efficacy in patients with KRASm NSCLC are discordant. This study assessed the routine efficacy of ICI in advanced KRASm NSCLC. Methods In this retrospective study, clinical data were extracted from the medical records of patients with advanced NSCLC treated with ICI and with available molecular analysis between April 2013 and June 2017. Analysis of PD-L1 expression was performed if exploitable tumor material was available. Results A total of 282 ICI-treated (in first line or more) advanced NSCLC (all histological subgroups) patients who were treated with ICI (anti-PD-1, anti PD-L1 or anti-CTLA-4 antibodies), including 162 (57.4%) with KRAS mutation, 27 (9.6%) with other mutations and 93 (33%) with a wild-type phenotype, were identified. PD-L1 analysis was available for 128 patients (45.4%), of whom 45.3% and 19.5% had PD-L1 expression ≥ 1% and 50%, respectively (49.5% and 21.2% respectively concerning 85 KRASm NSCLC patients). No significant difference was seen in terms of objective response rates (ORR), progression free survival (PFS) and overall survival (OS) between KRASm NSCLC and other NSCLC. No significant differences in OS or PFS were observed between the major KRAS mutation subtypes (G12A, G12C, G12D, G12V, and G13C). In KRASm NSCLC, unlike in non-KRASm NSCLC, the efficacy of ICI is consistently higher, eventhough not statistically significant, for patients with PD-L1 expression in ≥ 1% of tumor cells than for those with PD-L1 expression in < 1% of tumor cells, and this finding is especially true when PD-L1 expression is high (PD-L1 expression ≥ 50%). Discussion For patients with KRASm NSCLC (all mutational subtypes), the efficacy of ICI is similar to that of patients with other types of NSCLC. PD-L1 expression seems to be more relevant for predicting the efficacy of ICI in KRASm NSCLC than it is in other types of NSCLC.
Characteristics and outcomes of patients with metastatic KRAS mutant lung adenocarcinomas: The Lung Cancer Mutation Consortium experience J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-05 Badi El Osta, Madhusmita Behera, Sungjin Kim, Lynne D. Berry, Gabriel Sica, Rathi N. Pillai, Taofeek K. Owonikoko, Mark G. Kris, Bruce E. Johnson, David J. Kwiatkowski, Lynette M. Sholl, Dara L. Aisner, Paul A. Bunn, Fadlo R. Khuri, Suresh S. Ramalingam
Background Mutations in the KRAS gene are the most common driver oncogenes present in lung adenocarcinomas. We analyzed the largest multi-institutional database available containing patients with metastatic KRAS mutant lung adenocarcinomas. Methods The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional collaboration to study the genomic characteristics of lung adenocarcinomas, treat them with genomically directed therapeutic approaches, and assess their outcomes. Since its inception in 2009, the LCMC has enrolled over 1900 patients and has performed pretreatment, multiplexed, molecular characterization along with collecting clinical data. We evaluated the characteristics of patients with KRAS mutation in the LCMC and the association with overall survival (OS). Results Data from 1655 patients with metastatic lung adenocarcinomas were analyzed. 450 (27%) patients had a KRAS mutation, 58% female, 93% smokers, and median age of 65 years. Main KRAS subtypes were: G12C 39%; G12D and G12V at 18% each. Among patients with KRAS mutation, G12D had a higher proportion of never smokers (22%, P<0.001). Patients with KRAS mutant tumors had a trend toward shorter median survival compared to all others in the series (1.96 vs. 2.22; P=0.08) and lower 2-year survival rate (49% (95% CI: 44-54%) and 55% (95% CI: 52-58%), respectively. Conclusions In the LCMC study, 27% of lung adenocarcinomas patients harbored a KRAS mutation and up to third of them had another oncogenic driver. Patients with both KRAS and STK11 mutations had a significantly inferior clinical outcome.
Surgical resection of small cell lung carcinoma: prognostic factors and the tumor microenvironment J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-05 Xiaoliang Zhao, Bhaskar Kallakury, Joeffrey J. Chahine, Dan Hartmann, YuWen Zhang, Yulong Chen, Hua Zhang, Bin Zhang, Changli Wang, Giuseppe Giaccone
Background Surgery in small cell lung cancer (SCLC) is limited to very early stages, but several reports suggest a potential broader role. Little is known of the influence of microenvironment on the biology of SCLC. Methods We assessed the clinical prognostic factors in a large series of resected SCLC patients. The prognostic value of Programmed cell Death Ligand-1 (PD-L1) expression in tumor cells and tumor infiltrating lymphocytes (TILs), and the percentage of CD3, CD20, CD45 and CD68 positive cells, were also investigated. Results 205 SCLC cases were resected between 2005 and 2015 and the median follow-up was 29 months (range: 2-135 months). Median survival of all patients was 69 months, and 5-year survival rates were 63.8%, 65.5%, 34.9%, and 0% for pathological stages I, II, III, and IV, respectively. By multivariate analysis complete resection, cigarette index (CI), lymph node metastatic rate (LNR), percentage of CD3 positive cells and PD-L1 expression in tumor cells and TILs were independent prognostic factors. High PD-L1 expression was present in 3.2% and 33.5% of all tumor samples in tumor cells and TILs, respectively. High PD-L1 expression in tumor cells or TILs correlated with shorter survival, whereas high expression of CD3, CD20 and CD45 correlated with better survival. Conclusions Resected stage II SCLC patients have similar survival as stage I, suggesting that surgery could be extended to patients with hilar lymph node involvement. Survival was better in tumors with a higher percentage of T cells and B cells, whereas PD-L1 expression in tumor cells and TILs correlated with worse survival, which suggests a potential role of immunotherapy in resected SCLC.
Proposal for a combined histo-molecular algorithm to distinguish multiple primary adenocarcinomas from intrapulmonary metastasis in patients with multiple lung tumors J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-02 Audrey Mansuet-Lupo, Marc Barritault, Marco Alifano, Aurélie Janet-Vendroux, Makmoud Zarmaev, Jérôme Biton, Yoan Velut, Christine Le Hay, Isabelle Cremer, Jean-François Régnard, Ludovic Fournel, Bastien Rance, Marie Wislez, Pierre Laurent-Puig, Ronald Herbst, Diane Damotte, Hélène Blons
Introduction Multiple nodules in lung are diagnosed with an increasing frequency due to high quality CT-scan imaging. In patients suffering from lung cancer, this situation represents up to 10% of operated patients. For clinical management, it is important to classify the disease as intra-pulmonary metastasis or multiple primary lung carcinomas to define TNM classification and optimize therapeutic options. In the present study, we evaluated the respective and combined input of histological and molecular classification in order to propose a classification algorithm for multiple nodules. Methods we studied consecutive patients undergoing surgery with curative intent for lung adenocarcinoma (n=120) and harboring two tumors (n=240). Histological diagnosis according to the WHO 2015 classification and molecular profiling using a 22 hotspot genes targeted NGS allowed classifying samples as multiple primary lung adenocarcinomas (MPLA) or as intra-pulmonary metastasis (IPM). Results NGS identified molecular mutations in 91% (n=109/120) of tumor pairs. Genomic and histologic classification showed a fair agreement using kappa test (K = 0.43). Discordant cases (n=30/109, 27%) were reclassified using a combined histo-molecular algorithm. EGFR mutations (p=0.03) as well as node involvement (p=0.03) were significantly associated to IPM, whereas KRAS mutations (p=0.00005) were significantly associated to MPLA. EGFR mutations (p=0.02) and node involvement (p=0.004) were the only independent prognostic factors. Conclusion We showed that combined histo-molecular algorithm represents a relevant tool to classify multifocal lung cancers, which could guide adjuvant treatment decisions. Survival analysis underlines the good prognosis of EGFR mutated adenocarcinoma in patients with intra-pulmonary metastases.
Survival after SBRT for Clinically diagnosed or Biopsy-proven Early-stage Non-small Cell Lung Cancer: A Systematic Review and Meta-Analysis J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-02-02 Michiel A. IJsseldijk, Melina Shoni, Charles Siegert, Bastiaan M. Wiering, PhD. MD, K.C. Anton van Engelenburg, Abraham Lebenthal, Richard PG. ten Broek
Introduction SBRT is a promising curative treatment for early-stage NSCLC. IT is unclear if survival outcomes for SBRT are influenced by a lack of pathological confirmation of malignancy and staging of disease in these patients. In this systematic review and meta-analysis we assess survival outcomes after SBRT in studies with patients with clinically diagnosed vs biopsy-proven early-stage NSCLC. Methods The main databases were searched for trials and cohort studies without restrictions to publication status or language. Two independent researchers performed the screening and selection of eligible studies. Outcomes were overall survival, cancer-specific survival and disease-free survival. The inverse variance method and the random effects method for meta-analysis were utilized to assess pooled survival estimates. Results A total of 11195 non-duplicate records were identified by the original search strategy. After screening by title and abstract, 1051 potentially eligible records were identified. A total of 43 articles were included. The comparative studies showed lower 3-y overall survival and lower 2-y and 5-y cancer specific survival for biopsy-proven disease compared to clinical disease. However, 5-y OS was the same for both groups. For the pooled estimates, 3-y disease-free survival and 2-y cancer-specific survival were lower for biopsied disease. Conclusions Results of this systematic review and meta-analysis show a discrepancy in oncological outcomes for patients undergoing SBRT for suspected early-stage NSCLC in whom there is pathological conformation of malignancy and those who there is only a clinical diagnose of NSCLC. These results emphasize the importance of obtaining pathological proof of malignancy.
Health-Related Quality of Life in KEYNOTE-010: a Phase 2/3 Study of Pembrolizumab Versus Docetaxel in Patients With Previously Treated Advanced, PD-L1–Expressing NSCLC J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-31 F. Barlesi, E.B. Garon, D.-W. Kim, E. Felip, J.-Y. Han, J.-H. Kim, M.-J. Ahn, M.J. Fidler, M.A. Gubens, G. de Castro, V. Surmont, Q. Li, A.C. Deitz, G.M. Lubiniecki, R.S. Herbst
Background In the phase 2/3 KEYNOTE-010 study (ClinicalTrials.gov, NCT01905657), pembrolizumab significantly prolonged overall survival over docetaxel in patients with previously treated, programmed death 1 ligand 1 (PD-L1)–expressing (tumor proportion score [TPS] ≥1%), advanced non–small-cell lung cancer (NSCLC). Health-related quality of life (HRQoL) results are reported here. Methods Patients were randomized 1:1:1 to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel 75 mg/m2 Q3W. HRQoL was assessed using EORTC QLQ-C30, QLQ-LC13, and EuroQoL-5D. Key analyses included mean baseline-to-week-12 change in global health status (GHS)/quality of life (QoL) score, functioning and symptom domains, and time to deterioration (TTD) in a QLQ-LC13 composite endpoint of cough, dyspnea, and chest pain. Results Baseline compliance across all three instruments was high (≥90%) and was ≥85% at week 12, the key analysis time point. Pembrolizumab was associated with better QLQ-C30 GHS/QoL scores from baseline to 12 weeks than docetaxel, regardless of pembrolizumab dose or TPS status (not significant). Compared with docetaxel, fewer pembrolizumab-treated patients had “deteriorated” status and more had “improved” status in GHS/QoL. Nominally significant improvement was reported in many EORTC symptom domains with pembrolizumab, and nominally significant worsening was reported with docetaxel. Significant prolongation in true TTD for the QLQ-LC13 composite endpoint emerged for pembrolizumab 10 mg/kg compared to docetaxel (nominal two-sided P=0.03), but not for the 2 mg/kg dose. Conclusion These findings suggest that HRQoL and symptoms are maintained or improved to a greater degree with pembrolizumab than with docetaxel in this NSCLC patient population.
Survival with Parenchymal and Pleural Invasion of Non-small-cell Lung Cancers less than 30 mm J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-24 Rowena Yip, Teng Ma, Raja M. Flores, David Yankelevitz, Claudia I. Henschke,
Purpose To determine long-term survival of visceral pleural invasion (VPI) and parenchymal (PAI: angiolymphatic, vascular) invasion on survival of non-small-cell-lung-cancers (NSCLCs), less than 30 mm in maximum diameter. Methods Kaplan-Meier survival for NSCLCs, with and without VPI and/or PAI were determined for a prospective cohort of screening participants, stratified by pathologic tumor size (≤10mm, 11-20mm, and 21-30mm) and nodule consistency. Log-rank test statistics were calculated. Results Frequency of PAI or VPI was significantly lower in subsolid than solid nodules (4.9% vs. 27.7%, p<0.0001) and correspondingly, K-M-lung-cancer-survival significantly higher (99.1% vs. 91.3%, p=0.0009). Multivariable Cox regression found that only tumor diameter (adjusted HR=1.07, 95% CI:1.01-1.14, p=0.02) and PAI (adjusted HR=3.15, 95% CI:1.25-7.90, p=0.01) remained significant, while VPI was not significant (p=0.15). When clinical and CT findings were included with the pathologic findings, Cox regression showed that the risk of dying of lung cancer increased ten-fold (HR=10.06, 95% CI:1.35-75.30) for NSCLCs in solid nodules, moderate to severe emphysema 2.27 times (HR=2.27, 95% CI:1.01-5.11), and tumor diameter (HR=1.06, 95% CI:1.01-1.13) while PAI was no longer significant (p=0.19). Conclusions Nodule consistency on CT was a more significant prognostic indicator than either PAI or VPI. We propose that for patients with NSCLC with VPI whose maximum tumor diameter of 30mm or less, not be upstaged to T2 without further large, multi-center studies of NSCLCs, stratified by the new T status, and that classification be considered separately for patients with subsolid or solid nodules.
Phase II Study of Roniciclib in Combination with Cisplatin/Etoposide or Carboplatin/Etoposide as First-Line Therapy in Patients with Extensive-Disease Small-Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-21 Martin Reck, Leora Horn, Silvia Novello, Fabrice Barlesi, István Albert, Erzsebet Juhasz, Dariusz Kowalski, Gilles Robinet, Jacques Cadranel, Paolo Bidoli, John Chung, Arno Fritsch, Uta Drews, Andrea Wagner, Ramaswamy Govindan
Introduction This Phase II study evaluated the efficacy and safety of the pan-cyclin-dependent kinase inhibitor roniciclib with platinum-based chemotherapy in patients with extensive-disease small-cell lung cancer. Methods In this randomized, double-blind study, unselected patients with previously untreated ED-SCLC received roniciclib 5 mg or placebo twice daily in a 3 days on/4 day off schedule in 21-day cycles, with concomitant cisplatin or carboplatin on day 1, and etoposide on days 1–3. The primary endpoint was progression-free survival. Other endpoints included overall survival (OS), objective response rate (ORR), and safety. Results 140 patients received treatment: 70 with roniciclib + chemo and 70 with placebo + chemo. Median PFS was 4.9 months (95% confidence interval [CI]: 4.2–5.5) with roniciclib + chemo and 5.5 months (95% CI: 4.6–5.6) with placebo + chemo (hazard ratio [HR] = 1.242; 95% CI: 0.820–1.881; p = 0.8653). Median OS was 9.7 months (95% CI: 7.9–11.1) with roniciclib + chemo and 10.3 months (95% CI: 8.7–11.9) with placebo + chemo (HR = 1.281; 95% CI: 0.776–1.912; p = 0.7858). The objective response rate was 60.6% with roniciclib + chemo and 74.6% with placebo + chemo. Common treatment-emergent adverse events (TEAEs) in both groups included nausea, vomiting, and fatigue. Serious TEAEs were more common with roniciclib + chemo (57.1%) than placebo + chemo (38.6%). Conclusions Roniciclib combined with chemotherapy demonstrated an unfavorable risk–benefit profile in patients with ED-SCLC and the study was prematurely terminated.
Molecular Analysis of Plasma from Patients with ROS1-Positive Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-18 Ibiayi Dagogo-Jack, Marguerite Rooney, Rebecca J. Nagy, Jessica J. Lin, Emily Chin, Lorin A. Ferris, Jennifer Ackil, Jochen K. Lennerz, Richard B. Lanman, Justin F. Gainor, Alice T. Shaw
Background Circulating tumor DNA analysis is an emerging genotyping strategy that can identify tumor-specific genetic alterations in plasma including mutations and rearrangements. Detection of ROS1 fusions in plasma requires genotyping approaches that cover multiple breakpoints and target a variety of fusion partners. Compared to other molecular subsets of non-small cell lung cancer (NSCLC), experience with detecting ROS1 genetic alterations in plasma is limited. Patients and Methods To describe the spectrum of ROS1 fusions in NSCLC and determine sensitivity for detecting ROS1 fusions in plasma, we queried the Guardant Health plasma dataset and an institutional tissue database and compared plasma findings to tissue results. In addition, we used the Guardant360 NGS assay to detect potential genetic mediators of resistance in plasma from patients with ROS1-positive NSCLC who were relapsing on crizotinib. Results We detected seven distinct fusion partners in plasma, most of which (n=6/7) were also represented in the tissue dataset. Fusions pairing CD74 with ROS1 predominated in both cohorts (plasma: n=35/56, 63%; tissue: n=26/52, 50%). There was 100% concordance between the specific tissue- and plasma-detected ROS1 fusion for seven patients genotyped with both methods. Sensitivity for detecting ROS1 fusions in plasma at relapse on ROS1-directed therapy was 50%. Six (33%) of 18 post-crizotinib plasma specimens harbored ROS1 kinase domain mutations, five of which were ROS1 G2032R. Two (11%) post-crizotinib plasma specimens had genetic alterations (n=1 each BRAF V600E and PIK3CA E545K) potentially associated with ROS1-independent signaling. Conclusions Plasma genotyping captures the spectrum of ROS1 fusions observed in tissue. Plasma genotyping is a promising approach to detecting mutations that drive resistance to ROS1-directed therapies.
The relationship between air pollution and lung cancer in non-smokers in Taiwan J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-18 Chien-Hua Tseng, Ben-Jei Tsuang, Chun-Ju Chiang, Kai-Chen Ku, Jeng-Sen Tseng, Tsung-Ying Yang, Kuo-Hsuan Hsu, Kun-Chieh Chen, Sung-Liang Yu, Wen-Chung Lee, Tsang-Wu Liu, Chang-Chuan Chan, Gee-Chen Chang
Introduction For never-smokers (smoked <100 lifetime cigarettes), lung cancer (LC) has emerged as an important issue. We aimed to investigate the effects of prevalence changes in tobacco smoking and particulate matter (PM) 2.5 (PM2.5) levels on LC in Taiwan, in relation to contrasting PM2.5 levels, between northern Taiwan (NT) and southern Taiwan (ST). Methods We reviewed 371,084 patients with LC to assess smoking prevalence and correlations between the incidence of adenocarcinoma lung cancer (AdLC) and non-AdLC. Two subsets were selected to assess different AdLC stage trends and the effect of PM2.5 on survival of patients with AdLC. Results From 1995 to 2015, the proportion of male adult ever smokers decreased from 59.4% to 29.9% while the female smoking rate remained low (3.2%–5.3%). AdLC incidence in males and females increased from 9.06 to 23.25 and 7.05 to 24.22 per 100,000 population, respectively. Since 1993, atmospheric visibility in NT improved (from 7.6 to 11.5 km), but deteriorated in ST (from 16.3 to 4.2 km). In 2007, the annual percent change in AdLC stages IB to IV was 0.3% (95% confidence interval [CI], 1.9%–2.6%) in NT, and 4.6% (3.3%–5.8%) in ST; 53% patients with LC had never smoked. Five-year survival rates for never-smokers, those with EGFR wild-type genes, and female patients with AdLC were 12.6% in NT and 4.5% in ST (hazard ratio 0.79, 95% CI; 0.70–0.90). Conclusions In Taiwan, >50% patients with LC had never smoked. PM2.5 level changes can affect AdLC incidence and patient survival.
A Randomized Non-Comparative Phase 2 Study of Anti-Programmed Cell Death-Ligand 1 Atezolizumab or Chemotherapy as Second-Line Therapy in Patients with Small Cell Lung Cancer: Results from the IFCT-1603 Trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-18 Jean-Louis Pujol, Laurent Greillier, Clarisse Audigier-Valette, Denis Moro-Sibilot, Lionel Uwer, José Hureaux, Florian Guisier, Delphine Carmier, Jeannick Madelaine, Josiane Otto, Valérie Gounant, Patrick Merle, Pierre Mourlanette, Olivier Molinier, Aldo Renault, Audrey Rabeau, Martine Antoine, Marc G. Denis, Pierre-Jean Souquet
Introduction This randomized phase 2 trial aimed at evaluating the engineered programmed cell death-ligand 1 (PD-L1) antibody atezolizumab in small cell lung cancer progressing after first-line platinum–etoposide chemotherapy. Methods Patients were randomized 2:1 to atezolizumab (1200mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to six cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O’Brien-Fleming stopping rules was employed. The null hypothesis was rejected if > 12/45 patients were responders. Results Overall, 73 patients were randomized (atezolizumab n = 49; chemotherapy n = 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% CI 0.0; 6.8), while 8 others had stable disease (20.9% disease control rate; CI 8.8 ; 33.1). Among eligible chemotherapy patients (n=20), 10% achieved an objective response (65% disease control rate). Median pProgression-free survival was 1.4 months (CI 1.2; 1.5) with atezolizumab and 4.3 months (CI: 1.5; 5.9) with chemotherapy. Overall survival did not significantly differ between groups: median OS: 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively; (adjusted HRatezolizumab = 0.84 CI: 0.45 ;1.58) ; p=0.60. Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone). Conclusions Atezolizumab monotherapy in relapsed small cell lung cancer failed to demonstrate significant efficacy. No unexpected safety concerns were observed.
Expediting Comprehensive Molecular Analysis to Optimize Initial Treatment of Lung Cancer Patients with Minimal Smoking History J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-18 Ibiayi Dagogo-Jack, Hayley Robinson, Mari Mino-Kenudson, Anna F. Farago, Vashine Kamesan, A John Iafrate, Alice T. Shaw, Jochen K. Lennerz
Purpose Lung cancer patients with tumors harboring actionable alterations can achieve very durable responses to first-line targeted therapy. However, identifying targetable alterations using next-generation sequencing (NGS) is a complex and time-intensive process. As actionable genetic alterations are enriched in lung cancers arising in patients with limited smoking history, we designed a workflow to expedite NGS testing for this group. Patients and Methods We developed a protocol to allow for next-day extraction of nucleic acids from frozen tissue. Specimens were designated as high priority during sequencing. We determined the interval between biopsy and NGS results to evaluate whether the workflow reduced the pre-analytical period and in-laboratory turnaround time and allowed for rapid initiation of genotype-matched therapy. Results Between 1/2017 and 5/2018, twenty-one patients participated in the expedited sequencing program. The median interval between biopsy and NGS results was 10.7 days. Six patients received results within one week of biopsy. Performing molecular analysis on frozen tissue and prioritizing sequencing and analysis of these specimens reduced the pre-analytical period from 3.5 to 1.3 days (p<0.0001) and shortened in-laboratory turnaround time by 3 days (11.8 vs 8.4 business days, p<0.0001). Ninety-three percent of patients with an actionable molecular alteration received first-line targeted therapy. The median time-to-initiation of treatment was 19.7 days from biopsy. Conclusion Sequencing and analyzing nucleic acids from frozen tissue is a practical strategy for shortening the time to matched therapy. The significant advantage of upfront treatment with targeted therapies in subsets of lung cancer patients provides rationale for developing workflows that accelerate comprehensive molecular analysis.
Brief Report: Clinical Utility of Cerebrospinal Fluid Cell Free-DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-17 Mei-Mei Zheng, Yang-Si Li, Ben-Yuan Jiang, Hai-Yan Tu, Wen-Fang Tang, Jin-Ji Yang, Xu-Chao Zhang, Jun-Yi Ye, Hong-Hong Yan, Jian Su, Qing Zhou, Wen-Zhao Zhong, Xue-Ning Yang, Wei-Bang Guo, Shannon Chuai, Zhou Zhang, Hua-Jun Chen, Zhen Wang, Yi-Long Wu
Introduction Leptomeningeal metastases (LM) indicated a poor prognosis in non-small cell lung cancer (NSCLC). LM were more frequent in driver gene-mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR mutated LM. However, studies in ALK-rearranged NSCLC patients with LM are scarce. Methods Lung cancer patients with ALK rearrangement were screened from Sept 2011 to Feb 2018 at our institute. CSF and paired plasma were tested by next-generation sequencing (NGS). Results LM were diagnosed in 30 (10.3%) of 291 ALK-rearranged patients with lung cancer. A total of 11 paired CSF and plasma tested by NGS were analyzed. Driver genes were detected in 81.8% (9/11) CSF samples and 45.5% (5/11) plasma respectively (P=0.183). Max allelic fractions were all higher in CSF than in plasma (P=0.009). ALK and TP53 are the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutation were identified in CSF after resistance to Alectinib. Multiple copy number variants were mainly found in CSF, including EGFR, CCND1, FGF3, FGF4, MYC copy number gains and TP53, CDKN2A copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF was able to monitor disease development of LM and longitudinally monitor tumor response. Conclusion Liquid biopsy of CSF is more sensitive than plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in ALK-rearranged NSCLC patients with LM. Thus CSF might be promising as a medium of liquid biopsy in LM.
Lung adenocarcinomas manifesting as radiological part-solid nodules define a special clinical subtype J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-17 Ting Ye, Lin Deng, Shengping Wang, Jiaqing Xiang, Yawei Zhang, Hong Hu, Yihua Sun, Yuan Li, Lei Shen, Li Xie, Wenchao Gu, Yue Zhao, Fangqiu Fu, Weijun Peng, Haiquan Chen
Introduction Clinicopathologic features and prognostic predictors of radiological part-solid lung adenocarcinomas were unclear. Methods We retrospectively compared clinicopathologic features and survivals of part-solid tumors with those of pure ground glass nodules (pGGNs) and pure solid tumors receiving surgery at FUSCC, and evaluated prognostic implications of consolidation-to-tumor ratio (CTR), solid component size and tumor size for part-solid lung adenocarcinomas. Results 911 patients and 988 pulmonary nodules (including 329 part-solid nodules (PSNs), 501 pGGNs & 158 pure solid nodules) were analyzed. More female patients (P=0.015) and non-smokers (P=0.003) were seen in PSNs than those in pure solid nodules. Prevalence of lymphatic metastasis was lower in PSNs than that in pure solid tumors (2.2% vs 27%, P=0.000). 5-year lung cancer specific recurrence free survival (LCS-RFS) and overall survival (OS) of PSNs were worse than those of pGGNs (P<0.001; P=0.042), but better than those of pure solid tumors (P<0.001; P<0.0001), respectively. CTR (OR: 12.90; 95% CI: 1.85-90.04), solid component size (OR: 1.45; 95% CI: 1.28-1.64) and tumor size (OR: 1.23; 95% CI: 1.15-1.31) could predict pathologic invasive adenocarcinoma for PSNs. None of them could predict the prognosis. Patients receiving sublobar resection had comparable prognoses with those receiving lobectomy (5-year LCS-RFS: P=0.178; 5-year LCS-OS: P=0.319). Prognostic differences between patients with systemic lymph node dissection (sLND) and those without sLND were statistically insignificant. Conclusions Part-solid lung adenocarcinoma showed different clinicopathologic features compared with pure solid tumor. CTR, solid component size and tumor size could not predict the prognosis. Part-solid lung adenocarcinomas define one special clinical subtype.
Nivolumab Versus Docetaxel in a Predominantly Chinese Patient Population With Previously Treated Advanced Non-Small Cell Lung Cancer: CheckMate 078 Randomized Phase III Clinical Trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-17 Yi-Long Wu, Shun Lu, Ying Cheng, Caicun Zhou, Jie Wang, Tony Mok, Li Zhang, Hai-Yan Tu, Lin Wu, Jifeng Feng, Yiping Zhang, Alexander Valerievich Luft, Jianying Zhou, Zhiyong Ma, You Lu, Chengping Hu, Yuankai Shi, Christine Baudelet, Jianhua Chang
Introduction Data on immuno-oncology agents in Chinese patients are limited despite a need for new therapies. We evaluated the efficacy and safety of nivolumab in a predominantly Chinese patient population with previously treated non-small cell lung cancer (NSCLC). Methods CheckMate 078 was a randomized, open-label, phase III clinical trial in patients from China, Russia, and Singapore with squamous or non-squamous NSCLC that had progressed during/after platinum-based doublet chemotherapy (ClinicalTrials.gov: NCT02613507). Patients with EGFR/ALK alterations were excluded. Patients (N = 504) were randomized 2:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks), stratified by performance status, tumor histology, and tumor programmed death ligand 1 (PD-L1) expression. The primary end point was overall survival (OS); secondary end points included objective response rate (ORR), progression-free survival, and safety. Results OS was significantly improved with nivolumab (n = 338) versus docetaxel (n = 166); median OS (95% CI): 12.0 (10.4–14.0) versus 9.6 (7.6–11.2) months, respectively; hazard ratio (97.7% CI): 0.68 (0.52–0.90); p = 0.0006. ORR was 17% with nivolumab versus 4% with docetaxel; median duration of response was not reached versus 5.3 months. Minimum follow-up was 8.8 months. The frequency of grade ≥3 treatment-related adverse events was 10% with nivolumab and 48% with docetaxel. Conclusions This is the first phase III study in a predominantly Chinese population reporting results with a PD-1 inhibitor. In this population with previously treated advanced NSCLC, nivolumab improved OS versus docetaxel. Results were consistent with global CheckMate 017 and 057 studies.
FGFR1 cooperates with EGFR in lung cancer oncogenesis, and their combined inhibition shows improved efficacy J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-09 Alvaro Quintanal-Villalonga, Sonia Molina-Pinelo, Cristina Cirauqui, Laura Ojeda-Márquez, Ángela Marrugal, Rocío Suarez, Esther Conde, Santiago Ponce-Aix, Ana Belén Enguita, Amancio Carnero, Irene Ferrer, Luis Paz-Ares
Introduction There is substantial evidence for the oncogenic effects of Fibroblast Growth Factor Receptor (FGFR)1 in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. Methods We performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in an inmortalized lung cell lines, and carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitors sensitivity assays in vitro and in vivo in cell line and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of anti-EGFR therapy-treated adenocarcinoma cohort. Results We report a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We provide in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation, in EGFR-mutated and -wild type models. At the clinical level, we show that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of TKI-treated EGFR-mutated and –wild type lung adenocarcinoma patients. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line- and PDXs, suggesting that patients with tumors bearing these characteristics may benefit from EGFR/FGFR combined inhibition. Conclusion These results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting, in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.
Brief Report: DNA-based versus RNA-based detection of MET exon 14 skipping events in lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-09 Kurtis D. Davies, Aprille Lomboy, Carolyn A. Lawrence, Michael Yourshaw, Gregary T. Bocsi, D. Ross Camidge, Dara L. Aisner
Introduction Genomic variants that lead to MET exon 14 skipping represent a potential targetable molecular abnormality in non-small cell lung cancer (NSCLC). Consequently, reliable molecular diagnostic approaches that detect these variants are vital for patient care. Methods We screened NSCLC patient tumor samples for MET exon 14 skipping via two distinct approaches: a DNA-based next-generation sequencing (NGS) assay that employs an amplicon-mediated target enrichment, and an RNA-based NGS assay that employs anchored multiplex PCR for target enrichment. Results The DNA-based approach detected MET exon 14 skipping variants in 11 of 856 NSCLC samples (1.3%). The RNA-based approach detected MET exon 14 skipping in 17 of 404 samples (4.2%), a statistically significant increase compared to the DNA-based assay. Among 286 samples tested by both assays, RNA-based testing detected 10 positives, 6 of which were not detected by the DNA-based assay. Examination of primer binding sites in the DNA-based assay in comparison with published MET exon 14 skipping variants revealed genomic deletion involving primer binding sequences as the likely cause of false negatives. Two samples positive via the DNA-based approach were uninformative in the RNA-based approach due to poor quality RNA. Conclusions By circumventing an inherent limitation of DNA-based amplicon-mediated testing, RNA-based analysis detected a higher proportion of MET exon 14 skipping cases. However, RNA-based analysis was highly reliant on RNA quality, which can be suboptimal in some clinical samples.
Alcohol Intake Interacts with Functional Genetic Polymorphisms of Aldehyde Dehydrogenases (ALDH2) and Alcohol Dehydrogenase (ADH) to Increase Esophageal Squamous Cell Cancer Risk J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-09 Chen Suo, Yajun Yang, Ziyu Yuan, Tiejun Zhang, Xiaorong Yang, Tao Qing, Pei Gao, Leming Shi, Min Fan, Hongwei Cheng, Ming Lu, Li Jin, Xingdong Chen, Weimin Ye
Objectives Studies have reported alcohol consumption and genetic variants as major contributing factors for esophageal squamous cell carcinoma (ESCC). However, the complicated interactions between alcohol and genetic factors involved in alcohol metabolism have not been well elucidated with respect to augmented risk of ESCC. Design We performed a large population-based case-control study in a Chinese city with high ESCC incidence, by enrolling 1,190 cases and 1,883 controls. We integrated candidate single nucleotide polymorphisms (SNP) data, detailed alcohol consumption records, gene-alcohol interactions and SNP functional information to untangle the complicated relationship between alcohol, variants of genes encoding alcohol metabolism enzymes and ESCC risk. The gene-alcohol interaction was tested by including their product term in a multi-variable logistic regression model. Synergy index and ratio of ORs were calculated to assess interaction on additive and multiplicative scale, respectively. Results We confirmed two ESCC susceptibility loci, rs671 in ALDH2 and rs1042026 in ADH1B, which significantly altered alcohol consumption behavior, and subsequently modified the association between alcohol consumption and ESCC risk. The rs671[A] allele was associated with ESCC risk in alcohol drinkers (adjusted odds ratio [aOR] =1.98, 95% confidence intervals [CI]=1.51-2.60) but not in non-drinkers. Healthy individuals carry different ALDH2 and ADH1B genotypes exhibit diversified drinking behavior, with proportion of drinkers varying between 23.7% to 54.3%. Among individuals with a fast ethanol oxidization rate, we observed a strong interaction between heavy alcohol consumption and ethanal oxidization rate, on the additive scale (synergy index 4.80 [95% CI: 1.82-12.68]) and multiplicative scale (ratio of ORs 2.93 [95%: 1.39-6.35]), respectively. Conclusions The observation highlights the need in preventing excessive use of alcohol, especially in individuals harboring active ADH and inactive ALDH2 variants.
Prognostic Impact of tumor cell PD-L1 expression and immune cell infiltration in NSCLC J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-09 Karolina Edlund, Katrin Madjar, Johanna S.M. Mattsson, Dijana Djureinovic, Cecilia Lindskog, Hans Brunnström, Hirsh Koyi, Eva Brandén, Karin Jirström, Fredrik Pontén, Jörg Rahnenführer, Patrick Micke, Jan G. Hengstler
Introduction Infiltration of T and B/plasma cells has been linked to non-small cell lung cancer (NSCLC) prognosis, but this has not been thoroughly investigated in relation to the expression of programmed cell death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients, who were not treated with checkpoint inhibitors targeting the PD1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathological factors affect the prognostic association of lymphocytes. Methods CD3, CD8, CD4, FOXP3, CD20, CD79A, and IGKC positive cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (N=705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N=1724). Associations with OS were assessed by Kaplan-Meier plots, and uni- and multivariate Cox regression. Results Higher levels of T and B/plasma cells were associated with longer OS (P=0.004 and P<0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a non-stratified patient population; however, a significant association with shorter OS was observed in never-smokers (P=0.009 and P=0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1 positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histological subtype. Conclusions Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.
Brief Report: EGFR and ERBB2 Germline Mutations in Chinese Lung Cancer Patients and Their Roles in Genetic Susceptibility to Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2019-01-02 Shun Lu, Yongfeng Yu, Ziming Li, Ruoying Yu, Xue Wu, Hairong Bao, Yan Ding, Yang W. Shao, Hong Jian
Introduction Inherited genetic determinants of lung cancer risk remain relatively elusive. Germline mutations in EGFR and ERBB2 have been previously reported in lung cancers, which may be associated with genetic susceptibility to lung cancer. Methods We retrospectively analyzed a cohort of 12,833 Chinese lung cancer patients tested by targeted next-generation sequencing (NGS). Patients with EGFR and ERBB2 germline mutations were identified, and their clinical information and family history were summarized. Growth factor independency of EGFR germline mutations were further analyzed in vitro. Results Eight different heterozygous EGFR germline mutations from 14 adenocarcinoma patients (0.12%) were identified within or adjacent to the kinase domain, including K757R (n=5), R831H (n=2), D1014N (n=2), G724S, V786M, T790M, L792F and L844V. Only one patient harbored ERBB2-V1128I germline mutation. Five out of the 15 patients had family history of cancer. Notably, the patient with EGFR-T790M germline mutation had multiple maternal family members diagnosed with lung cancers, strongly supporting its role in inherited lung cancer. Concurrent known somatic driver mutations were not detected in five patients at diagnosis, one of whom harbor EGFR-L844V germline mutation and showed superior response to afatinib. Consistently, EGFR-K757R and L844V mutations were able to be IL-3 independent in vitro, and were sensitive to EGFR tyrosine kinase inhibitors (TKIs). Conclusions EGFR/ERBB2 germline mutations were rare in Chinese lung cancer patients with more diversity other than the previously reported EGFR-T790M, and with EGFR-K757R being the most common EGFR germline mutation. Patients with EGFR germline mutations without other known driver mutations might benefit from TKI treatment.
Natural history and factors associated with overall survival in stage IV ALK rearranged non-small-cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-30 J.M. Pacheco, D. Gao, D. Smith, W.T. Purcell, M. Hancock, P.A. Bunn, T.P. Robin, A.K. Liu, S. Karam, L.E. Gaspar, B.D. Kavanagh, C.G. Rusthoven, D.L. Aisner, R.C. Doebele, D.R. Camidge
Background Clinical variables describing the natural history and longitudinal therapy outcomes of stage IV anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC), and their relationship with long-term overall survival (OS) have not previously been described in detail. Methods Stage IV patients treated with an ALK inhibitor at University of Colorado Cancer Center from 2009 through November 2017 were identified retrospectively. OS curves were constructed using Kaplan Meier methods. Multivariate cox proportional hazard analysis was used to determine relationship of variables with OS. Results 110 ALK+ NSCLC patients were identified, 105 received crizotinib as their initial ALK inhibitor. With a median follow-up of 47 months, the median OS from diagnosis of stage IV disease was 81 months (6.8 years). Brain metastasis at diagnosis of stage IV disease (HR 1.01, p=0.971) and year of stage IV presentation (p=0.887) did not influence OS. More organs with tumor at diagnosis of stage IV disease associated with worse OS (HR 1.49 for each additional organ with disease including the CNS, p=0.002). Each additional month of pemetrexed based therapy associated with a 7% relative decrease in risk of death. Conclusion Stage IV ALK+ NSCLC patients can have prolonged OS. Brain metastasis at diagnosis of stage IV disease does not influence OS. More organs involved with tumor at stage IV presentation is associated with worse outcomes. Prolonged benefit from pemetrexed was associated with better outcomes.
Antibody-Drug Conjugates for the Therapy of Thoracic Malignancies J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-30 Hao Xie, Alex A. Adjei
Antibody-drug conjugates are a novel class of therapeutic agents incorporating both target-specific monoclonal antibodies and cytotoxic small molecules via a chemical linker. They were first introduced into the clinic for the treatment of advanced hematologic malignancies. The only approved antibody-drug conjugate for solid tumors targets HER2, a validated antigen in breast cancer. Many antibody-drug conjugates are under active investigation for various types of solid tumors. In this article, we review the literature from several perspectives including the design, pharmacology, and mechanism-based toxicities of antibody-drug conjugates. We then discuss antibody-drug conjugates currently in clinical development for thoracic malignancies.
K-ras mutation subtypes in NSCLC and associated co-occuring mutations in other oncogenic pathways J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-31 Matthias Scheffler, Michaela A. Ihle, Rebecca Hein, Sabine Merkelbach-Bruse, Andreas H. Scheel, Janna Siemanowski, Johannes Brägelmann, Anna Kron, Nima Abedpour, Frank Ueckeroth, Merle Schüller, Sophia Koleczko, Sebastian Michels, Jana Fassunke, Helen Pasternack, Carina Heydt, Monika Serke, Rieke Fischer, Jürgen Wolf
Background While KRAS mutations in non-small cell lung cancer (NSCLC) have been considered as mutually exclusive driver mutations for a long time, there is growing evidence now that KRAS-mutated NSCLC represents a genetically heterogeneous subgroup. We sought to determine genetic heterogeneity with respect to cancer-related comutations and their correlation with different KRAS mutation subtypes. Methods Diagnostic samples of 4507 NSCLC patients were analyzed by next-generation sequencing (NGS) using a panel of 14 genes and, in a subset of patients, fluorescence in-situ hybridization (FISH). NGS with an extended panel of 14 additional genes was performed in 101 patients. Molecular data were correlated with clinical data. Whole-exome sequencing (WES) was performed in two patients. Results We identified 1078 patients with KRAS mutations, whereof 53.5% had at least one additional mutation. Different KRAS mutation subtypes showed different patterns of co-occurring mutations. Beside mutations inTP53 (39.4%), STK11 (19.8%), KEAP1 (12.9%), ATM (11.9%), as well as MET amplifications (15.4%) and ERBB2 amplifications (13.8%, exclusively in G12C), we found rare co-occurrence of targetable mutations in EGFR (1.2%) and BRAF (1.2%). WES of two patients with co-occurring PIK3CA mutation revealed clonality of mutated KRAS in one patient and subclonality in the second, suggesting different evolutionary backgrounds. Conclusion KRAS-mutated NSCLC represents a genetically heterogeneous subgroup with a high frequency of co-occurring mutations in cancer-associated pathways, partly associated with distinct KRAS mutation subtypes. This diversity might have implications for understanding the variability of treatment outcome in KRAS-mutated NSCLC and for future trial design.
Integrative genomic analyses identifies GGA2 as a cooperative driver of EGFR mediated lung tumorigenesis J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-19 Hannah O’Farrell, Bryant Harbourne, Zimple Kurlawala, Yusuke Inoue, Amy L. Nagelberg, Victor D. Martinez, Daniel Lu, Min Hee Oh, Bradley P. Coe, Kelsie L. Thu, Romel Somwar, Stephen Lam, Wan L. Lam, Arun M. Unni, Levi Beverly, William W. Lockwood
Introduction Targeted therapies for lung adenocarcinoma (LAC) have improved patient outcomes; however, drug resistance remains a major problem. One strategy to achieve durable response is to develop combination-based therapies that target both mutated oncogenes and key modifiers of oncogene-driven tumorigenesis. This is based on the premise that mutated oncogenes, while necessary, are not sufficient for malignant transformation. We aimed to uncover genetic alterations that cooperate with mutant EGFR during LAC development. Methods and Results Through integrative genomic analyses of over 500 LAC tumors, we identified frequent amplifications/deletions of chromosomal regions affecting the activity of genes specifically in the context of EGFR mutation, including amplification of the mutant EGFR allele and deletion of the phosphatase DUSP4, which have both previously been reported. In addition, we identified the novel amplification of a segment of chromosome arm 16p in mutant-EGFR tumors corresponding to increased expression of Golgi Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 2 (GGA2), which functions in protein trafficking and sorting. Through co-immunoprecipitation and Western blot analysis, we found that GGA2 interacts with EGFR, increases EGFR protein levels and modifies EGFR degradation after ligand stimulation. Furthermore, we show that overexpression of GGA2 enhances EGFR mediated transformation while GGA2 knockdown reduces the colony and tumor forming ability of EGFR mutant LAC. Conclusions These data suggest that overexpression of GGA2 in LAC tumors results in the accumulation of EGFR protein and increased EGFR signaling, which helps drive tumor progression. Thus, GGA2 plays a cooperative role with EGFR during LAC development and is a potential therapeutic target for combination-based strategies in LAC.
Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-18 Yasushi Yatabe, Sanja Dacic, Alain C. Borczuk, Arne Warth, Prudence A. Russell, Sylvie Lantuejoul, Mary Beth Beasley, Erik Thunnissen, Giuseppe Pelosi, Natasha Rekhtman, Lukas Bubendorf, Mari Mino-Kenudson, Akihiko Yoshida, Kim R. Geisinger, Masayuki Noguchi, Lucian R. Chirieac, Johan Bolting, Jin-Haeng Chung, Andre L. Moreira
Since the 2015 WHO classification was introduced into clinical practice, the importance of immunohistochemistry (IHC) has figured prominently in lung cancer diagnosis. In addition to distinction of small versus non-small cell carcinoma (NSCC), patients’ treatment of choice is directly linked to histological subtypes of NSCC, which pertains to IHC results, particularly for poorly-differentiated tumors. The use of IHC has improved diagnostic accuracy in the lung carcinoma classification, but the interpretation remains challenging in some instances. Also, pathologists must be aware of many interpretation pitfalls, and the use of IHC should be efficient to spare the tissue for molecular testing. The IASLC Pathology Committee received questions on practical application and interpretation of IHC in lung cancer diagnosis. After discussions in several IASLC Pathology Committee meetings, the issues and caveats were summarized as eleven key questions, which cover common and important diagnostic situations in a daily clinical practice with some relevant challenging queries. The questions included best IHC markers for distinguishing NSCLC subtypes, differences in TTF1 clones, utility of IHC in diagnosing uncommon subtypes of lung cancer and distinguishing primary from metastatic tumors.” This article provides answers and explanations for the key questions about the use of IHC in lung carcinoma diagnosis representing viewpoints of experts in thoracic pathology that should assist the community in the appropriate use of IHC in diagnostic pathology.
ROS1 gene rearrangements are associated with an elevated risk of peri-diagnosis thromboembolic events J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-10 Terry L. Ng, Derek E. Smith, Rao Mushtaq, Tejas Patil, Anastasios Dimou, Shuo Yang, Qian Liu, Xuefei Li, Caicun Zhou, Robert T. Jones, Megan M. Tu, Flora Yan, I. Alex Bowman, Stephen V. Liu, Siera Newkirk, Joshua Bauml, Robert C. Doebele, Dara L. Aisner, D. Ross Camidge
Introduction We hypothesized that advanced ROS1 gene-rearranged non-small cell lung cancer (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate. Methods Venous and arterial TEE within +/- 365 days of diagnosis of ROS1+, ALK+, EGFR+ or KRAS+ advanced NSCLC at 5 academic centers in the USA and China were captured (October 2002–April 2018). The primary endpoint was incidence of TEE in ROS1+ compared to ALK+, EGFR+, and KRAS+ NSCLC within +/- 90 days of diagnosis. Logistic regression was used to assess if the odds of TEE differed among oncogene drivers. Results Eligible data from 95 ROS1+, 193 ALK+, 300 EGFR+, and 152 KRAS+ NSCLC patients were analyzed. The incidence rate of TEE was 34.7%(33/95), 22.3%(43/193), 13.7%(41/300), and 18.4%(28/152), respectively. In univariate analysis, the odds of a TEE in ROS1+ NSCLC were higher than ALK+, EGFR+ and KRAS+ cohorts. In multivariable analysis, the odds of a TEE were significantly higher for ROS1+ compared to EGFR+ and KRAS+ cohorts, OR:2.44, 95% CI: 1.31–4.57, p=0.005 and OR:2.62, 95% CI: 1.26–5.46, p=0.01, respectively. Although numerically superior, the odds for a TEE with ROS1+ compared to ALK+ was not statistically significant (OR:1.45, p=0.229). Overall survival was not significantly different in patients with or without TEE within +/-90 days of diagnosis in the overall study cohort or within each molecular group. Conclusion The risk of peridiagnosis TEEs is significantly elevated in patients with advanced ROS+ NSCLC compared to EGFR+ and KRAS+ cases. TEE risk may be similarly elevated in ALK+ NSCLC.
Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK gene rearrangements J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-11 Jason C. Chang, Lei Zhang, Alexander E. Drilon, Ping Chi, Rita Alaggio, Laetitia Borsu, Ryma Benayed, William D. Travis, Marc Ladanyi, Cristina R. Antonescu
Background Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor ALK gene rearrangements and overexpress ALK protein. The wide application of next generation sequencing (NGS) and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMT. Design In this study we investigate a series of pediatric and adult thoracic IMT for abnormalities in a wide spectrum of actionable kinases, by applying a variety of molecular and NGS techniques, including FISH, targeted RNA sequencing and NanoString. Results There were 33 thoracic IMTs, with a mean age of 37, including 5 children. Tumors showed a monomorphic spindle cell phenotype, except one with epithelioid morphology and moderate to severe atypia. By IHC, 24 cases were ALK positive, of which by FISH, 19 showed ALK rearrangements and 1 RET gene rearrangement. RNA sequencing was performed in the remaining 4 cases lacking ALK abnormalities by FISH, revealing ALK fusions in 3 cases, involving TMP4 and EML4 genes. NanoString was performed in the remaining case, revealing ALK-alternative transcription initiation (ALKATI). Nine cases lacking ALK abnormalities were further tested by FISH or targeted RNA sequencing, revealing ROS1 rearrangement in 6 cases and ETV6-NTRK3 fusion in 3, respectively. Conclusions By employing a battery of complementary molecular techniques, all thoracic IMTs harbored a tyrosine kinase abnormality, with 30% outside the ALK kinase, including gene fusions involving ROS1, NTRK3, and RET. We also describe for the first time ALKATI-induced ALK oncogenic activation is involved in the pathogenesis of IMTs.
Efficacy of Alectinib in Patients with ALK-Positive NSCLC and Symptomatic or Large CNS Metastases J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-07 Jessica J. Lin, Ginger Y. Jiang, Nencyben Joshipura, Jennifer Ackil, Subba R. Digumarthy, Sandra P. Rincon, Beow Y. Yeap, Justin F. Gainor, Alice T. Shaw
Background Central nervous system (CNS) metastases represent a significant source of morbidity and mortality for patients with ALK-positive non-small cell lung cancer (NSCLC). Alectinib has demonstrated robust CNS activity in both crizotinib-naïve and crizotinib-resistant settings. However, the CNS efficacy of alectinib has not been established in patients with untreated symptomatic, large CNS metastases. Methods In this retrospective study, patients were eligible if they had advanced ALK-positive NSCLC with large (defined as ≥1 cm) or symptomatic CNS metastases and received alectinib. Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results Of 19 patients, 15 (79%) had measurable CNS disease at baseline and were evaluable for response. CNS objective response rate (CORR) in these patients was 73.3% (95% CI, 44.9% to 92.2%), CNS disease control rate (CDCR) was 100.0% (95% CI, 78.2% to 100.0%), and median CNS duration of response (CDOR) was 19.3 months (95% CI, 14.3 months to not evaluable). In 18 evaluable patients with measurable and/or nonmeasurable baseline CNS disease, CORR was 72.2% (95% CI, 46.5% to 90.3%), CDCR was 100.0% (95% CI, 81.5% to 100.0%), and median CDOR was 17.1 months (95% CI, 14.3 to not evaluable). All eight patients with symptoms attributable to CNS metastases had clinical improvement upon starting alectinib. Six patients (32%) eventually required salvage brain radiotherapy. Conclusions Alectinib demonstrated meaningful CNS efficacy in ALK-positive NSCLC patients with untreated, symptomatic or large brain metastases.
Brief Report: Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced Non–Small-Cell Lung Cancer With Sensitizing EGFR Mutation J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-04 James Chih-Hsin Yang, Shirish M. Gadgeel, Lecia Van Dam Sequist, Chien-Liang Wu, Vassiliki A. Papadimitrakopoulou, Wu-Chou Su, Joseph Fiore, Sanatan Saraf, Harry Raftopoulos, Amita Patnaik
Introduction Anti-EGFR agents are standard treatments for patients with EGFR-mutant advanced NSCLC. The feasibility of combining erlotinib or gefitinib with anti-PD1 immunotherapy pembrolizumab was evaluated in the phase 1/2 KEYNOTE-021 (NCT02039674) study. Methods Adults with previously untreated stage IIIB/IV EGFR-mutant NSCLC were treated with pembrolizumab 2 mg/kg IV every 3 weeks plus oral erlotinib 150 mg daily in cohort E or oral gefitinib 250 mg daily in cohort F, using a 3+3 design with cohort expansion. Tumor response was evaluated per RECIST v1.1 by blinded independent central review. The primary objective was determination of a recommended phase 2 dose. Results Twelve patients enrolled to receive pembrolizumab plus erlotinib and 7 to receive pembrolizumab plus gefitinib. No dose-limiting toxicities or grade 5 events occurred. Pembrolizumab plus erlotinib was feasible, with adverse events (AEs) similar to those expected for monotherapy. However, pembrolizumab plus gefitinib was not feasible due to grade 3/4 liver toxicity in 5/7 patients (71.4%), leading to permanent treatment discontinuation in 4 patients. The most frequently occurring treatment-related AEs with pembrolizumab plus erlotinib were rash (50.0%), dermatitis acneiform, diarrhea, hypothyroidism, and pruritus (33.3% each). The objective response rate (ORR) was 41.7%, including response in all 4 patients with PD-L1 expression ≥50%. Conclusions Although pembrolizumab plus gefitinib was not feasible, the toxicity profile observed with pembrolizumab plus erlotinib suggests combining immunotherapy with anti-EGFR therapy is feasible. Pembrolizumab plus erlotinib did not improve ORR compared with previous monotherapy studies; further evaluation would be necessary to evaluate potential effects on other efficacy outcomes.
Biomarkers in lung cancer screening: achievements, promises and challenges J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-04 Luis M. Seijo, Nir Peled, Daniel Ajona, Mattia Boeri, John K. Field, Gabriella Sozzi, Ruben Pio, Javier J. Zulueta, Avrum Spira, Pierre P. Massion, Peter J. Mazzone, Luis M. Montuenga
The present review is an update of the research and development efforts regarding the use of molecular biomarkers in the lung cancer screening setting. The two main unmet clinical needs, namely, the refinement of risk in order to improve the selection of individuals undergoing screening and the characterization of undetermined nodules found during the CT-based screening process are the object of the biomarkers described in the present review. We first propose some principles to optimize lung cancer biomarker discovery projects. Then, we summarize the discovery and developmental status of currently promising molecular candidates such as autoantibodies, complement fragments, miRNAs, circulating tumor DNA, DNA methylation, blood protein profiling, or RNA airway or nasal signatures. We also mention other emerging biomarkers or new technologies to follow such as exhaled breath biomarkers, metabolomics, sputum cell imaging, genetic predisposition studies or the integration of NGS in circulating DNA. We also underline the importance of integrating different molecular technologies together with imaging, radiomics and artificial intelligence. We list a number of completed ongoing or planned trials to show clinical utility of molecular biomarkers. Finally we comment on the future research challenges in the field of biomarkers in the context of lung cancer screening and propose a design of a trial to test clinical utility of one or several biomarker candidates.
EGFR-mutant SCLC exhibits heterogeneous phenotypes and resistance to common antineoplastic drugs J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-03 Chih-An Lin, Sung-Liang Yu, Hsuan-Yu Chen, Huei-Wen Chen, Shr-Uen Lin, Chia-Ching Chang, Chong-Jen Yu, Pan-Chyr Yang, Chao-Chi Ho
Introduction Approximately 5% of patients with EGFR-activating mutations acquire EGFR-TKIs resistance through SCLC transformation. However, the reason for the poor outcome and the molecular basis of EGFR-mutant SCLC that has transformed from adenocarcinoma remain unclear. Methods In this study, we established 2 EGFR-mutant SCLC cell lines from lung adenocarcinoma patients after failed EGFR-TKI treatment to investigate their molecular basis and potential therapeutic strategies in the hope of improving patient outcome. Results These 2 EGFR-mutant SCLC cell lines displayed 2 different phenotypes: suspensive and adherent. Both phenotypes shared the same genomic alterations analyzed by array-based comparative genomic hybridization (aCGH) assay. Increased expression of EGFR and mesenchymal markers and decreased expression of neuroendocrine markers were observed in adherent cells. Principal component analysis (PCA) and hierarchical clustering analysis of RNA microarray revealed that these 2 cell lines displayed a unique gene expression pattern that was distinctly different from that in NSCLC and classical SCLC cells. Combined treatment using an EGFR-TKI and an AKT inhibitor attenuated cell viabilities in our 2 cell lines. Moreover, the use of a histone deacetylase (HDAC) inhibitor significantly inhibited the cell viabilities of both cell lines in vitro and in vivo. Conclusion Our findings suggest that EGFR-mutant SCLC may be a distinct subclass of SCLC that exhibits epithelial-mesenchymal transition (EMT) phenotypes, and adding an AKT or HDAC inhibitor to pre-existing therapies may be one of the therapeutic choices for transformed EGFR-mutant SCLC.
Interstitial Lung Disease Onset and Its Risk Factors in Japanese Patients with ALK-positive NSCLC Following Treatment with Crizotinib J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-03 Akihiko Gemma, Masahiko Kusumoto, Yasuyuki Kurihara, Noriyuki Masuda, Shigeo Banno, Yutaka Endo, Hiroyuki Houzawa, Naomi Ueno, Emiko Ohki, Akinobu Yoshimura
Introduction The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib in the real-world clinical setting. Methods Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive non-small cell lung cancer (NSCLC) who received crizotinib, during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of 5 medical specialists. Results The safety analysis set included 2,028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade ≥3. Pulmonary oedema-like shadows with or without diffuse alveolar damage pattern were observed in the crizotinib associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. The ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age ≥55 years, ECOG PS 2-4, smoking history, previous or concomitant ILD and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD. Conclusions Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.
The unique spatial–temporal treatment failure patterns of adjuvant gefitinib therapy: A post-hoc analysis of the ADJUVANT trial (CTONG 1104) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-03 Song-Tao Xu, Jun-Jie Xi, Wen-Zhao Zhong, Wei-Min Mao, Lin Wu, Yi Shen, Yong-Yu Liu, Chun Chen, Ying Cheng, Lin Xu, Jun Wang, Ke Fei, Xiao-Fei Li, Jian Li, Cheng Huang, Zhi-Dong Liu, Shun Xu, Ke-Neng Chen, Yi-Long Wu
Introduction Adjuvant gefitinib therapy prolonged disease-free survival (DFS) in patients with resected early-stage epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC) in the ADJUVANT study (CTONG 1104). However, treatment failure patterns after gefitinib therapy are less well characterized. Methods Overall, 222 stage N1–N2, EGFR-mutant NSCLC patients received gefitinib or vinorelbine plus cisplatin (VP) treatment. Tumor recurrences or metastases occurring during follow-up were defined as treatment failure, sites and data of first treatment failure were recorded. A post-hoc analysis of treatment failure patterns, which was estimated by Kaplan-Meier and hazard rate curves in modified intention-to-treat (mITT) patients was conducted. Results There were 114 recurrences and 10 deaths before recurrence across 124 progression events. Spatial distribution analysis showed that the first metastasis site was most frequently the CNS in the gefitinib group (29/106 [27.4%]), extracranial metastases were most frequent in the VP group (32/87 [36.8%]). Temporal distribution analysis demonstrated lower tumor recurrence with gefitinib than with VP 0–21 months post-surgery. However, recurrence with gefitinib showed a constant rate of increase 12 months post-surgery. The first peak of extracranial metastasis appeared during 9–15 months with VP and 24–30 months with gefitinib. The highest peak for CNS metastases post-surgery occurred after 12–18 months with VP and 24–36 months with gefitinib. Conclusions Adjuvant gefitinib showed advantages over VP chemotherapy in treatment failure patterns especially in extracranial metastasis. Adjuvant TKIs may be considered as a treatment option in resected stage N1–N2 EGFR-mutant NSCLC but longer duration should be explored.
Early impact of pulmonary stereotactic fractionated body radiotherapy (SBRT) on Quality of Life (QoL): Benefit for patients with low initial scores (STRIPE trial) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-12-03 Sonja Adebahr, Marlene Hechtner, Nele Schräder, Tanja Schimek-Jasch, Klaus Kaier, Viola Duncker- Rohr, Eleni Gkika, Felix Momm, Jan Gärtner, Gerhild Becker, Anca-Ligia Grosu, Ursula Nestle
Introduction Quality of life (QoL) of comorbid patients with pulmonary malignancies is a key issue in considering stereotactic fractionated body radiotherapy (SBRT) indication. This study investigates the early impact of SBRT on QoL. Methods 100 patients with pulmonary lesions were treated with SBRT from 02/2011 to 11/2014 within the prospective, monocenter, phase II STRIPE trial. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core module (EORTC QLQ-C30) and the QLQ-LC13 lung cancer-specific questionnaire were used to evaluate QoL before and 2, 7 weeks after SBRT, then 3-monthly for 2 years. We report on the analysis of early changes from baseline to 7 week-Follow up (FU). Impact of patient- and treatment-related factors on the change in QoL was analyzed. Results QoL was assessed in 97 patients; compliance was 92% and 85% at baseline and 7 weeks after SBRT. No clinically relevant changes ≥10 in QoL/Global health status (GHS), function scores and inquired symptoms were observed. Patients with baseline QoL below the median showed clinically relevant improvement in QoL/GHS (Δ16.7 ± 25.3, p=0.003), Emotional Function (Δ14.4 ± 25.4, p=0.013), and fatigue (Δ -10.1 ± 26.5, p=0.089), in contrast to patients with high initial scores. No changes were observed in the dichotomized subgroups of initial Karnofsky Index, Charlson Comorbidity Index, age, diagnosis and tumor localization. Conclusions In short-term FU QoL is well maintained after pulmonary SBRT. Especially patients with low initial QoL/GHS scores show benefit from SBRT with respect to QoL.
Quality of life in Non-Small Cell Lung Cancer survivors – a multicenter cross-sectional study J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-30 Marlene Hechtner, Martin Eichler, Beatrice Wehler, Roland Buhl, Martin Sebastian, Jan Stratmann, Heinz Schmidberger, Bernhard Gohrbandt, Jessica Peuser, Cornelius Kortsik, Ursula Nestle, Sebastian Wiesemann, Hubert Wirtz, Thomas Wehler, Robert Bals, Maria Blettner, Susanne Singer
Introduction The objective was to assess quality of life (QoL) in lung cancer survivors, compare it to the general population, and identify factors associated with global QoL, physical functioning, emotional functioning, fatigue, pain, and dyspnea. Methods Data from non-small-cell lung cancer (NSCLC) patients who had survived ≥1 year after diagnosis were collected cross-sectionally in a multicenter study. QoL was assessed with the EORTC QLQ-C30 and the lung cancer module QLQ-LC13 across different clinical subgroups and compared to age- and gender-standardized general population reference values. Multivariable linear regression analyses were performed to test the associations of patient-, tumor-, and treatment-related factors with the six primary QoL scales. Results 657 NSCLC patients participated in the study with a median time since diagnosis of 3.7 years (range, 1.0-21.2). Compared to the age- and gender-standardized general population, clinically meaningful differences in the QoL detriment were found on almost all domains: lung cancer survivors had clinically relevant poorer global QoL (10 points, p<0.001). Whereas in ≥12 months treatment-free patients this detriment was small (8.3), it was higher in patients currently in treatment (16.0). Regarding functioning and symptom scales, respective detriments were largest for dyspnea (41 points), role functioning (33 points), fatigue (27 points), social functioning (27 points), physical functioning (24 points), and insomnia (21 points), and observed across all subgroups. The main factor associated with poorer QoL in all primary QoL scales was mental distress (β |19-31|, all p<0.001). Detriments in QoL across multiple primary QoL scales were also observed with current treatment (β |8-12|, p<0.01), respiratory comorbidity (β |4-5|, p<0.01), and living on a disability pension (β |10-11|, p<0.01). The main factor associated with better QoL in almost all primary QoL scales was higher physical activity (β |10-20|, p<0.001). Better QoL was also observed in patients with high income (β |10-14|, p<0.01). Discussion Lung cancer survivors experience both functional restrictions and symptoms that persist long term after active treatment ends. This substantiates the importance of providing long-term supportive care.
Pathologic assessment after neoadjuvant chemotherapy for non-small cell lung cancer: Importance and implications of distinguishing adenocarcinoma from squamous cell carcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-29 Yang Qu, Katsura Emoto, Takashi Eguchi, Rania G. Aly, Hua Zheng, Jamie E. Chaft, Kay See Tan, David R. Jones, Mark G. Kris, Prasad S. Adusumilli, William D. Travis
Purpose Major pathologic response (MPR) following neoadjuvant chemotherapy (NAC) for non-small cell lung cancer (NSCLC) has been defined as ≤10% residual viable tumor, without distinguishing between histologic types. We sought to investigate whether the optimal cutoff percentage of residual viable tumor for predicting survival differs between lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Patients and Methods Tumor slides from 272 patients treated with NAC and surgery for clinical stage II-III NSCLC (ADC, n=192; SCC, n=80) were reviewed. The optimal cutoff percentage of viable tumor for predicting lung cancer–specific cumulative incidence of death (LC-CID) was determined using maximally selected rank statistics. LC-CID was analyzed using a competing-risks approach. Overall survival (OS) was evaluated using Kaplan-Meier methods and Cox proportional hazard analysis. Results Patients with SCC had a better response to NAC (median percentage of viable tumor: SCC vs ADC, 40% vs 60%; P=0.027). MPR (≤10% viable tumor) was observed in 26% of SCC cases versus 12% of ADC cases (P=0.004). The optimal cutoff percentage of viable tumor for LC-CID was 10% for SCC and 65% for ADC. On multivariable analysis, viable tumor ≤10% was an independent factor for better LC-CID (P=0.035) in patients with SCC; in patients with ADC, viable tumor ≤65% was a factor for better LC-CID (P=0.033) and OS (P=0.050). Conclusion In response to NAC, the optimal cutoff percentage of viable tumor for predicting survival differs between ADC and SCC. Our findings have implications for the pathologic assessment of resected specimens, especially in upcoming clinical trials design.
Adjuvant Systemic Therapy in Patients With Early-Stage Non-Small Cell Lung Cancer (NSCLC) Treated with Stereotactic Body Radiation Therapy (SBRT) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-29 Vinicius Ernani, Adams Kusi Appiah, Alissa Marr, Chi Zhang, Weining Zhen, Lynette M. Smith, Apar Kishor Ganti
Introduction Stereotactic body radiation therapy (SBRT) is commonly used to treat nonsurgical patients with early-stage NSCLC. There are no prospective data on the role of adjuvant chemotherapy in this setting. Methods Patients (≥18 years) diagnosed with clinical stages I-II NSCLC from 2004 to 2013 were identified using the National Cancer Database (n=11,836). The Kaplan-Meier method was used to estimate overall survival (OS) distributions and the log-rank test was used to compare distributions by treatment strategy. Clinical stages I and II were subdivided according to the TNM staging and log-rank tests was used to compare survival distributions by treatment strategy within each subgroup. Results In patients with T2bN0, median OS in the SBRT alone and SBRT plus adjuvant chemotherapy groups were 16.5 months versus 24.2 months respectively (95% CI, 14.1-20.1; and18.8-33.3; P<.001), while for T3N0 median OS were 13 months and 20.1 months (95% CI, 11.7-14.5 and 17.7-21.9 respectively; P<.001). For tumors ≥ 4 cm and node-negative disease, median OS was 15.9 months in the SBRT alone group, and 19 months in the SBRT plus chemotherapy group (95% CI, 15.1-16.8 and 17.9-20.8 respectively; P<.001). For patients with tumors < 4 cm and node-negative disease, the median OS was 28.5 months in the SBRT alone group and 24.3 months in the SBRT plus chemotherapy group (95% CI, 27.4-29.4 and 22.8-26.1 respectively; P<.001). Conclusion SBRT followed by adjuvant chemotherapy was associated with improved overall survival in comparison with SBRT alone in patients with T ≥ 4 cm, similar to that seen following surgery.
Impact of Checkpoint Inhibitor Pneumonitis on Survival in Non-Small Cell Lung Cancer Patients receiving Immune Checkpoint Immunotherapy J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-30 Karthik Suresh, Kevin J. Psoter, Khinh Ranh Voong, Bairavi Shankar, Patrick M. Forde, David S. Ettinger, Kristen A. Marrone, Ronan J. Kelly, Christine L. Hann, Benjamin Levy, Josephine L. Feliciano, Julie R. Brahmer, David Feller-Kopman, Andrew D. Lerner, Hans Lee, Lonny Yarmus, Russell K. Hales, Franco D’Alessio, Jarushka Naidoo
With increasing use of immune checkpoint inhibitors (ICI) for advanced non-small cell lung cancer (NSCLC), there is increasing recognition of immune related adverse events (irAEs) associated with ICI use. We recently reported increased incidence of checkpoint inhibitor pneumonitis (CIP) in ICI-treated NSCLC patients. Since development of irAEs in other organ systems has been associated with either no change or even improvement in tumor response/cancer outcomes, we sought to better understand the impact of CIP development on overall survival in ICI-treated NSCLC patients. Using baseline and follow-up data collected on a cohort of 205 ICI-treated NSCLC patients, we employed a multi-state modeling approach to understand the effect of developing CIP on the risk of death. We observed time-dependent changes in risk of developing and recovery from CIP, with an increased risk of both developing and recovering from CIP in the first year after initiating ICI. Interestingly, we found that developing CIP independently increased the risk of transitioning to death in both adjusted and unadjusted models. In the multi-variate model, we found that the increase in mortality associated with CIP was only seen in patients with adenocarcinoma tumor histology. Collectively, these findings suggest that in NSCLC, development of CIP worsens survival in patients receiving immunotherapy.
24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-21 Hossein Borghaei, Corey J. Langer, Shirish Gadgeel, Vassiliki A. Papadimitrakopoulou, Amita Patnaik, Steven F. Powell, Ryan D. Gentzler, Renato G. Martins, James P. Stevenson, Shadia I. Jalal, Amit Panwalkar, James Chih-Hsin Yang, Matthew Gubens, Lecia V. Sequist, Mark M. Awad, Joseph Fiore, Sanatan Saraf, Steven M. Keller, Leena Gandhi
Introduction Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42‒1.91). Herein, we present an updated analysis. Methods A total of 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR and/or ALK receptor tyrosine kinase gene (ALK) aberrations were randomized 1:1 to four cycles of PC with or without pembrolizumab, 200 mg every 3 weeks. Pembrolizumab treatment continued for 2 years; maintenance pemetrexed was permitted in both groups. Eligible patients in the PC-alone group with radiologic progression could cross over to pembrolizumab monotherapy. p Values are nominal (one-sided p < 0.025). Results As of December 1, 2017, the median follow-up time was 23.9 months. The ORR was 56.7% with pembrolizumab plus PC versus 30.2% with PC alone (estimated difference 26.4% [95% CI: 8.9%‒42.4%, p = 0.0016]). PFS was significantly improved with pembrolizumab plus PC versus PC alone (HR = 0.53, 95% CI: 0.33‒0.86, p = 0.0049). A total of 41 patients in the PC-alone group received subsequent anti‒programmed death 1/anti‒programmed death ligand 1 therapy. The HR for OS was 0.56 (95% CI: 0.32‒0.95, p = 0.0151). Forty-one percent of patients in the pembrolizumab plus PC group and 27% in the PC-alone group had grade 3 to 5 treatment-related adverse events. Conclusions The significant improvements in PFS and ORR with pembrolizumab plus PC versus PC alone observed in the primary analysis were maintained, and the HR for OS with a 24-month median follow-up was 0.56, favoring pembrolizumab plus PC.
BRIEF REPORT: Association of PALB2 Messenger RNA Expression with platinum-docetaxel efficacy in advanced non-small cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-22 Niki Karachaliou, Jillian Wilhelmina Paulina Bracht, Manuel Fernandez Bruno, Ana Drozdowskyj, Ana Gimenez Capitan, Teresa Moran, Enric Carcereny, Manuel Cobo, Manuel Domine, Imane Chaib, Jose Luis Ramirez, Carlos Camps, Mariano Provencio, Alain Vergnenegre, Guillermo Lopez-Vivanco, Margarita Majem, Bartomeu Massuti, Rafael Rosell
Introduction PALB2, the partner and localizer of BRCA2, is essential for homologous recombination repair. We examined messenger ribonucleic acid (mRNA) levels of DNA-repair genes including PALB2, RNF8, RIF1, ATM, and 53BP1 as predictive biomarkers for cisplatin-docetaxel in the European phase III BRCA1-RAP80 expression customization (BREC) phase III clinical trial (NCT00617656). Methods The study was a pre-specified secondary objective of the BREC trial. We assessed mRNA levels of PALB2 and four more DNA repair genes, RNF8, RIF1, ATM and 53BP1, as biomarkers in tissue from 177 cisplatin-docetaxel treated NSCLC patients. We examined the relationship of gene expression levels with progression-free survival (PFS), overall survival (OS) and response. Results In 177 (median age 62 years; 140 men; 91 adenocarcinoma) NSCLC patients, only high PALB2 mRNA expression was predictive in the PFS Cox-regression analysis (Hazard ratio [HR], 0.63; 95% Confidence Interval [CI], 0.42-0.83; p=0.0080). PALB2 was also predictive of OS (HR, 0.68; 95% CI, 0.42-0.90; p=0.0266). Among 158 patients evaluable for response, high PALB2 was predictive of response to cisplatin-docetaxel. Specifically, an objective response rate of 77% to cisplatin-docetaxel was observed for patients with high PALB2 mRNA expression compared to only 23 % for those with low PALB2 mRNA expression (p=0.0448). Conclusions High PALB2 mRNA expression identified NSCLC patients who significantly benefited from cisplatin-docetaxel chemotherapy in the European BREC phase III clinical trial. The combination of chemotherapy with immunotherapy becomes a new standard of care, and a predictive marker of response to chemotherapy may accurately guide therapeutic decision making.
Impact of Age on Outcomes with Immunotherapy in Patients with Non-Small Cell Lung Cancer (NSCLC) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-23 Morgan Lichtenstein, Ryan D. Nipp, Alona Muzikansky, Kelly Goodwin, Danyon Anderson, Richard A. Newcomb, Justin F. Gainor
Introduction Immunotherapy has revolutionized the treatment of non-small cell lung cancer (NSCLC), but little is known about the activity of PD-(L)1 blockade across age groups. Methods We retrospectively evaluated patients with NSCLC initiated on PD-(L)1 inhibitors from 1/2013-7/2017. Medical records and radiographic imaging were reviewed to determine progression-free survival (PFS) and overall survival (OS). We also compared immunotherapy-related toxicities, steroid use, and hospitalizations by age. Results Of 245 patients, 26.1% were age<60 years, 31.4% were age 60-69, 31.0% were age 70-79, and 11.4% were ≥80 years. Median PFS by age group was: age<60, 1.81 months; 60-69, 2.53 months; 70-79, 3.75 months; ≥80, 1.64 months (log-rank p-value=0.055). Median OS by age group was: age<60, 13.01 months; 60-69, 14.56 months; 70-79, 12.92 months; ≥80, 3.62 months (log-rank p-value=0.011). Rates of immunotherapy-related toxicities, steroid use, and hospitalizations did not differ by age. Conclusions Although the OS and PFS benefits of immunotherapy differ by age, rates of toxicity are similar regardless of age.
Electromagnetic Navigation Bronchoscopy for Peripheral Pulmonary Lesions: One-Year Results of the Prospective, Multicenter NAVIGATE Study J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-23 Erik E. Folch, Michael A. Pritchett, Michael A. Nead, Mark R. Bowling, Septimiu D. Murgu, William S. Krimsky, Boris A. Murillo, Gregory P. LeMense, Douglas J. Minnich, Sandeep Bansal, Blesilda Q. Ellis, Amit K. Mahajan, Thomas R. Gildea, Rabih I. Bechara, Eric Sztejman, Javier Flandes, Otis B. Rickman, Sadia Benzaquen, Sandeep J. Khandhar
Introduction Electromagnetic navigation bronchoscopy (ENB) is a minimally invasive technology that guides endoscopic tools to pulmonary lesions. ENB has been evaluated primarily in small, single-center studies; thus, the diagnostic yield in a generalizable setting is unknown. Methods NAVIGATE is a prospective, multicenter, cohort study that evaluated ENB using the superDimension™ navigation system. In this United States cohort analysis, 1,215 consecutive subjects were enrolled at 29 academic and community sites from April 2015 to August 2016. Results The median lesion size was 20.0 mm. Fluoroscopy was used in 91% of cases (lesions visible in 60%) and radial endobronchial ultrasound in 57%. The median ENB planning time was 5 minutes; the ENB-specific procedure time was 25 minutes. Among 1,157 subjects undergoing ENB-guided biopsy, 94% (1,092/1,157) had navigation completed and tissue obtained. Follow-up was completed in 99% of subjects at 1 month and 80% at 12 months. The 12-month diagnostic yield was 73%. Pathology results of the ENB-aided tissue samples showed malignancy in 44% (484/1,092). Sensitivity, specificity, positive predictive value, and negative predictive value for malignancy were 69%, 100%, 100%, and 56%, respectively. ENB-related CTCAE Grade ≥2 pneumothoraces (requiring admission or chest tube placement) occurred in 2.9%. The ENB-related CTCAE Grade ≥2 bronchopulmonary hemorrhage and Grade ≥4 respiratory failure rates were 1.5% and 0.7%, respectively. Conclusions NAVIGATE demonstrates that an ENB-aided diagnosis can be obtained in approximately three quarters of evaluable patients across a generalizable cohort based on prospective 12-month follow-up in a pragmatic setting, with a low procedural complication rate.
Pseudoprogression in previously treated patients with non-small cell lung cancer who received nivolumab monotherapy: A multicenter retrospective cohort study J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-20 Daichi Fujimoto, Hiroshige Yoshioka, Yuki Kataoka, Takeshi Morimoto, Tae Hata, Young Hak Kim, Keisuke Tomii, Tadashi Ishida, Masataka Hirabayashi, Satoshi Hara, Manabu Ishitoko, Yasushi Fukuda, Moon Hee Hwang, Naoki Sakai, Motonari Fukui, Hitoshi Nakaji, Mitsunori Morita, Tadashi Mio, Toyohiro Hirai
Introduction Nivolumab is effective in the treatment of previously treated patients with advanced non-small cell lung cancer (NSCLC). However, its radiological evaluation is challenging because of atypical patterns of responses such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and who developed pseudoprogression. Methods We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the pseudoprogression cases, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors (RECIST)-defined first progressive disease and PFS2 as the time to RECIST-defined second progressive disease or death. Results Among the 542 patients included, 20% and 53% showed typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (N = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the pseudoprogression cases than the PFS in the typical-response cases (P < 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than patients showing typical progression (P = 0.001). Conclusions Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression.
Disparities in the diagnosis and treatment of lung cancer among people with disabilities J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-16 Dong Wook Shin, Jongho Cho, Jae Myoung Noh, Hyesook Han, Kyungdo Han, Sang Hyun Park, So Young Kim, Jong Heon Park, Jong Hyock Park, Ichiro Kawachi
Introduction Potential disparities in the diagnosis, treatment, and survival of lung cancer patients with and without disabilities were rarely investigated. Methods We conducted a retrospective cohort study with a dataset linking the KNHS database, disability registration data, and Korean Central Cancer Registry data. A total of 13,591 people with disabilities who were diagnosed with lung cancer and 43,809 age- and sex-matched control subjects with diagnosed lung cancer were included. Results Unknown stage was more common in people with severe disabilities (13.1% vs. 10.3%), especially those with communication (14.2%) or mental/cognitive disability (15.7%). People with disabilities were less likely to undergo surgery (adjusted odds ratio [aOR] 0.82, 95% confidence interval [95% CI] 0.77-0.86), chemotherapy (aOR=0.80, 95% CI 0.77-0.84), or radiotherapy (aOR=0.92, 95% CI 0.88-0.96). This was more evident for people with severe communication impairment (aORs 0.46 for surgery; 0.64 for chemotherapy) and severe brain/mental impairment (aORs 0.39 for surgery; 0.47 for chemotherapy; 0.49 for radiotherapy). Patients with disabilities had a slightly higher overall mortality compared to people with no disability (adjusted hazard ratio [aHR] 1.08; 95% CI, 1.06-1.11), especially in the severe disability group (aHR, 1.20; 95% CI 1.16-1.24). Conclusions Lung cancer patients with disabilities, especially severe ones, underwent less staging work-up and treatment even though their treatment outcomes were only slightly worse than those of people without a disability. While some degree of disparity might be attributed to reasonable clinical judgement, unequal clinical care for people with communication and brain/mental disabilities suggests unjustifiable disability-related barriers which need to be addressed.
Role of low-dose computerized tomography in lung cancer screening among never-smokers J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-13 Hye-Rin Kang, Jun Yeun Cho, Sang Hoon Lee, Yeon Joo Lee, Jong Sun Park, Young-Jae Cho, Ho Il Yoon, Kyung Won Lee, Jae Ho Lee, Choon-Taek Lee
Introduction The incidence of lung cancer among never-smokers has been increasing rapidly. The United States National Lung Screening Trial (NLST) study and NELSON trial showed that screening using low-dose computerized tomography effectively reduced lung cancer mortality among heavy smokers. However, its effectiveness in never-smokers has not been well investigated. This study investigated the role of low-dose computerized tomography (LDCT) in lung cancer screening among never-smokers. Methods The study was designed as a single-center, retrospective cohort study. We analyzed data of patients who received low-dose computerized tomography screening between May 2003 and June 2016. Nodules detected by computerized tomography were classified according to the Lung Imaging Reporting and Data System criteria. The detection rate and lung cancer outcomes (pathology, staging of lung cancer, and mortality) according to smoking history were determined. Results Among 28,807 enrolled patients, 12,176 patients were never-smokers; of these, 7,744 (63.6%) were women and lung nodules were found in 1,218 (10.0%) patients. Overall, lung cancer was diagnosed in 55 (0.45%) never-smokers. In contrast, lung cancer was diagnosed in 143 (0.86%) patients among 16,631 ever-smokers. Among never-smokers with lung cancer, 51 (92.7%) presented with stage I, and all patients had adenocarcinomas. Conclusions In the never-smoker population, low-dose computerized tomography screening helped to detect a significant number of lung cancers. Most of these lung cancers were detected at a very early stage. The positive results of NLST in the US and the NELSON trial may have established the value of LDCT screening for heavy smokers, but future research should consider the value of using LDCT screening in the never-smoker population.
Evaluation of the Prognostic Significance of TNM Staging Guidelines in Lung Carcinoid Tumors J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-08 J.Y. Yoon, K. Sigel, J. Martin, R. Jordan, M.B. Beasley, C. Smith, A. Kaufman, J. Wisnivesky, M. Kang Kim
Background The Tumor Lymph Node and Metastasis (TNM) classification for lung cancer, originally designed for non-small cell lung carcinoma, is applied to staging of bronchopulmonary carcinoid tumors. The validity of the 8th Edition staging system for carcinoid tumors has not been assessed. In this study, we evaluated its prognostic accuracy using data from a large national population-based cancer registry. Patients and Methods Patients with typical and atypical bronchopulmonary carcinoids, diagnosed between 2000 and 2013, were identified from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) registry. We used competing risks analysis to compare 10-year disease-specific survival (DSS) across stages. Results Overall, 4,645 patients with bronchopulmonary carcinoid tumors were identified. Worsening DSS with increasing TNM status and stage was demonstrated across both typical and atypical carcinoids, with overlaps between adjacent subcategories. The combined stages (I vs II, II vs III, III vs IV) showed greater separation in DSS despite persistent overlaps between groups. For typical carcinoids, we found decreased DSS for stage II, stage III, and stage IV with HR 3.8 (95% CI: 2.6-5.6), HR 4.3 (95% CI: 3.0-6.1), and HR 9.0 (95% CI: 6.1-13.1), respectively, compared to stage I. Conclusion The combined stage categories of the 8th Edition TNM staging system provide useful information on outcomes for typical and atypical carcinoids. However, persistent overlaps in combined stage and subcategories of the staging system limit the usefulness of the TNM staging system, particularly in intermediate stages. These limitations suggest the need for further future study and refinement.
Neoadjuvant Crizotinib in Resectable Locally Advanced Non-Small-Cell Lung Cancer with ALK-rearrangement: A Brief Report J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Chao Zhang, Shao-lei Li, Qiang Nie, Song Dong, Yang Shao, Xue-ning Yang, Yi-long Wu, Yue Yang, Wen-zhao Zhong
Background Locally advanced non-small-cell lung cancer (NSCLC) is one of the most heterogeneous condition with multidimensional treatments involved. Neoadjuvant therapy was commonly considered as an optimal management for operable locally advanced patients. However, as targeted therapy has been widely applied in advanced NSCLC, neoadjuvant targeted therapy remains poorly explored in locally advanced disease. Methods We described 11 ALK (anaplastic lymphoma kinase)-positive patients with pathologically confirmed N2 NSCLC who were treated with neoadjuvant crizotinib. All patients were treatment naïve and received crizotinib at a starting dose of 250mg twice daily. Case 3 was provided dynamic monitoring before and after neo-adjuvant therapy through next generation sequencing (NGS) of plasma and tissue. Case 4 was performed NGS for preoperative tissue. Results 10 patients were partial response and one was stable disease after neoadjuvant crizotinib with one suffered from grade 4 hepatic damage. 10/11 (91.0%) patients received R0 resection and 2 patients achieved pathological complete response (pCR) to neoadjuvant crizotinib. 6 patients had disease recurrence and 5 of them receiving crizotinib as first line treatment achieved long duration of response. Dynamic monitoring with both plasma and tissue indicated simultaneously decrease of sensitive ALK-signaling in the patient with partial response (-50%) and no ALK-dependent resistant variants were captured. Conclusion Neoadjuvant crizotinib may be feasible and well-tolerated in locally advanced disease for complete resection. crizotinib prior to surgery may provide thorough elimination of circulating molecular residual disease and not influence the reusing of first-line crizotinib, but ongoing prospective trials are warranted to prove its efficacy in neoadjuvant setting.
Peripheral blood DNA methylation as potential biomarker of Malignant Pleural Mesothelioma in asbestos-exposed subjects J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Simonetta Guarrera, Clara Viberti, Giovanni Cugliari, Alessandra Allione, Elisabetta Casalone, Marta Betti, Daniela Ferrante, Anna Aspesi, Caterina Casadio, Federica Grosso, Roberta Libener, Ezio Piccolini, Dario Mirabelli, Irma Dianzani, Corrado Magnani, Giuseppe Matullo
Introduction Malignant pleural mesothelioma (MPM) is an aggressive tumour strongly associated with asbestos exposure. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for non-invasive early diagnosis tests to monitor asbestos-exposed people. Methods We used a genome-wide methylation array to identify, in asbestos-exposed subjects, novel blood DNA methylation markers of MPM in 163 MPM cases and 137 cancer-free controls (82/68 Training Set; replication in 81/69, Test Set) sampled from the same areas. Results Evidence of differential methylation between MPM cases and controls was found (>800 CpG sites, Pfdr<0.05), mainly in immune system related genes. Considering the “top” differentially methylated signals, 7 single-CpGs and 5 genomic regions of coordinated methylation replicated with similar effect size in the Test Set (pfdr<0.05). The top hypomethylated single-CpG (cases vs controls effect size<-0.15, pfdr <0.05 in both Training and Test sets) was detected in FOXK1 (Forkhead-box K1) gene, an interactor of BAP1 which was found mutated in MPM tissue and as germline mutation in familial MPM. In the Test set, comparison of receiver operating characteristic (ROC) curves and the area under the curve (AUC) of two models, including/excluding methylation, showed a significant increase in case/control discrimination when considering DNA methylation together with asbestos exposure (AUC=0.81 vs AUC=0.89, DeLong’s test p=0.0013). Conclusions We identified signatures of differential methylation in DNA from whole blood between asbestos exposed MPM cases and controls. Our results provide the rationale to further investigate, in prospective studies, the potential use of blood DNA methylation profiles for the identification of early changes related to MPM carcinogenic process.
A population-based study of outcomes in surgically resected T3N0 non-small cell lung cancer in the Netherlands, defined using TNM-7 and TNM-8; justification of changes and an argument to incorporate histology in the staging algorithm? J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Hans Blaauwgeers, Ronald Damhuis, Birgit Lissenberg-Witte, Adrianus J. de Langen, Suresh Senan, Erik Thunnissen
Purpose To study outcomes in patients surgically staged as pT3N0 non-small cell lung cancer (NSCLC) in a population registry, comparing TNM-7 and TNM-8 staging classifications. Materials and Methods Details of patients who underwent surgery for a pT3N0M0 NSCLC from 2010 to 2013, based on the TNM-7 classification, were retrieved from the Netherlands Comprehensive Cancer Organization (IKNL). These were next matched with corresponding pathology data from a nationwide registry. Patients were categorized into 4 major pT3 subgroups: ‘> 7cm’ tumor diameter, ‘separate tumor nodules in the same lobe’ (2nd+ nodule), ‘parietal pleural invasion’ and a ‘mixed group’ (mainly ‘> 7 cm’ combined with ‘parietal pleural invasion’). Results 683 patients were eligible for analysis. The 3- and 5-years overall survival (OS) for the subtype ‘> 7 cm’ were 59.9% and 47.2%, respectively, and comparable to the subtype with pleural invasion were 50.4% and 45.3%, respectively. The ‘mixed group’ had a worse 3- and 5-year OS probability of 37.5% and 28.7%, which were comparable to outcomes for TNM-8 staged IIIB and pT4 cases in the IASLC database. For the subtype 2nd+ nodule, 3- and 5-year OS were 70.6% and 62.8%, respectively, with patients with adenocarcinoma showing a significantly better OS compared to squamous cell carcinoma: 5-years OS of 65.1% versus 47.2%, respectively (p<0.001), suggesting that prognosis for the adenocarcinoma subgroup may be comparable to the pT2 category, whereas squamous cell carcinoma nodules can remain pT3. Conclusion This population analysis of overall survivals in pT3N0 subcategories for NSCLC suggests that histology is a relevant descriptor in the 2nd+ nodule category. The findings do not support migration of the ‘>7 cm’ group to the pT4 category in TNM-8, and suggest that a combination of two pT3 descriptors (‘mixed group’) merits migration to pT4.
Co-expression analysis reveals mechanisms underlying the varied roles of NOTCH1 in non-small cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-05 Sara L. Sinicropi-Yao, Joseph M. Amann, David Lopez Y. Lopez, Ferdinando Cerciello, Kevin R. Coombes, David P. Carbone
Introduction Notch receptor family dysregulation can be tumor promoting or suppressing depending on cellular context. Our studies shed light on the mechanistic differences that are responsible for NOTCH1’s opposing roles in lung adenocarcinoma and lung squamous cell carcinoma. Methods We integrated transcriptional patient-derived datasets with gene co-expression analyses to elucidate mechanisms behind NOTCH1 function in subsets of non-small cell lung cancer. Differential co-expression was examined using hierarchical clustering and principal component analysis. Enrichment analyses was used to examine pathways associated with the underlying transcriptional networks. These pathways were validated in vitro and in vivo. Endogenously epitope-tagged NOTCH1 was used to identify novel interacting proteins. Results NOTCH1 co-expressed genes in lung adenocarcinoma and squamous carcinoma were distinct, and associated with either angiogenesis and immune system pathways or cell cycle control and mitosis pathways, respectively. Tissue culture and xenograft studies of lung adenocarcinoma and lung squamous models with NOTCH1 knockdown demonstrated growth differences and opposing effects on these pathways. Differential NOTCH1 interacting proteins were identified as potential mediators of these differences. Conclusions Recognition of the opposing role of NOTCH1 in lung cancer, downstream pathways, and interacting proteins in each context may help direct the development of rational NOTCH1 pathway-dependent targeted therapies for specific tumor subsets of non-small cell lung cancer.
Compliance and outcome of elderly patients treated in the Concurrent ONce daily VErsus twice-daily RadioTherapy (CONVERT) trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-10-31 Marianna Christodoulou, Fiona Blackhall, Hitesh Mistry, Ahmet Leylek, Joost Knegjens, Vincent Remouchamps, Isabelle Martel-Lafay, Nuria Farré, Matjaz Zwitter, Delphine Lerouge, Nicolas Pourel, Henri Janicot, Arnaud Scherpereel, Caroline Tissing-Tan, Karin Peignaux, Xavier Geets, Krzysztof Konopa, Corinne Faivre-Finn
Introduction There is a lack of data on the efficacy and safety of concurrent chemo-radiotherapy in elderly, limited-stage, patients with small cell lung cancer. Methods We compared outcomes of patients aged ≥70 years vs. younger patients within the Concurrent ONce-daily VErsus twice-daily RadioTherapy (CONVERT) trial. Patients were randomised to receive 45Gy/30 twice-daily fractions/3 weeks or 66Gy/33 once-daily fractions/6.5 weeks concurrently with platinum-based chemotherapy. Overall survival (OS) and progression free survival (PFS) were evaluated using Kaplan-Meier methodology and Cox proportional hazards regression. Results Of 547 patients randomised between April 2008-November 2013, 57 did not receive protocol treatment and were excluded. Of the 490 patients included, 67 (14%) were aged ≥70 years (median age: 73 years; range 70-82). Fewer older patients received the optimal number of radiotherapy fractions (73% vs. 85%; p=0.03); however, chemotherapy compliance was similar in both groups (p=0.24). Neutropenia grade 3/4 occurred more frequently in the elderly (84% vs. 70%; p=0.02) but rates of neutropenic sepsis (4% vs. 7%; p=0.07) and death (3% vs. 1.4%; p=0.67) were similar in both groups. With a median follow-up of 46 months; median survival in the elderly vs. younger groups was 29 (95% confidence interval (CI) 21-39) vs. 30 months (95% CI 26-35) respectively; (hazard ratio (HR) 1.15, 95% CI 0.84-1.59; p=0.38). Median time to progression in the elderly vs. younger groups was 18 (95% CI 13-31) vs. 16 months (95% CI 14-19) respectively; (HR 1.04, 95% CI 0.76-1.41; p=0.81). Conclusions Concurrent chemo-radiotherapy with modern radiotherapy techniques should be a treatment option for fit, older patients.
PET scan-directed chemoradiation for esophageal squamous cell carcinoma: no benefit for a change in chemotherapy in PET non-responders J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-11-01 M. Greally, J. Chou, D. Molena, V.W. Rusch, M.S. Bains, B.J. Park, A.J. Wu, K.A. Goodman, D.P. Kelsen, Y.Y. Janjigian, D.H. Ilson, G.Y. Ku
Introduction Pre-operative or definitive chemoradiation is an accepted treatment for locally advanced esophageal squamous cell carcinoma (ESCC). The MUNICON study demonstrated that PET response following induction chemotherapy was predictive of outcomes in patients with gastroesophageal junction adenocarcinoma. We evaluated the predictive value of PET following induction chemotherapy in ESCC patients and assessed the impact of changing chemotherapy during radiation in PET non-responders. Methods We retrospectively reviewed all patients with locally advanced ESCC who received induction chemotherapy and chemoradiation; all patients had a PET before and after induction chemotherapy. Survival was calculated from date of repeat PET using Kaplan-Meier analysis and compared between groups using the log-rank test. Results Of 111 patients, 70 (63%) were PET responders (defined as ≥35% decrease in maximum standard uptake value) to induction chemotherapy. PET responders received the same chemotherapy during radiation. Of 41 PET non-responders, 16 continued with the same chemotherapy and 25 were changed to alternative chemotherapy with radiation. Median progression-free (PFS; 70.1 vs. 7.1 months, p<0.01) and overall survival (OS; 84.8 vs. 17.2 months, p<0.01) were improved for PET responders vs. non-responders. Median PFS and OS for PET non-responders who changed chemotherapy vs. those who did not were 6.4 vs. 8.3 months (p=0.556) and 14.1 vs. 17.2 months (p=0.81), respectively. Conclusions PET after induction chemotherapy highly predicts for outcomes in ESCC patients who receive chemoradiation. However, our results suggest that PET non-responders do not benefit from changing chemotherapy during radiation. Future trials should utilize PET non-response after induction chemotherapy to identify poor prognosis patients for novel therapies.
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