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 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, 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); hazard ratio (HR) for overall survival (OS) was 0.90 (95% CI, 0.42‒1.91). Herein, we present an updated analysis. Methods 123 patients with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR/ALK aberrations were randomized 1:1 to 4 cycles of PC with/without pembrolizumab 200 mg Q3W. 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, median follow-up was 23.9 mo. 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). 41 patients in the PC alone group received subsequent anti-PD-1/anti-PD-L1 therapy. The HR for OS was 0.56 (95% CI, 0.32‒0.95; P=0.0151). 41% of patients in the pembrolizumab plus PC group and 27% in the PC alone group had grade 3‒5 treatment-related adverse events. Conclusions 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 24-month median follow-up was 0.56, favoring pembrolizumab plus PC.
Systemic therapy in advanced thymic epithelial tumors: Insights from the RYTHMIC prospective cohort J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-21 Claire Merveilleux du Vignaux, Eric Dansin, Laurent Mhanna, Laurent Greillier, Eric Pichon, Mallorie Kerjouan, Christelle Clement-Duchene, Bertrand Mennecier, Virginie Westeel, Marie Robert, Xavier Quantin, Gérard Zalcman, Luc Thiberville, Hervé Lena, Thierry Molina, Fabien Calcagno, Pierre Fournel, Julien Mazieres, Nicolas Girard
Background Thymic epithelial tumors (TET) are rare malignancies that may be aggressive and difficult to treat. In the advanced setting, systemic treatments may be delivered as primary therapy before surgery or definitive radiotherapy, as exclusive treatment when no focal treatment is feasible, or in the setting of recurrences. RYTHMIC is the nationwide network for TET in France. The objective of the study was to describe the modalities and analyze the efficacy of systemic treatments for patients with advanced TET included in the RYTHMIC prospective database hosted by the French Thoracic Cancer Intergroup (IFCT). Methods All consecutive patients for whom systemic treatment was discussed at the RYTHMIC MTB from 2012 to 2015 and who received at least one cycle of treatment were included. Main endpoints were objective response and progression-free survival (PFS). Results 236 patients were included in this analysis. 91 patients received primary chemotherapy, leading to a response rate of 83% for thymomas and 75% for thymic carcinomas, and a median PFS of 23.2 months. A strong predictor of longer PFS was histology of thymoma (p<0.001). Exclusive chemotherapy was delivered to 54 patients. Response rate was 31% for thymomas, and 37% for thymic carcinomas. Median PFS was 6.2 months, and was correlated to response rate (p=0.001). Systemic therapy for 1st, 2nd, 3rd and 4th recurrence was delivered to 114, 81, 51 and 27 patients, respectively. Response rates ranged between 15% and 39% for thymomas, and 4% to 21% for thymic carcinomas. Median PFS were 7.7, 6.2, 5.9, and 6.5 months, respectively. Conclusion Patients with advanced thymic malignancies may receive multiple lines of systemic therapy, with an opportunity of clinically relevant PFS rates, for which objective response may be a surrogate. Our real-life study provide with landmark efficacy data that are needed when designing clinical trials to assess innovative agents.
An integrative analysis of transcriptome and epigenome features of ASCL1-positive lung adenocarcinomas J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-16 Naoya Miyashita, Masafumi Horie, Hiroshi I. Suzuki, Masahito Yoshihara, Dijana Djureinovic, Johan Persson, Hans Brunnström, Cecilia Lindskog, Hedvig Elfving, Patrick Micke, Akira Saito, Takahide Nagase
A subgroup of lung adenocarcinoma shows neuroendocrine differentiation and expression of achaete-scute complex homolog 1 (ASCL1), common to high-grade neuroendocrine tumors, small cell lung cancer and large cell neuroendocrine carcinoma. The aim of this study was to characterize clinical and molecular features of ASCL1-positive lung adenocarcinoma by utilizing recent transcriptome profiling in multiple patient cohorts and genome-wide epigenetic profiling including data from The Cancer Genome Atlas (TCGA). The ASCL1-positive subtype of lung adenocarcinoma developed preferentially in current or former smokers and usually did not harbor epidermal growth factor receptor (EGFR) mutations. In transcriptome profiling, this subtype overlapped with the recently proposed proximal-proliferative molecular subtype. Gene expression profiling of ASCL1-positive cases suggested generally poor immune cell infiltration and none of the tumors were positive for programmed cell death ligand 1 (PD-L1) protein expression. Genome-wide methylation analysis demonstrated global DNA hypomethylation in ASCL1-positive cases. ASCL1 was associated with super-enhancers in ASCL1-positive lung adenocarcinoma cells, and ASCL1 silencing suppressed other super-enhancer-associated genes, suggesting that ASCL1 acts as a master transcriptional regulator. This was further reinforced by the essential roles of ASCL1 in cell proliferation, survival, and cell cycle control. These results suggest that ASCL1 defines a subgroup of lung adenocarcinoma with distinct molecular features by driving super-enhancer-mediated transcriptional programs.
A Phase II Study of Pemetrexed in Patients with Recurrent Thymoma and Thymic Carcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-16 Olumide B. Gbolahan, Ryan F. Porter, John T. Salter, Constantin Yiannoutsos, Matthew Burns, E. Gabriella Chiorean, Patrick. J. Loehrer
BackgroundThymoma and thymic carcinoma are neoplastic diseases with reported chemosensitivity to a broad range of agents. However, due to the rarity of these diseases, few prospective trials have been conducted in patients with advanced thymic malignancies. We conducted a prospective phase II trial to evaluate the clinical activity of pemetrexed, a multi-targeted anti-folate agent, in previously treated patients with thymoma (THY) and thymic carcinoma (TC).Patients and MethodsTwenty-seven previously treated patients (THY = 16, TC = 11) with advanced, unresectable disease were treated with pemetrexed 500 mg/m2 IV every three weeks for a maximum of 6 cycles or until undue toxicity or progressive disease. All patients received folic acid, vitamin B12 and steroid prophylaxis.ResultsThe median number of cycles administered was 6 (range 1-6). Nine patients with a total of 14 events had grade 3 toxicities; no grade 4 toxicities were noted. In 26 fully-evaluable patients, two complete and three partial responses (RECIST) were documented (all in patients with stage IVA THY, except one partial response with stage IVA TC). Fourteen patients completed the full 6 cycles of treatment, 7 patients progressed while on therapy, 5 patients discontinued therapy for intolerance, and 1 patient discontinued for progressive Morvan's Syndrome. The median progression free survival for all patients was 10.6 months (THY = 12.1 months vs. TC = 2.9 months). With 23 deaths at data cutoff, the median overall survival is 28.7 months (THY = 46.4 months vs. TC = 9.8 months).ConclusionsPemetrexed is an active agent in this heavily pretreated population of patients with recurrent thymic malignancies, especially thymoma.
The Clinical Impact of Comprehensive Genomic Testing of Circulating Cell-Free DNA in Advanced Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-16 Smadar Laufer-Geva, Anna Belilovski Rozenblum, Tal Twito, Roxana Grinberg, Addie Dvir, Lior Soussan-Gutman, Maya Ilouze, Laila C. Roisman, Elizabeth Dudnik, Alona Zer, Ofer Rotem, Richard B. Lanman, Nir Peled
IntroductionNext-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) enables non-invasive genomic analysis of non-small cell lung cancer (NSCLC) patients. Although plasma-detected genomic alterations (GAs) have been shown to predict targeted therapy response, evidence of durability of response is lacking or limited to small cohorts as is the impact of cfDNA NGS results on clinical decisions.MethodsThis retrospective study of stage IIIB/IV NSCLC patients between the years 2014-2017 in Israel utilized cfDNA NGS (Guardant360) to identify targetable GAs.ResultsWe consecutively tested 116 NSCLC patients, 41.4% (48/116) before 1st line therapy (Group A), 34.5% (40/116) upon progression on chemotherapy or immunotherapy (Group B1) and 24.1% (28/116) upon progression on EGFR TKIs (Group B2). Targetable GAs were found in 31% of group A (15/48), 32.5% in group B1 (13/40) and 71% in group B2 (20/28). Treatment decision was changed to targeted therapy in 23% (11/48), 25% (10/40) and 32% (9/28), respectively (total cohort 26%; 30/116). Objective response rate (RECIST) was 43% (12/28) including one complete response, partial response in 39% (11/28), stable disease in 32% (9/28) and progressive disease in 25% (7/28). Disease control rate was 75% for 5 months median treatment duration.ConclusionsComprehensive cfDNA testing impacted clinical decisions in 1/4 to 1/3 of initial and subsequent lines of treatment in advanced NSCLC patients. This retrospective study extends previous reports by showing that responses based on cfDNA are durable and change treatment decisions at initial presentation and at progression.
State of the Art review - Surgery in Malignant Pleural Mesothelioma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-16 Raphael Bueno, Isabelle Opitz,
Surgical intervention plays an important role in the diagnosis, staging and treatment of malignant pleural mesothelioma (MPM) and can be applied with curative or palliative intent. The overall aim of surgery should be, as in any oncologic surgery, the macroscopic complete resection (MCR) of the tumor. Most importantly, the majority of patients with the diagnosis of MPM should be appropriately staged and initially evaluated in a multidisciplinary setting, including medical oncology, radiation oncology, and surgery after histological diagnosis. Surgical staging, including determination of the histological subtype and lymph node status, as well as clinical staging with PET-CT scan and determination of cardiopulmonary reserve are crucial. Herein, we summarize the role of surgical resection, specifically MCR, performed as EPP or (e)P/D in multimodality treatment settings and advocate for optimal patient selection for one or the other procedure. In addition, the roles of surgery in diagnosis of MPM and in palliative care are discussed.
Targeted Sequencing Analysis of Pulmonary Adenocarcinoma with Multiple Synchronous Ground-glass/Lepidic Nodules J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-16 Eunhyang Park, Soyeon Ahn, Hyojin Kim, Soo Young Park, Jisun Lim, Hyun Jung Kwon, Yeon Bi Han, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung
IntroductionLung adenocarcinoma (ADC) and synchronous ground-glass/lepidic (GG/L) nodules are considered a distinct disease entity in multiple synchronous lung cancers. Few studies have performed next-generation sequencing (NGS) analysis on these synchronous sequential lesions, and genetic alterations of GG/L nodules must be further investigated.MethodsWe performed targeted sequencing in ADC with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), or minimally invasive adenocarcinoma (MIA) from 16 patients. NGS was performed using a customized panel including 154 cancer-associated genes.ResultsMultiple synchronous lesions in the same patient showed different mutation profiles, and some shared identically mutated genes. In five patients harboring EGFR-mutant ADC, their synchronous GG/L nodules had EGFR mutation; however, none was observed in EGFR-wild type ADC. The average number of exonic mutations was 4.2, 5.4, 4.0, and 5.4 in AAH, AIS, MIA, and ADC, respectively. In each lesion type, various mutations including LRP1B, KRAS, EGFR, and BRAF were observed in AAH, and EGFR mutations were the most frequently observed in ADC. 80% of mutations with variant allele frequency (VAF) ≥ 20%, which contained driver gene mutations, were identified in ADC. Intratumoral heterogeneity of the genetic profile was found between the lepidic and invasive areas of ADC, but driver gene mutations were similar.ConclusionsThis study suggested that ADC and synchronous GG/L nodules are genetically independent tumors. Intratumoral genetic heterogeneity of ADC was present, but driver gene mutations were homogeneously distributed. Driver gene mutations with high VAF were identified in the invasive tumor. These findings support the relevance of molecular characterization of lung ADC and synchronous GG/L nodules.
Results of PROFILE 1029, a Phase III Comparison of First-Line Crizotinib versus Chemotherapy in East Asian Patients with ALK-Positive Advanced Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-14 Yi-Long Wu, Shun Lu, You Lu, Jianying Zhou, Yuan-kai Shi, Virote Sriuranpong, James C.M. Ho, Choo Khoon Ong, Chun-Ming Tsai, Chin-Hee Chung, Keith D. Wilner, Yiyun Tang, Elizabeth T. Masters, Paulina Selaru, Tony S. Mok
Introduction The phase III randomized PROFILE 1014 study demonstrated superiority of crizotinib to first-line chemotherapy in prolonging progression-free survival (PFS) in previously untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced nonsquamous non-small cell lung cancer (NSCLC). This result was consistent in the smaller subset of East Asian patients in PROFILE 1014. The subsequent study reported here prospectively evaluated crizotinib in a larger East Asian patient population. Methods In this open-label phase III study (PROFILE 1029), patients were randomized 1:1 to receive oral crizotinib 250 mg twice daily continuously (3-week cycles) or intravenous pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin (area under the concentration–time curve: 5–6 mg·min/mL) every 3 weeks (maximum of six cycles). PFS confirmed by independent radiology review was the primary endpoint. Results Crizotinib significantly prolonged PFS (HR, 0.402; 95% CI, 0.286–0.565; p<0.001). Median PFS was 11.1 months with crizotinib and 6.8 months with chemotherapy. The objective response rate (ORR) was 87.5% (95% CI, 79.6–93.2%) with crizotinib versus 45.6% (95% CI, 35.8–55.7%) with chemotherapy (p<0.001). The most common adverse events were elevated transaminases, diarrhea and vision disorders with crizotinib and leukopenia, neutropenia and anemia with chemotherapy. Significantly greater improvements from baseline in patient-reported outcomes were seen in crizotinib-treated versus chemotherapy-treated patients. Conclusions First-line crizotinib significantly improved PFS, ORR and patient-reported outcomes compared with standard platinum-based chemotherapy in East Asian patients with ALK-positive advanced NSCLC, similar to results from PROFILE 1014. Crizotinib and chemotherapy safety profiles were consistent with those previously published.
Activity of Afatinib in Heavily Pretreated Patients with HER2 Mutation-Positive Advanced NSCLC: Findings from a Global Named Patient Use Program J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-07 Solange Peters, Alessandra Curioni-Fontecedro, Hovav Nechushtan, Jin-Yuan Shih, Wei-Yu Liao, Oliver Gautschi, Vito Spataro, Mojca Unk, James Chih-Hsin Yang, Robert M. Lorence, Philippe Carrière, Agnieszka Cseh, Gee-Chen Chang
Introduction Approximately 1–4% of non-small-cell lung cancer (NSCLC) tumors harbor a human epidermal growth factor receptor 2 (HER2) mutation; there is no approved targeted treatment for this subgroup. Methods Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating epidermal growth factor receptor (EGFR) or HER2 mutations, had exhausted other treatments, and were ineligible for afatinib trials, were enrolled in a named patient use (NPU) program, receiving afatinib 30–50 mg/day on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with HER2 mutation-positive NSCLC. Results Twenty-eight heavily pretreated patients in the NPU program had a documented HER2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF > 1 year. Objective response rate (ORR) was 19% (3/16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11/16). Among 12 patients for whom type of HER2 mutation was specified, ten had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib > 1 year. This subgroup had median TTF of 9.6 months, ORR 33% (2/6), and DCR 100% (6/6). Conclusions This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in HER2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with HER2-targeted treatment.
Brief Report: CUX1-ALK, a Novel ALK Rearrangement That Responds to Crizotinib in Non-Small-Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-08-07 Meiling Zhang, Qian Wang, Yan Ding, Guoqun Wang, Yunqian Chu, Xiang He, Xue Wu, Yang W. Shao, Kaihua Lu
Introduction Lung cancer is the leading cause of cancer-related deaths worldwide. ALK rearrangement has been identified in 3% to 5% non-small-cell lung cancer (NSCLC) patients. The most common ALK rearrangement is EML4-ALK with several variants which can be targeted by the tyrosine kinase inhibitor crizotinib. Methods In this study, using comprehensive next-generation sequencing targeting 416 pan-cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel CUX1-ALK fusion gene in a lung adenocarcinoma patient. The exact CUX1-ALK fusion transcript was determined via RNA-seq, and confirmed by RT-PCR. The oncogenic ability of CUX1-ALK fusion gene was further validated in 293T cells for the activation of ALK self-phosphorylation and downstream signaling pathways. Results After the detection of CUX1-ALK fusion gene, RNA-seq analysis of FFPE sections from the primary tumor specimen was applied to reveal a 97 nt fragment from CUX1 intron 8 inserted before the 53 nt position in ALK exon 20. Expression of the CUX1-ALK fusion protein in 293T cells confirmed the self-phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including MAPK, JAK-STAT, and PI3K/AKT signaling pathways, which all could be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib with a progression-free survival of 20 months. Conclusions This study provides the novel finding of CUX1-ALK fusion gene from NSCLC patient which could provide personalized treatment solutions for the maximum benefit to NSCLC patients.
Stereotactic body radiation therapy (SBRT) for central early stage non-small cell lung cancer: results of a prospective phase I/II trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-26 Michael C. Roach, Cliff G. Robinson, Todd A. DeWees, Jehan Ganachaud, Daniel Przybysz, Robert Drzymala, Sana Rehman, Rojano Kashani, Jeffrey D. Bradley
IntroductionWe report results from a prospective phase I/II trial for patients with centrally-located, early-stage non-small cell lung cancer (NSCLC) receiving stereotactic body radiation therapy (SBRT).MethodsEligible patients were medically inoperable with biopsy-proven NSCLC within 2 cm of the proximal bronchial tree or 5 mm of the mediastinal pleura or parietal pericardium. Phase I had 4 dose levels using 5 fractions: 9, 10, 11, and 12 Gy per fraction. The primary phase II objective was to determine if the maximum tolerated dose in phase I achieved local control >80% at 2 years.ResultsSeventy-four patients were enrolled; 23 to phase I and 51 to phase II. Two phase I patients treated with 10 Gy x5 developed unrelated acute grade 3 lung toxicities which resolved. The phase II dose level selected was 11 Gy x5 fractions. The median follow-up for living phase II patients was 27 months (range: 9-58). Two-year local control using 11 Gy x5 fractions was 85% (95% CI: 62-95%). Two-year overall survival was 43% (95% CI: 28-57%). Three patients (6%, 95% CI: 1-17%) experienced acute grade 3 and 4 cardiac or pulmonary toxicities. Of the 41 patients evaluable for late cardiac and pulmonary toxicity, 11 (27%, 95% CI: 14-43%) developed grade 3, 5 (12%, 95% CI: 4-26%) developed grade 4, and 1 (4%, 95% CI: 0-13%) died of grade 5 toxicity.ConclusionSBRT for central NSCLC using 11 Gy x5 fractions is tolerable and has excellent local control, but is associated severe late toxicity in some patients.
Strong PD-L1 expression predicts poor response and de novo resistance to EGFR TKIs among non-small cell lung cancer patients with EGFR mutation J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-26 Shan Su, Zhong-Yi Dong, Zhi Xie, Li-Xu Yan, Yu-Fa Li, Jian Su, Si-Yang Liu, Kai Yin, Rui-Lian Chen, Shu-Mei Huang, Zhi-Hong Chen, Jin-Ji Yang, Hai-Yan Tu, Qing Zhou, Wen-Zhao Zhong, Xu-Chao Zhang, Yi-Long Wu
IntroductionThis study evaluated whether tumor expression of programmed death-ligand 1 (PD-L1) could predict the response of EGFR-mutated non-small cell lung cancer (NSCLC) to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy.MethodsWe retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC at the Guangdong Lung Cancer Institute between April 2016 and September 2017 and were not enrolled in clinical studies. The patients' EGFR and PD-L1 statuses were simultaneously evaluated.ResultsAmong the 101 eligible patients, strong PD-L1 expression significantly decreased objective response rate (ORR), compared with weak or negative PD-L1 expression (35.7% vs 63.2% vs 67.3%, P=0.002), and shortened progression-free survival (PFS, 3.8 vs 6.0 vs 9.5 months, P<0.001), regardless of EGFR mutation type (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% vs 30.2%, P=0.009). Notably, we found a high proportion of PD-L1 and CD8 dual-positive cases among patients with de novo resistance (46.7%, 7/15). Finally, one patient with de novo resistance to EGFR-TKIs and PD-L1 and CD8 dual positivity experienced a favorable response to anti-PD-1 therapy.ConclusionThis study revealed the adverse effects of PD-L1 expression on EGFR-TKI efficacy, especially in NSCLC patients with de novo resistance. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1 and CD8 dual positivity and suggest potential therapeutic sensitivity to PD-1 blockade.
Mismatch repair protein defects and microsatellite instability in malignant pleural mesothelioma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-26 Surein Arulananda, Bibhusal Thapa, Marzena Walkiewicz, Giada V. Zapparoli, David S. Williams, Alexander Dobrovic, Thomas John
IntroductionMalignant pleural mesothelioma is an aggressive malignancy with limited systemic therapy options. Promising results have been reported with use of anti-PD-1 therapy, however it appears to be confined to a subgroup of patients. Microsatellite instability (MSI) results from the inactivation of DNA mismatch repair genes and results in a high tumour mutational burden, a phenomenon that has not been seen with mesothelioma. MSI and protein absence have been shown to correlate in colorectal cancer, such that most centres have adopted IHC to screen for MSI-high colorectal cancers. We profiled a large mesothelioma cohort to determine the rate of negative immunohistochemistry for the four common mismatch repair proteins.DesignA tissue microarray comprising 335 patients with malignant pleural mesothelioma were used. Immunohistochemistry (IHC) for the four common mismatch repair proteins (MLH1, PMS2, MSH2 and MSH6) was performed. PD-L1 IHC staining with the E1L3N clone was also performed. DNA was isolated from IHC equivocal samples and analysed for microsatellite instability using the Promega MSI Analysis System, Version 1.2.ResultsOf 335 patients profiled, 329 had intact mismatch repair proteins by immunohistochemistry. Six samples with absent mismatch repair protein immunohistochemistry analysis were analysed for MSI and confirmed to be negative. Of the six IHC+ samples, five were absent for PD-L1 staining and one sample had more than 5% staining.ConclusionIn this large retrospective series, we were unable to identify any malignant pleural mesothelioma patients with microsatellite instability. Response to anti-PD-1 based immunotherapy may be driven by other mechanisms.
Phase II Study of Maintenance Pembrolizumab in Patients with Extensive-Stage Small Cell Lung Cancer (SCLC) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-17 Shirish M. Gadgeel, Nathan A. Pennell, Mary Jo Fidler, Balazs Halmos, Philip Bonomi, James Stevenson, Bryan Schneider, Ammar Sukari, Jaclyn Ventimiglia, Wei Chen, Cathy Galasso, Antoinette Wozniak, Julie Boerner, Gregory P. Kalemkerian
Objective The aim of this study was to assess the efficacy of maintenance pembrolizumab in patients with extensive-stage SCLC after treatment with platinum and etoposide. Methods Patients with extensive-stage SCLC with a response or stable disease after induction chemotherapy were eligible. Pembrolizumab at a dose of 200 mg administered intravenously every 3 weeks was initiated within 8 weeks of the last cycle of chemotherapy. The primary end point of the study was progression-free survival (PFS) from study registration, with overall survival (OS) as a key secondary end point. Available tumor tissue was assessed for expression of programmed death ligand 1 (PD-L1) both in the tumor cells and in the surrounding stroma. Blood for circulating tumor cells was collected before the first, second, and third cycles of pembrolizumab. Results Of the 45 patients enrolled, 56% were male and 22% had treated brain metastases. The median PFS was 1.4 months (95% confidence interval [CI]: 1.3–2.8), with a 1-year PFS of 13%. The median OS was 9.6 months (95% CI: 7.0–12), with a 1-year OS of 37%. Of the 30 tumors that could be assessed, three had PD-L1 expression (≥1%) in the tumor cells. A total of 20 tumors could be assessed for PD-L1 expression in the stroma. The median PFS in the eight patients with tumors positive for expression of PD-L1 at the stromal interface was 6.5 months (95% CI: 1.1–12.8) compared with 1.3 months (95% CI: 0.6–2.5) in 12 patients with tumors negative for this marker. No unexpected toxicities were observed. Conclusion Maintenance pembrolizumab did not appear to improve median PFS compared with the historical data. However, the 1-year PFS rate of 13% and OS rate of 37% suggest that a subset of patients did benefit from pembrolizumab.
Long-term Active Surveillance of Screening Detected Subsolid Nodules is a Safe Strategy to Reduce Overtreatment J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-16 Mario Silva, Mathias Prokop, Colin Jacobs, Giovanni Capretti, Nicola Sverzellati, Francesco Ciompi, Bram van Ginneken, Cornelia M. Schaefer-Prokop, Carlotta Galeone, Alfonso Marchianò, Ugo Pastorino
IntroductionLung cancer presenting as subsolid nodule (SSN) can show slow growth, hence treating SSN is controversial. Our aim was to determine the long-term outcome of subjects with unresected SSNs in lung cancer screening.MethodsSince 2005, the Multicenter Italian Lung Detection (MILD) screening trial implemented active surveillance for persistent SSN, as opposed to early resection. Presence of SSNs was related to diagnosis of cancer at the site of SSN, elsewhere in the lung or in the body. The risk of overall mortality and lung cancer mortality was tested by Cox proportional hazards model.ResultsSSN were found in 16.9% (389/2,303) of screenees. During 9.3±1.2 years of follow-up, the hazard ratio (HR) of lung cancer diagnosis in subjects with SSN was 6.77 (95%CI:3.39-13.54), with 73% (22/30) of cancers not arising from SSN (median time to diagnosis 52 months from SSN). Lung cancer-specific mortality in subjects with SSN was significantly increased (HR 3.80; 95%CI:1.24-11.65) compared to subjects without lung nodules. Lung cancer arising from SSN did not lead to death within the follow-up period.ConclusionsSubjects with SSN in the MILD cohort showed a high risk of developing lung cancer elsewhere in the lung, with only a minority of cases arising from SSN, and never representing the cause of death. These results demonstrate the safety of active surveillance for conservative management of SSN until signs of solid component growth, and the need for prolonged follow-up because of high risk of other cancers.
Prognostic Impact of Tumor Mutation Burden in Patients With Completely Resected Non–Small Cell Lung Cancer: Brief Report J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-12 Yuki Owada-Ozaki, Satoshi Muto, Hironori Takagi, Takuya Inoue, Yuzuru Watanabe, Mitsuro Fukuhara, Takumi Yamaura, Naoyuki Okabe, Yuki Matsumura, Takeo Hasegawa, Jun Ohsugi, Mika Hoshino, Yutaka Shio, Hideaki Nanamiya, Jun-ichi Imai, Takao Isogai, Shinya Watanabe, Hiroyuki Suzuki
IntroductionTumor mutation burden (TMB) is thought to be associated with the amount of neoantigen in the tumor and to have an important role in predicting the effect of immune checkpoint inhibitors. However, the relevance of TMB to prognosis is not yet fully understood. In this study, we investigated the clinical significance of TMB in patients with NSCLC and examined the relationship between TMB and prognosis.MethodsWe calculated TMB within individual tumors by whole-exome sequencing analysis using next-generation sequencing. We included that there were 90 patients with NSCLC who underwent surgery in the Hospital of Fukushima Medical University from 2013 to 2016. No patients received chemotherapy or immunotherapy before surgery. We assessed the correlation between TMB and prognosis.ResultsTMB greater than 62 was associated with worse overall survival (OS) of patients with NSCLC (hazard ratio [HR] = 6.633, p = 0.0003). Multivariate analysis showed poor prognosis with high TMB (HR = 12.31, p = 0.019). In patients with stage I NSCLC, higher TMB was associated with worse prognosis for both OS (HR = 7.582, p = 0.0018) and disease-free survival (HR = 6.07, p = 0.0072).ConclusionsHigh TMB in NSCLC is a poor prognostic factor. If high TMB is a predictor of the efficacy of immune checkpoint inhibitors, postoperative adjuvant therapy with immune checkpoint inhibitors may contribute to improvement of recurrence and OS.
Exploring Radiotherapy Targeting Strategy and Dose: A Pooled Analysis of Cooperative Group Trials of Combined Modality Therapy for Stage III NSCLC J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-22 Steven E. Schild, Herbert H. Pang, Wen Fan, Thomas E. Stinchcombe, Everett E. Vokes, Suresh S. Ramalingam, Jeffrey D. Bradley, Karen Kelly, Xiaofei Wang
IntroductionConcurrent chemoradiotherapy (CRT) is standard therapy for locally advanced NSCLC (LA-NSCLC) patients. This study was performed to examine thoracic radiotherapy (TRT) parameters and their impact on patient survival.MethodsWe collected individual patient data from 3600 LA-NSCLC patients participating in 16 cooperative group trials of concurrent CRT. The primary TRT parameters examined included field design strategy (elective nodal irradiation [ENI] compared to involved-field TRT (IF-TRT)), total dose, and biologically effective dose (BED). Hazard ratios (HRs) for overall survival were calculated with univariable and multivariable Cox models.ResultsTRT doses ranged from 60 Gy to 74 Gy with most treatments administered once-daily. ENI was associated with poorer survival than IF-TRT (univariable HR = 1.37, 95% confidence interval [CI]: 1.24–1.51, p < 0.0001; multivariable HR = 1.31, 95% CI: 1.08–1.59, p = 0.002). The median survival times of the IF and ENI patients were 24 months and 16 months, respectively. Patients were divided into three dose groups: low total dose (60 Gy), medium total dose (>60 Gy to 66 Gy), and high total dose (>66 Gy to 74 Gy). With reference to the low-dose group, the multivariable HRs were 1.08 for the medium-dose group (95% CI: 0.93–1.25) and 1.12 for the high-dose group (95% CI: 0.97–1.30).The univariate p = 0.054 and multivariable p = 0.17. BED was grouped as follows: low (<55.5 Gy10), medium (55.5 Gy10), or high (>55.5 Gy10). With reference to the low-BED group, the HR was 1.00 (95% CI: 0.85–1.18) for the medium-BED group and 1.10 (95% CI: 0.93–1.31) for the high-BED group. The univariable p = 0.076 and multivariable p = 0.16.ConclusionsFor LA-NSCLC patients treated with concurrent CRT, IF-TRT was associated with significantly better survival than ENI-TRT. TRT total and BED dose levels were not significantly associated with patient survival. Future progress will require research focusing on better systemic therapy and TRT.
Estimating the Cost-Effectiveness of Lung Cancer Screening with Low-Dose Computed Tomography for High-Risk Smokers in Australia J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-22 Stephen Wade, Marianne Weber, Michael Caruana, Yoon-Jung Kang, Henry Marshall, Renee Manser, Shalini Vinod, Nicole Rankin, Kwun Fong, Karen Canfell
IntroductionHealth economic evaluations of lung cancer screening with low-dose computed tomography (LDCT) that are underpinned by clinical outcomes are relatively few.MethodsWe assessed the cost-effectiveness of LDCT lung screening in Australia by applying Australian cost and survival data to the outcomes observed in the U.S. National Lung Screening Trial (NLST), in which a 20% lung cancer mortality benefit was demonstrated for three rounds of annual screening among high-risk smokers age 55 to 74 years. Screening-related costs were estimated from Medicare Benefits Schedule reimbursement rates (2015), lung cancer diagnosis and treatment costs from a 2012 Australian hospital–based study, lung cancer survival rates from the New South Wales Cancer Registry (2005–2009), and other-cause mortality from Australian life tables weighted by smoking status. The health utility outcomes, screening participation rates, and lung cancer rates were those observed in the NLST. Incremental cost effectiveness ratios (ICER) were calculated for a 10-year time horizon.ResultsThe cost-effectiveness of LDCT lung screening was estimated at AU$138,000 (80% confidence interval: AU$84,700–AU$353,000)/life-year gained and AU$233,000 (80% confidence interval: AU$128,000–AU$1,110,000)/quality-adjusted life year (QALY) gained. The ICER was more favorable when LDCT screening impact on all-cause mortality was considered, even when the costs of incidental findings were also estimated in sensitivity analyses: AU$157,000/QALY gained. This can be compared to an indicative willingness-to-pay threshold in Australia of AU$30,000 to AU$50,000/QALY.ConclusionsLDCT lung screening using NLST selection and implementation criteria is unlikely to be cost-effective in Australia. Future economic evaluations should consider alternative screening eligibility criteria, intervals, nodule management, the impact and cost of new therapies, investigations of incidental findings, and incorporation of smoking cessation interventions.
Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-24 Dwight Owen, Benjamin Chu, Amy M. Lehman, Lakshmanan Annamalai, Jennifer H. Yearley, Konstantin Shilo, Gregory A. Otterson
IntroductionThymic epithelial tumors (TETs) including thymoma and thymic carcinoma are rare tumors with little data available to guide treatment. Immunotherapy with checkpoint blockade has shown promising activity, but data regarding the expression patterns and prognostic implications of programmed death 1 (PD-1) and its ligand (PD-L1) in TETs have yielded conflicting results. Intratumoral heterogeneity of PD-1/L1 expression has been shown in other cancers, but has not been described in the TET literature.MethodsWe performed a retrospective single-center review of 35 patients with resected TET. PD-1/L1 expression was assessed by immunohistochemistry using PD-1 clone: NAT105 and PD-L1 clone: 22C3. Tumor samples from 35 patients were evaluated including 32 patients with thymoma and 3 patients with thymic carcinoma.ResultsPD-L1 expression was detected in 83% (29 of 35) tumor samples, including 100% (3 of 3) of thymic carcinoma patients and 81% (26 of 32) of thymoma patients. PD-1 expression was detected in 77% (27 of 35), including 33% (1 of 3) of thymic carcinoma patients and 81% (26 of 32) thymoma patients. High PD-1 expression was associated with lower grade tumors. Unlike prior studies, PD-L1 expression was not associated with higher grade tumors or higher stage. Neither PD-L1 nor PD-1 expression was significantly associated with survival. Three patients with thymoma had multiple tumor sections evaluated for expression of PD-1/L1, with differing expression patterns of both PD-L1 and PD-1 observed in two patients.ConclusionsThis study confirms high expression of PD-L1 and PD-1 in TET and shows for the first time intratumoral heterogeneity of PD-L1 and PD-1 in thymoma patients.
Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion–Positive Advanced NSCLC J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-24 Bianca van Veggel, Adrianus J. de Langen, Sayed M.S. Hashemi, Kim Monkhorst, Daniëlle A.M. Heideman, Erik Thunnissen, Egbert F. Smit
IntroductionEGFR exon 20 insertions comprise 4% to 9% of EGFR mutated NSCLC. Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses.MethodsFour patients with EGFR exon 20 insertion–positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250 mg/m2 to 500 mg/m2 every 2 weeks.ResultsAll patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n = 4) and EGFR TKI (n = 2). Three of four patients showed a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Median progression-free survival was 5.4 months (95% confidence interval: 0.0 – 14.2 months; range 2.7 months – 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients.ConclusionsDual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion–positive NSCLC.
PD-L1 Expression Heterogeneity in Non–Small Cell Lung Cancer: Defining Criteria for Harmonization between Biopsy Specimens and Whole Sections J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-04-25 Enrico Munari, Giuseppe Zamboni, Gianluigi Lunardi, Luigi Marchionni, Marcella Marconi, Marco Sommaggio, Matteo Brunelli, Guido Martignoni, George J. Netto, Mohammad O. Hoque, Francesca Moretta, Maria Cristina Mingari, Maria Cristina Pegoraro, Alessandro Inno, Simona Paiano, Alberto Terzi, Alberto Cavazza, Giulio Rossi, Giuseppe Bogina
IntroductionDetermination of programmed death ligand 1 (PD-L1) expression defines eligibility for treatment with pembrolizumab in patients with advanced NSCLC. This study was designed to better define which value across core biopsy specimens from the same case more closely reflects the PD-L1 expression status on whole sections and how many core biopsy specimens are needed for confident classification of tumors in terms of PD-L1 expression.MethodsWe built tissue microarrays as surrogates of biopsies collecting five cores per case from 268 cases and compared PD-L1 staining results obtained by using the validated clone SP263 with the results obtained by using whole tumor sections.ResultsWe found an overall positivity in 39% of cases at a cutoff of 1% and in 10% of cases at a cutoff of 50%. The maximum value across cores was associated with high concordance between cores and whole sections and the lowest number of false-negative cases overall. To reach high concordance with whole sections, four and three cores are necessary at cutoffs of 1% and 50%, respectively. Importantly, with 20% as the cutoff for core biopsy specimens, fewer than three cores showed high sensitivity and specificity in identifying cases with 50% or more of tumor cells positive for PD-L1 on whole sections. Specifically, for PD-L1 expression values of 20% to 49% on cores, the probabilities of a tumor specimen expressing PD-L1 in at least 50% of cells on a whole section were 46% and 24% with one and two biopsy specimens, respectively.ConclusionsAn accurate definition of the criteria to determine the PD-L1 status of a given tumor may greatly help in selecting those patients who could benefit from anti–programmed cell death 1/PD-L1 treatment.
Proteogenomic Analysis of Surgically Resected Lung Adenocarcinoma J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-11 Michael F. Sharpnack, Nilini Ranbaduge, Arunima Srivastava, Ferdinando Cerciello, Simona G. Codreanu, Daniel C. Liebler, Celine Mascaux, Wayne O. Miles, Robert Morris, Jason E. McDermott, James L. Sharpnack, Joseph Amann, Christopher A. Maher, Raghu Machiraju, Vicki H. Wysocki, Ramaswami Govindan, Parag Mallick, Kevin R. Coombes, David P. Carbone
Introduction Despite apparently complete surgical resection, approximately half of resected early stage lung cancer patients relapse and die of their disease. Adjuvant chemotherapy reduces this risk by only 5-8%. Thus, there is a need for better identifying who benefits from adjuvant therapy, the drivers of relapse and novel targets in this setting. Methods RNAseq and LC/LC MS proteomics data was generated from 51 surgically resected non-small cell lung tumors with known recurrence status. Results We present a rationale and framework for the incorporation of high-content RNA and protein measurements into integrative biomarkers and demonstrate the potential of this approach for predicting risk of recurrence in a group of lung adenocarcinomas. In addition, we characterize the relationship between mRNA and protein measurements in lung adenocarcinoma and show that it is outcome specific. Conclusions Our results suggest that mRNA and protein data possess independent biological and clinical importance, which can be leveraged to create higher-powered expression biomarkers.
Brief Report: Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients with RET-Rearranged Lung Cancers J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-11 Alexander Drilon, Jessica J. Lin, Thomas Filleron, Ai Ni, Julie Milia, Isabella Bergagnini, Vaios Hatzoglou, Vamsidhar Velcheti, Michael Offin, Bob Li, David P. Carbone, Benjamin Besse, Tony Mok, Mark M. Awad, Jurgen Wolf, Dwight Owen, D. Ross Camidge, Gregory J. Riely, Oliver Gautschi
Background In RET-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. Methods A global, multi-institutional registry (cohort A, n=114) and a bi-institutional data set (cohort B, n=71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. Results The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95%CI 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95%CI 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p=0.0039) between RET-, ROS1-, and ALK-rearranged lung cancers, with RET intermediate between the other two groups. While intracranial response data was not available in cohort A, the median progression-free survival (PFS) of multikinase inhibitor therapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95%CI 1.3-2.9 months, n=10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (±everolimus), ponatinib, or alectinib; the median overall PFS (intracranial and extracranial) was 3.9 months (95%CI 2.0-4.9 months). Conclusions Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.
Nedaplatin plus Docetaxel versus Cisplatin plus Docetaxel as First-Line Chemotherapy for Advanced Squamous Cell Carcinoma of the Lung - A Multicenter, Open-label, Randomized, Phase III Trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-11 Shun Lu, Zhiwei Chen, Chengping Hu, Jian Zhang, Yuan Chen, Yong Song, Qiong Zhao, Yun Fan, Gang Wu, Zhiyong Ma, Jian Fang, Qitao Yu, Zhe Liu
Hypothesis To compare the efficacy of first-line nedaplatin (80 mg/m2) plus docetaxel (75 mg/m2) (ND) versus cisplatin (75 mg/m2) plus docetaxel (75 mg/m2) (CD) in patients with advanced squamous cell lung carcinoma. Methods This was an open-label, randomized controlled phase III trial carried out at 12 hospitals in China. Patients with squamous cell lung carcinoma were randomized to four cycles of ND or CD. The primary endpoint was progression-free survival (PFS). Secondary endpoints included time to progression (TTP), best overall response and adverse events. Results In the intent-to-treat analysis set (ND: n=141; CD: n=139), median PFS was 4.63 months (95%confidence interval (CI),4.43-5.10) for the ND and 4.23 months (95%CI,3.37-4.53) for CD groups (P=0.056). No significant difference in TTP was observed between the two groups. Best overall responses and disease control rate were better with ND 51.5%, than with CD 38.1% (P=0.033 and P=0.0004, respectively). Grade III or IV adverse events and Grade 3-4 nausea and fatigue were more frequent in the CD group compared with the ND group (all P<0.05). Conclusion There is no improvement in PFS with the nedaplatin and docetaxel combination in the intent-to-treat analysis. More hematological toxicities were observed in the ND group (compared with CD), while more non-hematological toxicities were observed in the CD group. ND could be a new treatment option for advanced or relapsed squamous cell lung cancer.
New Subsolid Pulmonary Nodules in Lung Cancer Screening: The NELSON Trial J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-12 Joan E. Walter, Marjolein A. Heuvelmans, Uraujh Yousaf-Khan, Monique D. Dorrius, Erik Thunnissen, Anna Schermann, Harry J.M. Groen, Carlijn M. van der Aalst, Kristiaan Nackaerts, Rozemarijn Vliegenthart, Harry J. de Koning, Matthijs Oudkerk
Introduction Low-dose computed tomography (LDCT) lung cancer screening is recommended in the United States. While new solid nodules after baseline screening have a high lung cancer probability at small size and require lower size cutoff values than baseline nodules, there only is limited evidence on management of new subsolid nodules. Methods Within the Dutch-Belgian randomized controlled LDCT lung cancer screening trial (NELSON), 7557 participants underwent baseline screening between April 2004 and December 2006. Participants with new subsolid nodules detected after the baseline screening round were included. Results In the three incidence screening rounds, 60 new subsolid nodules (43 [72%] part-solid, 17 [28%] nonsolid) not visible in retrospect were detected in 51 participants, representing 0.7% (51 of 7295) of participants with at least one incidence screening. Eventually, 6% (3 of 51) of participants with a new subsolid nodule were diagnosed with (pre-)malignancy in such a nodule. All (pre-)malignancies were adenocarcinoma (in situ) and diagnostic workup (referral 950, 364, and 366 days after first detection, respectively) showed favorable staging (stage I). Overall, 67% (33 of 49) of subsolid nodules with an additional follow-up screening were resolving. Conclusions Less than 1% of participants in LDCT lung cancer screening presents with a new subsolid nodule after baseline. Contrary to new solid nodules, data suggest that new subsolid nodules may not require a more aggressive follow-up.
Diverse EGFR Exon 20 Insertions and Co-Occurring Molecular Alterations Identified by Comprehensive Genomic Profiling of Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-05 Jonathan W. Riess, David R. Gandara, Garrett M. Frampton, Russell Madison, Nir Peled, Jose A. Bufill, Grace Dy, Sai-Hong Ignatius Ou, Philip J. Stephens, John McPherson, Primo N. Lara, Rebekah A. Burich, Jeffrey S. Ross, Vincent A. Miller, Siraj M. Ali, Philip C. Mack, Alexa B. Schrock
IntroductionEGFR exon 20 insertions (EGFRex20ins) comprise an uncommon subset of EGFR activating alterations relatively insensitive to first and second-generation EGFR tyrosine kinase inhibitors (TKIs). However, recent early clinical data suggests these patients may benefit from newer generation EGFR-TKIs. Comprehensive genomic profiling (CGP) identifies a broad spectrum of EGFRex20ins and associated co-occurring genomic alterations (GA) present in non-small cell lung cancer (NSCLC)MethodsHybrid capture-based CGP was performed prospectively on 14,483 clinically annotated consecutive NSCLC specimens to a mean coverage depth of >650X for 236 or 315 cancer-related genes.ResultsOf 14,483 NSCLC cases, CGP identified 263 (1.8%) cases with EGFRex20ins, representing 12% (263/2,251) of cases with EGFR mutations. 64 unique EGFRex20ins were identified, most commonly D770_N771>ASVDN (21%) and N771_P772>SVDNP (20%). EGFR amplification occurred in 22% (57/263). The most common co-occurring GA effected TP53 (56%), CDKN2A (22%), CDKN2B (16%), NKX2-1 (14%) and RB1 (11%); co-occurring GA in other known lung cancer drivers were rare (5%). Average tumor mutational burden (TMB) was low (mean 4.3, range 0-40.3 mutations/Mb). Clinical outcomes to first- and second-generation EGFR TKIs were obtained for 5 patients and none responded.ConclusionIn the largest series of EGFRex20ins NSCLC, diverse EGFRex20ins were detected in 12% of EGFR-mutant NSCLC, a higher frequency than previously reported in smaller single-institution studies. Clinical outcomes demonstrated lack of response to EGFR TKIs. TMB was low, consistent with non-smoking associated NSCLC. Comprehensive sequencing revealed increased proportion and wide variety of EGFRex20ins, representing a population of patients significant enough for focused efforts on effective interventions.
A longitudinal investigation of internalized stigma, constrained disclosure, and quality of life across 12 weeks in lung cancer patients on active oncologic treatment J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-05 Timothy J. Williamson, Alyssa K. Choi, Julie C. Kim, Edward B. Garon, Jenessa R. Shapiro, Michael R. Irwin, Jonathan W. Goldman, Krikor Bornyazan, James M. Carroll, Annette L. Stanton
IntroductionInternalized lung cancer stigma (i.e., feelings of regret, shame, and self-blame about one’s lung cancer) is related to poorer psychological outcomes. Less is known about how internalized stigma relates to physical and functional outcomes or how constrained disclosure (i.e., avoidance of or discomfort about disclosing one’s lung cancer status to others) relates to well-being. Furthermore, no study has examined whether internalized stigma and constrained disclosure predict changes in well-being for lung cancer patients. This longitudinal study characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional outcomes.MethodsParticipants (N=101, 52.4% male, 63.4% currently/formerly smoked) were lung cancer patients on active medical treatment who completed questionnaires on stigma and well-being at study entry and at 6- and 12-week follow-up. Multivariable linear regressions characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional well-being at study entry and across time.ResultsParticipants who currently or formerly smoked reported higher levels of internalized stigma (but not constrained disclosure), compared to never smokers (p<.001). Higher internalized stigma and constrained disclosure were uniquely associated with poorer emotional and physical/functional well-being at study entry (all p<.05), beyond sociodemographic characteristics, time elapsed since diagnosis, and smoking status. Higher internalized stigma predicted significant declines in emotional well-being across 6 and 12 weeks (all p<.01) and declines in physical/functional well-being across 6 weeks (p<.05).ConclusionsInternalized lung cancer stigma and constrained disclosure relate to emotional and physical/functional maladjustment. Findings carry implications for provider- and patient-focused interventions to reduce internalized stigma and promote well-being.
The incidence of brain metastases in stage IV ROS1-rearranged non-small cell lung cancer and rate of central nervous system progression on crizotinib J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-05 Tejas Patil, Derek E. Smith, Paul A. Bunn, Dara L. Aisner, Anh T. Le, Mark Hancock, William T. Purcell, Daniel W. Bowles, D. Ross Camidge, Robert C. Doebele
IntroductionCentral nervous system (CNS) metastases in lung cancer are a frequent cause of morbidity and mortality. There are conflicting data on the incidence of CNS metastases in stage IV ROS1+ non-small cell lung cancer (NSCLC) and rate of CNS progression on crizotinib.MethodsA retrospective review of 579 patients with stage IV NSCLC between June 2008 to December 2017 was performed. Brain metastases and oncogene status (ROS1, ALK, EGFR, KRAS, BRAF, and other) were recorded. We measured progression free survival (PFS) and time to CNS progression (P-CNS) in ROS1+ and ALK+ patients on crizotinib.ResultsWe identified 33 ROS1+ and 115 ALK+ patients with stage IV NSCLC. The incidence of brain metastases for treatment-naïve, stage IV ROS1+ and ALK+ NSCLC was 36% (12/33) and 34% (39/115) respectively. There were no statistically significant differences in incidence of brain metastases across ROS1, ALK, EGFR, KRAS, BRAF or other mutations. Complete survival data was available for 19 ROS1+ and 83 ALK+ patients. Median PFS for ROS1+ and ALK+ patients was 11 and 8 months (p = 0.304). The CNS was the first and sole site of progression in 47% (9/19) of ROS1+ and 33% ALK+ (28/83) patients with no differences between these groups (p = 0.610).ConclusionsBrain metastases are common in treatment-naïve stage IV ROS1+ NSCLC, though the incidence does not differ from other oncogene cohorts. The CNS is a common first site of progression in ROS1+ patients on crizotinib. This study reinforces the importance of developing CNS-penetrant TKIs for patients with ROS1+ NSCLC.
Lung Cancer Stigma Across the Social Network: Patients’ and Caregivers’ Perspectives J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-05 Stefano Occhipinti, Jeff Dunn, Dianne L. O’Connell, Gail Garvey, Patricia C. Valery, David Ball, Kwun M. Fong, Shalini Vinod, Suzanne Chambers
ObjectiveTo examine the personal experiences of people with lung cancer and of their caregivers and how stigma manifests throughout the patient’s social network.MethodsQualitative thematic analysis conducted on interviews with 28 lung cancer patients and caregivers. Telephone interviews were conducted and transcribed verbatim. Data analysis was guided by contemporary stigma theory.ResultsPatients and caregivers reported high levels of felt stigma and concomitant psychological distress in response to the diagnosis of lung cancer. Three overarching themes emerged: the nexus of lung cancer and smoking; moralization; attacking the link between lung cancer and smoking. Stigma was inevitably linked to smoking and this formed the hub around which other themes were organised. Caregivers reported feeling invisible and noted a lack of support systems for families and caregivers. As well, there was evidence that caregivers experienced stigma-by-association as members of the patients’ close networks. Both groups responded ambivalently to stigmatizing antismoking advertisements.ConclusionsThe qualitative analysis demonstrated the complex interplay of the social and the personal domains in the experience and outcomes of stigma in lung cancer. There is a significant potential for caregivers of lung cancer patients to experience exacerbations of psychosocial distress as a consequence of widely shared negative views about lung cancer and its prognosis. It remains for researchers and practitioners to incorporate such complexity in addressing stigma and psychosocial distress in both patients and caregivers.
Carcinoid Heart Disease in Patients with Bronchopulmonary Carcinoid J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-07 Tais De Jesus, S. Allen Luis, Jay H. Ryu, Julian R. Molina, Heidi M. Connolly, Joseph J. Maleszewski, Patricia A. Pellikka
IntroductionThe prevalence of carcinoid heart disease (CaHD) in bronchopulmonary carcinoid and its relationship with left-sided valvular disease are unknown.MethodsAll patients with a pathologic diagnosis of bronchopulmonary carcinoid and echocardiography performed at our institution between 2001 and 2016 were retrospectively reviewed. Echocardiograms were reviewed for features of CaHD including valvular leaflet thickening and retraction with resulting regurgitation and/or stenosis.ResultsBronchopulmonary carcinoid was present in 185 patients (age 67±13 years, 63% female). Carcinoid syndrome was present in 7.7% and liver metastases in 10%. Echocardiographic features of CaHD were present in just 2 (1%) patients. A 62-year-old woman underwent resection of stage 1A bronchopulmonary carcinoid without carcinoid syndrome and also received 7 months dexfenfluramine therapy. During 15 year follow-up, mitral regurgitation decreased and tricuspid regurgitation remained stable, a course more consistent with diet-drug related valve disease than CaHD. A 71-year-old woman status-post resection of a grade 1 hilar carcinoid tumor with carcinoid syndrome, liver metastases, and elevated 5-hydroxyindole acetic acid had typical thickening and retraction of tricuspid and pulmonary valves with severe regurgitation. The aortic valve was mildly thickened and retracted with mild regurgitation. She underwent tricuspid and pulmonary valve replacement and closure of a patent foramen ovale. Pathologic examination confirmed CaHD.ConclusionsCaHD occurs in <1% of patients with bronchopulmonary carcinoid. Bronchopulmonary carcinoid was associated with neither CaHD in the absence of liver metastases nor left-sided valve involvement in the absence of patent foramen ovale.
Pathologic grading of malignant pleural mesothelioma: An evidence-based proposal J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-07 Giuseppe Pelosi, Mauro Papotti, Luisella Righi, Giulio Rossi, Stefano Ferrero Bogetto, Silvano Bosari, Fiorella Calabrese, Izidor Kern, Patrick Maisonneuve, Angelica Sonzogni, Adriana Albini, Sergio Harari, Fausto Barbieri, Enrica Capelletto, Anna Maria Catino, Domenica Cavone, Angela De Palma, Nicola Fusco, Gabriella Serio
A pathologic grading score (PGS) in malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options and activate clinical trials.A series of 940 MPM patients (328 in a training set and 612 in a validation set) diagnosed between October 1980 and June 2015 at the participant Institutions was retrospectively assembled. PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (Kappa value > 0.75), different scores based on the increase of corresponding hazard ratios (HR). The relevant PGS ranged thus from 0 to 8 points within individual MPM patients.PGS was composed of histology (epithelioid/biphasic=0 point; sarcomatoid=2), necrosis (absent=0 vs. present=1), mitotic count per 1 mm2 (cut-offs: 1-2=0; 3-5=1; 6-9=2; 10 or more=4) and Ki-67 labeling index on 2000 cells (<30%=0; ≥30=1), all independent factors in both patient sets after adjusting for stage and age at diagnosis. No heterogeneity was seen across the validation centers (p=0.19). Epithelioid/biphasic MPM patterning and biopsy vs. resection did not affect survival, while PGS outperformed mitotic count and Ki-67 LI in both training (AUC-ROC=0.76) and validation sets (AUC-ROC=0.73) (p<0.01). Patient survival progressively deteriorated from score 0 (median=26.3 and 26.9 mo.) to score 1-3 (median=12.8 and 14.4 mo.) and score 4-8 (median=3.7 and 7.7 mo.) in both sets of patients, with HR for one point increase of score being 1.46 (95% CI=1.36-1.56) in the training set and 1.28 (95% CI=1.22-1.34) in the validation set (after adjusting for age and when available, tumor stage). PGS was effective even in subgroup analysis (epithelioid, biphasic and sarcomatoid tumors).A simple and reproducible multi-parametric PGS effectively predicted survival in MPM patients.
Predictors of physical and functional loss in advanced stage lung cancer patients receiving platinum chemotherapy J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-04 Emily Kinsey, Elizabeth Ajazi, Xiaofei Wang, Mary Ann (Mayzie) Johnston, Jeffrey Crawford
IntroductionMuscle wasting has detrimental effects including increased mortality. Identifying patients at risk can guide treatment efforts.MethodsPOWER 1 and 2 were randomized, double blind, placebo-controlled, multinational Phase III trials of 600 lung cancer patients initiating chemotherapy to assess the efficacy of enobosarm on prevention and treatment of muscle loss. We performed a secondary analysis restricted to the control group using a cumulative logit model for ordinal outcome to determine which baseline characteristics predicted physical and functional loss during chemotherapy.ResultsFifty three percent of patients had loss of lean body mass and 49% had loss of stair climb power (SCP) at day 84 of treatment. Of the 322 placebo patients, 232 with observable outcome and baseline covariates were included for LBM analysis and 236 for SCP analysis. More advanced disease predicted higher probability of greater physical loss (OR 1.96, 95%CI 1.14-3.36). Three factors predicted higher probability of SCP loss including taxane chemotherapy (OR 1.73, 95%CI 1.06-2.83), tobacco use before (OR 2.15, 95%CI 1.10-4.18), and SCP at baseline (OR 1.01, 95%CI 1.004-1.015). Higher BMI was a protective factor for functional loss (OR 0.85, 95%CI 0.73-0.98). A higher ECOG PS trended toward being predictive for greater probability of both physical (0.767) and functional loss (0.070), but the results were not statistically significant.ConclusionsApproximately 50% of patients with advanced lung cancer on chemotherapy had ongoing loss of muscle mass and muscle function. Advanced stage predicted physical loss. Tobacco use and taxane chemotherapy predicted functional loss. BMI was a protective factor for functional loss. We identified predictors of physical and functional loss that could be used as therapeutic targets or to guide treatment efforts.
Rare Variants in Known Susceptibility Loci and Their Contribution to Risk of Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-07-04 Yanhong Liu, Christine M. Lusk, Michael H. Cho, Edwin K. Silverman, Dandi Qiao, Ruyang Zhang, Michael E. Scheurer, Farrah Kheradmand, David A. Wheeler, Spiridon Tsavachidis, Georgina Armstrong, Dakai Zhu, Ignacio I. Wistuba, Chi-Wan B. Chow, Carmen Behrens, Claudio W. Pikielny, Christine Neslund-Dudas, Susan M. Pinney, Margaret R. Spitz
BackgroundGenome-wide association studies (GWAS) are widely used to map genomic regions contributing to lung cancer (LC) susceptibility but they typically do not identify the precise disease-causing genes/variants. To unveil the inherited causal LC variants, we performed focused exome sequencing analyses on genes located in 121 GWAS loci previously implicated in the risk of LC, chronic obstructive pulmonary disease, pulmonary function level and smoking behavior.MethodsGermline DNA from 260 LC cases and 318 controls were sequenced utilizing VCRome 2.1 exome capture. Filtering was based upon enrichment of rare and potential deleterious variants in cases (risk alleles) or controls (protective alleles). Allelic association analyses of single variant and gene-based burden tests of multiple variants were performed. Promising candidates were tested in two independent validation studies with a total of 1,773 cases and 1,123 controls.ResultsWe identified 48 rare variants with deleterious effects in the discovery analysis and validated 12 of the 43 candidates that were covered in the validation platforms. The top validated candidates included one well-established truncating variant BRCA2 K3326X (OR 2.36, 95% CI 1.38 - 3.99) and three newly identified variations: LTB p.Leu87Phe (OR 7.52, 95% CI 1.01 - 16.56), P3H2 p.Gln185His (OR 5.39, 95% CI 0.75 - 15.43), and DAAM2 p.Asp762Gly (OR 0.25, 95% CI 0.10 - 0.79). Burden tests revealed strong associations between ZNF93, DAAM2, BRD9, and LTB genes and LC susceptibility.ConclusionOur results extend the catalogue of regions associated with LC and highlight the importance of germline rare coding variants in LC susceptibility.
Histology, tumor volume, and radiation dose predict outcomes in non-small cell lung cancer patients after stereotactic ablative radiotherapy J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-27 Kevin Shiue, Alberto Cerra-Franco, Ronald Shapiro, Neil Estabrook, Edward M. Mannina, Christopher R. Deig, Sandra Althouse, Sheng Liu, Jun Wan, Yong Zang, Namita Agrawal, Pericles Ioannides, Yongmei Liu, Chen Zhang, Colleen DesRosiers, Greg Bartlett, Marvene Ewing, Mark P. Langer, Gordon Watson, Richard Zellars, Feng-Ming Kong, Tim Lautenschlaeger
IntroductionIt remains unclear if histology should be independently considered when choosing stereotactic ablative body radiotherapy (SABR) dose prescriptions for non-small cell lung cancer (NSCLC).MethodsThe study population included 508 patients with 561 lesions between 2000 and 2016, of which 442 patients with 482 lesions had complete dosimetric information. Eligible patients had histologically or clinically diagnosed early-stage NSCLC and were treated with 3 to 5 fractions. The primary endpoint was in-field tumor control censored by either death or progression. Involved lobe control was also assessed.ResultsAt 6.7 years median follow-up, 3-year in-field control, involved lobe control, overall survival, and progression-free survival were 88.1%, 80.0%, 49.4%, and 37.2%, respectively. Gross tumor volume (GTV, HR=1.01 per mL, p=0.0044) and histology (p=0.0225) were independently associated with involved lobe failure; GTV (HR=1.013, p=0.001) and GTV dose (cutoff of 110Gy, biologically effective dose with α/β=10 [BED10], HR=2.380, p=0.0084) were independently associated with in-field failure. For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12Gyx4 or 10Gyx5 vs. 18Gy or 20Gyx3: HR=3.530, p=0.0447, confirmed by propensity score matching) and was independent of GTV (HR=1.014 per mL, 95% CI 1.005-1.022, p=0.0012). For adenocarcinomas, there were no differences in in-field control observed using the above dose groupings (p=0.12 and p=0.31).ConclusionsIn the absence of level I data, GTV and histology should be considered to personalize radiation dose for SABR. We suggest lower prescription doses (i.e., 12Gyx4 or 10Gx5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.
5T4 is associated with favorable outcome for mesothelioma and a target for antibody drug conjugates J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-27 Laurel M. Schunselaar, Kim Monkhorst, Vincent van der Noort, Ruud Wijdeven, Dennis Peters, Wilbert Zwart, Jacques Neefjes, Paul Baas
ObjectivesThe prognosis for patients with mesothelioma is poor, which urges the need for the development of better treatment options. Antibody drug conjugates (ADCs) are gaining interest as a therapeutic strategy in mesothelioma. 5T4 is an oncofetal protein overexpressed in mesothelioma with low expression in normal tissue and therefore a good candidate for ADC treatment. Here, we evaluated and manipulated 5T4 as a suitable antigen for ADC targeted therapy in patients with mesothelioma.MethodsExpression of the 5T4 antigen is evaluated in (primary) mesothelioma cell lines and biopsies, and correlated with clinical outcome. Internalization was assessed in 5T4 expressing cells. The cytotoxicity of three different 5T4-targeting ADCs was tested on (primary) mesothelioma cells.Results5T4 was expressed in 10 out of 12 (primary) cell lines. Most biopsies stained positive for the 5T4 antigen, with marked differences in staining intensity and percentage of positive cells. High expression correlated with long progression-free survival. Both, free antibody and ADCs targeting 5T4, were internalized and entered lysosomal compartments. Cytotoxicity experiments showed that cell lines with a high expression for 5T4 were sensitive to two out of three ADCs. Lack of efficacy for the third ADC could be restored by neutralizing lysosomal compartments with chloroquine.ConclusionThe 5T4 antigen is expressed in mesothelioma and 5T4-based ADCs are internalized in lysosomes. Two out of three ADCs were capable of killing the mesothelioma cells, the third ADC required additional lysosomal neutralization for its effect. 5T4-based ADC would be a selective strategy for the treatment of mesothelioma.
Innate genetic evolution of lung cancers and spatial heterogeneity: analysis of treatment naïve lesions J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-19 Kenichi Suda, Jihye Kim, Isao Murakami, Leslie Rozeboom, Masaki Shimoji, Shigeki Shimizu, Christopher J. Rivard, Tetsuya Mitsudomi, Aik-Choon Tan, Fred R. Hirsch
Introduction Data regarding the pre-treatment inter-tumor heterogeneity of potential biomarkers in advanced-stage lung cancers is limited. A finding of such heterogeneity between primary and metastatic lesions would prove valuable to determine if a metastatic lesion can be a surrogate for the primary tumor, as more biomarkers will likely be used in the future to inform treatment decisions. Methods We performed RNA sequencing to analyze inter-tumor heterogeneity in thirty specimens (primary tumors, intra-thoracic, and extra-thoracic metastatic lesions) obtained from five treatment-naïve lung cancer patients. Results The global unsupervised clustering analysis showed that the lesions clustered at the individual patient level, rather than on the metastatic sites, suggesting that the characteristics of specific tumor cells have a greater impact on the gene expression signature than the microenvironment in which the metastasis develops. While, the mutational and transcriptional data highlight the presence of inter-tumor heterogeneity, showing that the primary tumors are usually distinct from metastatic lesions. Through a comparison between metastatic lesions and the primary tumors, we observed that pathways related to cell proliferation were upregulated, while immune-related pathways were downregulated in metastatic lesions. Conclusion These data not only provide insight into the evolution of lung cancers, but also imply possibilities and limitations of biomarker-based treatment in lung cancers.
Brigatinib in Patients with Alectinib-Refractory ALK-Positive Non-Small Cell Lung Cancer: A Retrospective Study J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-20 Jessica J. Lin, Viola W. Zhu, Adam J. Schoenfeld, Beow Y. Yeap, Ashish Saxena, Lorin A. Ferris, Ibiayi Dagogo-Jack, Anna F. Farago, Angela Taber, Anne Traynor, Smitha Menon, Justin F. Gainor, Jochen K. Lennerz, Andrew J. Plodkowski, Subba R. Digumarthy, Sai-Hong Ignatius Ou, Alice T. Shaw, Gregory J. Riely
Background The second-generation ALK inhibitor alectinib recently demonstrated superior efficacy compared to the first-generation ALK inhibitor crizotinib in advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), establishing alectinib as the new standard first-line therapy. Brigatinib, another second-generation ALK inhibitor, has demonstrated substantial activity in patients with crizotinib-refractory ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is unknown. Methods A multicenter, retrospective study was performed at three institutions. Patients were eligible if they had advanced, alectinib-refractory ALK-positive NSCLC and were treated with brigatinib. Medical records were reviewed to determine clinical outcomes. Results Twenty-two patients were eligible for this study. Confirmed objective responses to brigatinib were observed in 3 of 18 patients (17%) with measurable disease. Nine patients (50%) had stable disease on brigatinib. The median progression-free survival was 4.4 months [95% confidence interval (CI), 1.8-5.6 months] with a median duration of treatment of 5.7 months (95% CI, 1.8-6.2 months). Among nine patients in this study who underwent post-alectinib/pre-brigatinib biopsies, five had an ALK I1171X or V1180L resistance mutation; of these, one had a confirmed partial response and three had stable disease on brigatinib. One patient had an ALK G1202R mutation in a post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best overall response to brigatinib. Conclusions Brigatinib has limited clinical activity in alectinib-refractory ALK-positive NSCLC. Additional studies are needed to establish biomarkers of response to brigatinib and to identify effective therapeutic options for alectinib-resistant ALK-positive NSCLC patients.
Comparison of molecular testing modalities for detection of ROS1 rearrangements in a cohort of positive patient samples J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-20 Kurtis D. Davies, Anh T. Le, Jamie Sheren, Hala Nijmeh, Katherine Gowan, Kenneth L. Jones, Marileila Varella-Garcia, Dara L. Aisner, Robert C. Doebele
Introduction ROS1 gene fusions are a well-characterized class of oncogenic driver found in approximately 1-2% of non-small cell lung cancer patients. ROS1-directed therapy in these patients is more efficacious and is associated with fewer side effects compared to chemotherapy and is thus now considered standard-of-care for patients with advanced disease. Consequently, accurate detection of ROS1 rearrangements/fusions in clinical tumor samples is vital. In this study, we compared the performance of three common molecular testing approaches on a cohort of ROS1 rearrangement/fusion-positive patient samples. Methods Twenty-three ROS1 rearrangement/fusion-positive clinical samples were assessed by at least two of the following molecular testing methodologies: break-apart fluorescence in situ hybridization (FISH), DNA-based hybrid capture library preparation followed by next-generation sequencing (NGS), and RNA-based anchored multiplex PCR library preparation followed by NGS. Results None of the testing methodologies demonstrated 100% sensitivity in detection of ROS1 rearrangements/fusions. FISH results were negative in 2 out of 20 tested samples, the DNA-based NGS assay was negative in 4 out of 18 tested samples, and the RNA-based NGS assay was negative in 3 of 19 tested samples. For all three testing approaches, we identified assay characteristics that likely contributed to false-negative results. Additionally, we report that genomic breakpoints are an unreliable predictor of breakpoints at the transcript level, likely due to alternative splicing. Conclusions ROS1 rearrangement/fusion detection in the clinical setting is complex and all methodologies have inherent limitations of which users must be aware in order to correctly interpret results.
Brief report: Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-20 Susan Combs Scott, Nathan A. Pennell
Background Checkpoint inhibitors augment the immune system’s natural surveillance mechanisms and have increasing applications in non-small cell lung cancer (NSCLC). Immunosuppressive corticosteroids are also frequently used in this population to treat unwanted inflammation. Based on this mechanistic opposition, we investigated the interaction between nivolumab and corticosteroids in patients with advanced NSCLC. Methods A retrospective chart review of 210 NSCLC patients treated with nivolumab at the Cleveland Clinic was performed. Use of systemic corticosteroids (equivalent to >10 mg prednisone per day) during nivolumab therapy was associated with objective outcomes of number of nivolumab cycles and overall survival. Results Sixty-six patients (31%) received concurrent systemic corticosteroids during nivolumab therapy. The most common indications included sequelae from active or treated brain metastases (27%) and COPD or other respiratory disease (21%). For patients with early exposure to steroids within the first 30 days of nivolumab therapy (12%, n=25), the median number of nivolumab cycles was two, compared to five cycles in patients not exposed to corticosteroids (p=0.002). Median overall survival for patients on steroids during the first 30 days was 4.3 months, compared to 11 months for patients not on steroids, hazard ratio for death 2.30 (95% CI 1.27-4.16, p=0.006) in multivariate analysis. Conclusion Nearly one-third of NSCLC patients treated with nivolumab were prescribed concurrent corticosteroids during the course of nivolumab therapy. Patients exposed to corticosteroids during the first cycle of nivolumab received fewer total cycles of nivolumab, suggesting decreased clinical benefit, and had shorter overall survival.
Comparison of Risk Stratification Models to Predict Recurrence and Survival in Pleuropulmonary Solitary Fibrous Tumor J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-20 Janani S. Reisenauer, Wadad Mneimneh, Sarah Jenkins, Aaron S. Mansfield, Marie Christine Aubry, Karen J. Fritchie, Mark S. Allen, Shanda H. Blackmon, Stephen D. Cassivi, Francis C. Nichols, Dennis A. Wigle, K Robert Shen, Jennifer M. Boland
Introduction Solitary fibrous tumors (SFT) are rare mesenchymal neoplasms. Most follow a benign course, but a subset will recur or metastasize. Various risk stratification schemes have been proposed for SFT, but none have been universally endorsed and few have focused on pleuropulmonary SFT. Methods Histologic sections were examined from surgically resected pleuropulmonary SFT, with confirmatory immunohistochemistry. Patients were risk stratified using 4 prediction models as proposed by de Perrot, Demicco (original and modified), and Tapias. Kaplan–Meier analysis estimated overall survival (OS) and progression-free survival (PFS). Results The 147 study patients included 78 females (53.1%), with a median age of 61.5 years (range 25-87). Median follow up was 5.5 years (range 0-33). Recurrence or metastasis occurred in 15 patients (10.2%), with 5 deaths from disease. Significant predictors of worse OS included male gender, age ≥ 55, size≥10 cm, non-pedunculated growth, severe atypia, necrosis, and mitoses ≥ 4/10 high powered fields (hpf). Predictors of recurrence included size ≥10 cm, severe atypia, necrosis, ≥4 mitosis/10 hpf, and Ki-67 ≥2%. All systems predicted PFS, but only Demicco and Tapias significantly predicted OS. The modified Demicco system provided the best discrimination for PFS (C-statistic=0.80 compared to 0.78). Conclusion Risk scoring systems proposed by Tapias and Demicco were both predictive of OS and PFS. The Demicco system has the advantages of simplicity and applicability to SFTs from other sites, as well as providing best discrimination for PFS, and thus may be the best system to apply in general practice.
Development and Validation of a Nomogram Prognostic Model for Small-Cell Lung Cancer Patients J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-11 Shidan Wang, Lin Yang, Bo Ci, Matthew Maclean, David E. Gerber, Guanghua Xiao, Yang Xie
Background Small-cell lung cancer (SCLC) accounts for almost 15% of lung cancer cases in the United States. Nomogram prognostic models could greatly facilitate risk stratification and treatment planning, as well as more refined enrollment criteria for clinical trials. We developed and validated a new nomogram prognostic model for SCLC patients using a large SCLC patient cohort from the National Cancer Database (NCDB). Methods Clinical data of 24,680 SCLC patients diagnosed from 2004 to 2011 were used to develop the nomogram prognostic model. The model was then validated using an independent cohort of 9,700 SCLC patients diagnosed from 2012 to 2013. The prognostic performance was evaluated using p value, concordance index and integrated Area Under the (time-dependent Receiver Operating Characteristic) Curve. Results The following variables were contained in the final prognostic model: age, gender, race, ethnicity, Charlson/Deyo Score, TNM Stage (assigned according to the AJCC 8th edition), treatment type (combination of surgery, radiation therapy and chemotherapy), and laterality. The model was validated in an independent testing group with a concordance index of 0.722 ± 0.004 and an integrated AUC of 0.79. The nomogram model has a significantly higher prognostic accuracy than previously developed models, including the AJCC 8th edition TNM-staging system. We implemented the proposed nomogram and four previously published nomograms in an online webserver. Conclusions We developed a nomogram prognostic model for SCLC patients, and validated the model using an independent patient cohort. The nomogram performs better than earlier models, including models using AJCC staging.
IASLC Statement Paper: Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-06 Christian Rolfo, Philip C. Mack, Giorgio V. Scagliotti, Paul Baas, Fabrice Barlesi, Trever G. Bivona, Roy S. Herbst, Tony S. Mok, Nir Peled, Robert Pirker, Luis E. Raez, Martin Reck, Jonathan W. Riess, Lecia V. Sequist, Frances A. Shepherd, Lynette M. Sholl, Daniel SW. Tan, Heather A. Wakelee, Ignacio I. Wistuba, Murry W. Wynes, David P. Carbone, Fred R. Hirsch., David R. Gandara
The isolation of circulating cell-free tumoral DNA (ctDNA) in plasma and its subsequent molecular analysis is a powerful tool that can help improve clinical outcomes across multiple cancer types, including non-small cell lung cancer (NSCLC). Assays of this nature that utilize blood as opposed to tumor samples are frequently referred to as liquid biopsies. An increasing number of new platforms have been recently developed that improve not only the fidelity of the molecular analysis of the liquid biopsy but also the number of tests performed on a single specimen. ctDNA assays for detection of both epidermal growth factor receptor (EGFR) sensitizing and resistance mutations have already entered clinical practice and many other molecular tests – such as resistance mutations for ALK rearrangements - are likely to do so in the near future. Due to an abundance of new evidence, an appraisal was warranted to review strengths and weaknesses, to describe what is already in clinical practice and what has yet to be implemented, and to highlight areas in need of further investigation. A multidisciplinary panel of experts in the field of thoracic oncology with interest and expertise in liquid biopsy and molecular pathology, was convened by the International Association for the Study of Lung Cancer (IASLC) to evaluate current available evidence with the aim of producing a set of recommendations for the use of liquid biopsy for molecular analysis in in guiding the clinical management of advanced NSCLC patients as well as identifying unmet needs.
Racial disparities in lung cancer survival: The contribution of stage, treatment, and ancestry J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-06 Carissa C. Jones, Sarah Fletcher Mercaldo, Jeffrey D. Blume, Angela S. Wenzlaff, Ann G. Schwartz, Heidi Chen, Stephen A. Deppen, William S. Bush, Dana C. Crawford, Stephen J. Chanock, William J. Blot, Eric L. Grogan, Melinda C. Aldrich
Introduction Lung cancer is a leading cause of cancer-related death worldwide. Racial disparities in LC survival exist between blacks and whites, yet are limited by categorical definitions of race. We sought to examine the impact of African ancestry on overall survival among black and white non-small cell lung cancer (NSCLC) cases. Methods Black and white incident NSCLC cases from the prospective Southern Community Cohort Study (N=425) were identified via linkage with state cancer registries in 12 Southern states. Vital status was determined by linkage with the National Death Index and Social Security Administration. We evaluated the impact of African ancestry, estimated using genome-wide ancestry informative markers, on overall survival by calculating the time-dependent area under the curve (AUC) for Cox proportional hazards models, adjusting for relevant covariates such as stage and treatment. We replicated our findings in an independent population of black NSCLC cases. Results Global African ancestry was not significantly associated with overall survival among NSCLC cases. There was no change in model performance when comparing Cox proportional hazards models with and without African ancestry (AUC=0.79 for each model). Removal of stage and treatment reduced the average time-dependent AUC from 0.79 to 0.65. Similar findings were observed in our replication study. Conclusions Stage and treatment are more important predictors of survival than African ancestry. These findings suggest that racial disparities in lung cancer survival may disappear with similar early detection efforts for blacks and whites alike.
Receptor Tyrosine Kinase fusions and BRAF kinase fusions are rare but actionable resistance mechanisms to EGFR tyrosine kinase inhibitors J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-05 Alexa B. Schrock, Viola W. Zhu, Wen-Son Hsieh, Russell Madison, Benjamin Creelan, Jeffrey Silberberg, Dan Costin, Anjali Bharne, Ioana Bonta, Thangavijayan Bosemani, Petros Nikolinakos, Jeffrey S. Ross, Vincent A. Miller, Siraj M. Ali, Samuel J. Klempner, Sai-Hong Ignatius Ou
Introduction We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR TKIs. Methods EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (FFPE tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians. Results Clinical samples from 3,505 unique EGFR+ NSCLCs were identified from June-2012 to October-2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALK, 6 (19%) RET, 6 (19%) FGFR3, 1 (3.2%) EGFR, and 1 (3.2%) NTRK1, including two novel fusions (SALL2-BRAF and PLEKHA7-ALK). 27/31 patients had either a known prior history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre-treatment samples where the fusion was not present prior to treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7-ALK fusion achieving a durable partial response with combination of full-dose osimertinib and alectinib. Conclusion RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.
Breathprinting and early diagnosis of lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-03-08 Gaetano Rocco, Giorgio Pennazza, Marco Santonico, Filippo Longo, Raffaele Rocco, Pierfilippo Crucitti, Raffaele Antonelli Incalzi
The electronic nose (e-nose) is a promising technology to be used as a useful addition to the currently available modalities to achieve lung cancer diagnosis. The e-nose can assess the volatile organic compounds (VOCs) detected in the breath and derived from the cellular metabolism. VOCs can be analyzed to identify either the individual chemical elements as well as their pattern of expression to reproduce a sensorial combination similar to a fingerprint (breathprint). The e-nose can be used alone, mimicking the combinatorial selectivity of the human olfactory system, or as part of a multisensorial platform. This review analyzes the progress made by investigators interested in this technology as well as the perspectives for its future utilization.
Translation of knowledge to practice - Improving awareness in NSCLC molecular testing J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-03-11 Alona Zer, Jean Claude Cutz, Harman Sekhon, David M. Hwang, Christina Sit, Manjula Maganti, Mike Sung, Matthew Binnie, Anthony Brade, Tae Bong Chung, Suzanne Kamel-Reid, Paul Narinder, Ming S. Tsao, Tom Waddell, Gilda da Cunha Santos, Milan Patel, Ron F. Carter, Natasha B. Leighl
Background Molecular testing in advanced lung cancer is standard in guiding treatment selection. However, population-wide implementation of testing remains a challenge. We developed a knowledge translation intervention to improve understanding among diagnostic specialists about molecular testing and appropriate diagnostic sampling in lung cancer. Methods Specialty-specific education programs were developed from existing literature and input from Canadian leaders in lung pathology, respirology, interventional radiology, thoracic surgery, radiation and medical oncology. The programs, including key messages, review of current data, existing guidelines, group discussion and participant feedback, were administered at provincial and national specialty meetings. Participant knowledge was assessed before and after the intervention using anonymous questionnaires. Molecular testing rates (EGFR) in Ontario were also evaluated before and after the intervention period. Results Ten programs were administered to diagnostic specialists including respirologists, pathologists, thoracic surgeons, radiologists, radiation and medical oncologists, with completion of 255 pre- and 219 post-intervention surveys. At baseline, 30% were unsure of tissue handling methods for molecular testing, 20% chose an incorrect technique and half were unfamiliar with how to initiate testing. Post-intervention, specialist knowledge improved regarding tissue handling, appropriate fixation techniques, and uncertainty decreased from 30% to 2% (p<0.001). A 12% increase (relative 57%) in molecular testing requests (EGFR) in Ontario was observed over the intervention period (p=0.0032). Conclusions Significant knowledge gaps exist among diagnostic specialists regarding molecular testing and targeted therapy in lung cancer. This initiative significantly improved understanding of the importance and methods of successful molecular testing, and correlated with increased testing rates.
Intrinsic and Extrinsic Regulation of PD-L2 Expression in Oncogene-Driven Non–Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-03-27 Daisuke Shibahara, Kentaro Tanaka, Eiji Iwama, Naoki Kubo, Keiichi Ota, Koichi Azuma, Taishi Harada, Jiro Fujita, Yoichi Nakanishi, Isamu Okamoto
Introduction The interaction of programmed cell death ligand 2 (PD-L2) with programmed cell death 1 is implicated in tumor immune escape. The regulation of PD-L2 expression in tumor cells has remained unclear, however. We here examined intrinsic and extrinsic regulation of PD-L2 expression in NSCLC. Methods PD-L2 expression was evaluated by reverse transcription and real-time polymerase chain reaction analysis and by flow cytometry. Results BEAS-2B cells stably expressing an activated mutant form of EGFR or the echinoderm microtubule associated protein like 4 (EML4)–ALK receptor tyrosine kinase fusion oncoprotein manifested increased expression of PD-L2 at both the mRNA and protein levels. Furthermore, treatment of NSCLC cell lines that harbor such driver oncogenes with corresponding EGFR or ALK tyrosine kinase inhibitors or depletion of EGFR or ALK by small interfering RNA transfection suppressed expression of PD-L2, demonstrating that activating EGFR mutations or echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) fusion intrinsically induce PD-L2 expression. We also found that interferon gamma (IFN-γ) extrinsically induced expression of PD-L2 through signal transducer and activator of transcription 1 signaling in NSCLC cells. Oncogene-driven expression of PD-L2 in NSCLC cells was inhibited by knockdown of the transcription factors signal transducer and activator of transcription 3 (STAT3) or c-FOS. IFN-γ also activated STAT3 and c-FOS, suggesting that these proteins may also contribute to the extrinsic induction of PD-L2 expression. Conclusions Expression of PD-L2 is induced intrinsically by activating EGFR mutations or EML4-ALK fusion and extrinsically by IFN-γ, with STAT3 and c-FOS possibly contributing to both intrinsic and extrinsic pathways. Our results thus provide insight into the complexity of tumor immune escape in NSCLC.
Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-03-29 Yingmei Li, Boxiang Liu, Ian David Connolly, Bina Wasunga Kakusa, Wenying Pan, Seema Nagpal, Stephen B. Montgomery, Melanie Hayden Gephart
When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases. We found that taste 2 receptor member 31 gene (TAS2R31) and phosphodiesterase 4D interacting protein gene (PDE4DIP) were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with a retrospective review of the charts of an additional 44 patients with NSCLC LMD, we discovered a surprisingly low number of KRAS mutations (n = 4 [7.7%]) but a high number of EGFR mutations (n = 33 [63.5%]). The median interval for development of LMD from NSCLC was shorter in patients with mutant EGFR (16.3 months) than in patients with wild-type EGFR (23.9 months) (p = 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic tool kit, and correlations of EGFR in LMD and KRAS in solid metastases suggest that molecular distinctions or systemic treatment pressure underpin the differences in growth patterns within the brain.
Next generation sequencing assisted in establishing the diagnosis and treatment for a Chinese patient with breast and lung multiple primary malignancies J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-03-30 Chunqing Song, Zhengxing Gao, Jiabao Zong, Junping Shi, Ming Yao, Guilong Lu, Xiaoliang Liu, Kai Wang, Lei Han
Introduction A case of primary lung cancer was reported, which was misdiagnosed as breast cancer metastasis to the lung based on pathology in combination with a history of breast cancer. Methods The common driver gene mutation was detected in different lesions by next generation sequencing (NGS), and it was shown that the genomic profiling of lung lesion and breast lesion were inconsistent. Results The typical driver mutation of EGFR L858R in lung cancer was found in lung lesion, and the patient received the first-generation EGFR-TKI, icotinib, as treatment and achieved a partial response. Conclusions With NGS detection in this case, the specific driver gene in the tumor site was identified, which facilitated the diagnosis of a double primary cancer, and resulted in a change in treatment.
Time-to-Treatment-Failure and Related Outcomes Among 1000+ Advanced Non–Small Cell Lung Cancer Patients: Comparisons Between Older Versus Younger Patients (Alliance A151711) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-03-30 Ajeet Gajra, Tyler J. Zemla, Aminah Jatoi, Josephine L. Feliciano, Melisa L. Wong, Hongbin Chen, Ronald Maggiore, Ryan P. McMurray, Arti Hurria, Hyman B. Muss, Harvey J. Cohen, Jacqueline Lafky, Martin J. Edelman, Rogerio Lilenbaum, Jennifer G. Le-Rademacher
Introduction Time-to-treatment-failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. Methods Pooled analyses were conducted with first-line chemotherapy trials for advanced NSCLC (CALGB 9730, 30203, and 30801). Comparisons among patients who were 65 years and older and 70 years and older were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. Results Among 1006 patients, 460 (46%) were older than 65 years of age. One hundred forty-five older patients (32% of this age cohort) completed all six planned chemotherapy cycles as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval: 2.7– 3.2) in older patients and 3 months (95% confidence interval: 2.9–3.5) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age-based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cutpoint of 70+ years showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. Conclusions TTF was comparable between older and younger patients; but different, age-based, and potentially modifiable reasons account for it.
A Phase II Study of Pembrolizumab in EGFR-mutant, PD-L1+, Tyrosine Kinase Inhibitor (TKI) Naïve Patients with Advanced NSCLC J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-06-01 A. Lisberg, A. Cummings, J.W. Goldman, K. Bornazyan, N. Reese, T. Wang, P. Coluzzi, B. Ledezma, M. Mendenhall, J. Hunt, B. Wolf, B. Jones, J. Madrigal, J. Horton, M. Spiegel, J. Carroll, J. Gukasyan, T. Williams, L. Sauer, C. Wells, A. Hardy, P. Linares, C. Lim, L. Ma, C. Adame, E.B. Garon
Background Despite the significant antitumor activity of pembrolizumab in non-small cell lung cancer (NSCLC), clinical benefit has been less frequently observed in patients whose tumors harbor epidermal growth factor receptor (EGFR) mutations compared to EGFR wild-type patients. Our single center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with PD-L1 expression >50%. Methods We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation positive, advanced NSCLC and PD-L1 positive (>1%, 22C3 antibody) tumors. Pembrolizumab was administered 200mg q3wks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab. Results Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. 82% of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression >50%. Only 1 patient had an objective response (ORR: 9%), but repeat analysis of this patient’s tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern. Conclusions Pembrolizumab’s lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression >50%, suggests that it is not an appropriate therapeutic choice in this setting.
EGFR L792H and G796R: Two Novel Mutations Mediating Resistance to the Third-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Osimertinib J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-30 Qi Zhang, Xu-Chao Zhang, Jin-Ji Yang, Zhen-Fan Yang, Yu Bai, Jian Su, Zheng Wang, Zhou Zhang, Yang Shao, Qing Zhou, Jin Kang, E.-E. Ke, Yi-Chen Zhang, Zhong-Yi Dong, Zhi-Hong Chen, Hai-Yan Tu, Wen-Zhao Zhong, Xue-Ning Yang, Yi-Long Wu
Background The third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) osimertinib has been approved in many countries to treat advanced non-small cell lung cancer (NSCLC) in patients with the EGFR T790M mutation. As the development of acquired resistance is inevitable, the mechanisms of such resistance must be urgently clarified. Patients and methods DNA samples from a cohort of 340 lung adenocarcinoma patients taking osimertinib were subjected to next-generation sequencing (NGS) and screened in terms of the frequencies of the L792H and G796R mutations. Ba/F3 cells stably expressing the EGFR L858R/T790M mutations (in cis) with either the L792H or G796R mutation were created to investigate the impact of the two novel mutations on EGFR TKIs and other potential drug combinations in vitro. Structural analyses were performed using Schrodinger/Maestro ver. 11.1.012. Result L792H and G796R were detected in 1.76% (6/340) and 0.56% (2/340) of lung adenocarcinoma patients treated with osimertinib, respectively. The introduction of L792H or G796R mutations into an L858R/T790M background caused dramatic reductions in osimertinib-sensitivity. Structural modelling showed that mutations in cis with T790M either forced the ligand (osimertinib) to rotate out (breaking binding) or pulled the hinge loop (breaking the hinge). Various other drug combinations including cetuximab with EAI045 failed to inhibit either cis mutant effectively. Conclusion EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations conferred resistance to osimertinib both in vitro and in silico. For patients in whom the two resistance mutations occur at low frequency, more precise treatment strategies and additional combinational approaches are required.
Consolidative local ablative therapy improves the survival of patients with synchronous oligometastatic NSCLC harboring EGFR activating mutation treated with first-line EGFR-TKIs J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-29 Qinghua Xu, Fei Zhou, Hui Liu, Tao Jiang, Xuefei Li, Yaping Xu, Caicun Zhou
Introduction The aim of the current study was to investigate whether consolidative local ablative therapy (LAT) can improve the survival of patients with stage IV EGFR-mutant NSCLC who have oligometastatic disease treated with first-line EGFR-TKI therapy. Materials and Methods Patients with stage IV EGFR-mutant NSCLC and no more than five metastases within 2 months of diagnosis were identified. All patients were treated with first-line EGFR-TKIs. Consolidative LAT included radiotherapy, surgery or both. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves. Results From October 2010 to May 2016, 145 patients were enrolled, including 51 (35.2%) who received consolidative LAT to all oligometastatic sites (All-LAT group), 55 (37.9%) who received consolidative LAT to either primary tumor or oligometastatic sites (Part-LAT group), and 39 (26.9%) who did not receive any consolidative LAT (Non-LAT group). The median PFS in All-LAT, Part-LAT, and Non-LAT group were 20.6, 15.6, and 13.9 months, respectively (P<0.001). The median OS in All-LAT, Part-LAT, and Non-LAT group were 40.9, 34.1, and 30.8 months, respectively (P<0.001). The difference was statistically significant between All-LAT group and Part-LAT or Non-LAT group but was not between Part-LAT and Non-LAT group. The median OS was significantly improved with consolidative LAT for primary tumor (40.5 versus 31.5 months, P<0.001), brain metastases (38.2 versus 29.2 months, P=0.002), adrenal metastases (37.1 versus 29.2 months, P =0.032). Adverse events (Grade ≥ 3) due to radiotherapy included pneumonitis (7.7%) and esophagitis (16.9%). Conclusion The current study demonstrated that consolidative LAT to all metastatic sites was a feasible option for patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with consolidative LAT to partial sites or observation alone.
Multilevel Opportunities to Address Lung Cancer Stigma across the Cancer Control Continuum J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-23 Heidi A. Hamann, Elizabeth S. Ver Hoeve, Lisa Carter-Harris, Jamie L. Studts, Jamie S. Ostroff
Introduction The public health imperative to reduce the burden of lung cancer has seen unprecedented progress in recent years. Realizing fully the advances in lung cancer treatment and control requires attention to potential barriers in their momentum and implementation. In this analysis, we present and evaluate the argument that stigma is a highly significant barrier to fulfilling the clinical promise of advanced care and reduced lung cancer burden. Methods This evaluation of lung cancer stigma is based on a multilevel perspective that incorporates the individual, persons in their immediate environment, the healthcare system, and the larger societal structure which shapes perceptions and decisions. We also consider current interventions and interventional needs within and across aspects of the lung cancer continuum, including prevention, screening, diagnosis, treatment, and survivorship. Results Current evidence suggests that stigma detrimentally impacts psychosocial, communication, and behavioral outcomes over the entire lung cancer control continuum and across multiple levels. Interventional efforts to alleviate stigma in the context of lung cancer show promise, yet more work is needed to evaluate their impact. Conclusions Understanding and addressing the multi-level role of stigma is a crucial area for future study in order to realize the full benefits offered by lung cancer prevention, control, and treatment. Coordinated, interdisciplinary, and well-conceptualized efforts have the potential to reduce the barrier of stigma in the context of lung cancer and facilitate demonstrable improvements in clinical care and quality of life.
Nivolumab Plus Erlotinib in Patients with Epidermal Growth Factor Receptor-Mutant Advanced Non-Squamous Non-Small Cell Lung Cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-23 Scott Gettinger, Matthew D. Hellmann, Laura Q.M. Chow, Hossein Borghaei, Scott Antonia, Julie R. Brahmer, Jonathan W. Goldman, David E. Gerber, Rosalyn A. Juergens, Frances A. Shepherd, Scott A. Laurie, Tina C. Young, Xuemei Li, William J. Geese, Naiyer Rizvi
Introduction This phase I study evaluated nivolumab combined with erlotinib in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). Methods Patients with advanced EGFR-mutant NSCLC who were EGFR tyrosine kinase inhibitor (TKI)-naive or TKI-treated but had not received chemotherapy were treated with nivolumab 3 mg/kg every 2 weeks and erlotinib 150 mg/day until disease progression or unacceptable toxicity. The primary objective was safety and tolerability. Results Twenty patients with TKI-treated and one with TKI-naive EGFR-mutant NSCLC were treated with nivolumab plus erlotinib. Treatment-related grade 3 toxicities occurred in five patients (liver enzyme elevations, n = 2; diarrhea, n = 2; weight loss, n = 1), with no grade ≥4 toxicities. In the TKI-treated population, the objective response rate was 15% (3/20, including one complete response), and the 24-week progression-free survival rate was 48%. Responses lasted 13.8, 17.6, and 38.2 months per investigator records. A fourth patient had a non-conventional immune-related response lasting 12.5 months. Among these four patients, two were never-smokers and one each had 35– and <1–pack-year histories. Post-EGFR TKI pre-trial tumor biopsies from these patients detected EGFR T790M mutations in two patients and MET amplification in a third; two patients each had primary EGFR exon 19 deletions or L858R mutations. The TKI-naive patient, who had compound EGFR mutations (L858R and S768I) and ultimately achieved a complete response, had an ongoing response lasting more than 5 years based on investigator records. Conclusion Nivolumab plus erlotinib was tolerable, with durable responses in patients with EGFR-mutant, TKI-treated NSCLC.
Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab vs docetaxel in patients with previously treated advanced non-small cell lung cancer J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-17 L. Fehrenbacher, J. von Pawel, K. Park, A. Rittmeyer, D.R. Gandara, S. Ponce Aix, J.-Y. Han, S.M. Gadgeel, T. Hida, D.L. Cortinovis, M. Cobo, D.M. Kowalski, F. De Marinis, M. Gandhi, B. Danner, C. Matheny, M. Kowanetz, P. He, F. Felizzi, H. Patel, A. Sandler, M. Ballinger, F. Barlesi
Introduction The efficacy and safety of atezolizumab vs docetaxel as second- or third-line treatment in patients with advanced non-small cell lung cancer in the primary (n=850; ITT850) and secondary (n=1225; ITT1225) efficacy populations of the randomized phase III OAK study at an updated data cutoff were assessed. Methods Patients received atezolizumab 1200mg or docetaxel 75mg/m2 intravenously every 3 weeks until loss of clinical benefit or disease progression, respectively. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population and programmed death-ligand 1 (PD-L1)-expressing subgroup. A sensitivity analysis was conducted to evaluate the impact of subsequent immunotherapy use in the docetaxel arm on observed survival benefit with atezolizumab. Results Atezolizumab demonstrated OS benefit vs docetaxel in the updated ITT850 (hazard ratio [HR] 0.75; 95% CI 0.64–0.89; P = .0006) and the ITT1225 (HR 0.80; 0.70–0.92; P = .0012) after minimum follow-up of 26 and 21 months, respectively. Improved survival with atezolizumab was observed across PD-L1 and histology subgroups. The relative OS benefit with atezolizumab was slightly greater in the immunotherapy sensitivity analysis in the ITT850 (HR 0.69) and ITT1225 (HR 0.74) compared to conventional OS estimation. Fewer patients receiving atezolizumab experienced grade 3/4 treatment-related adverse events (14.9%) than those receiving docetaxel (42.4%); no grade 5 events related to atezolizumab were observed. Conclusions The updated ITT850 and initial ITT1225 analyses were consistent with the primary efficacy analysis demonstrating survival benefit with atezolizumab vs docetaxel. Atezolizumab continued to demonstrate a favorable safety profile after longer treatment exposure and follow-up.
Racial-Ethnic Disparities in End-of-Life Care Quality among Lung Cancer Patients: A SEER-Medicare–Based Study J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-10 Siddharth Karanth, Suja S. Rajan, Gulshan Sharma, Jose-Miguel Yamal, Robert O. Morgan
Introduction Cancer end-of-life care and associated racial-ethnic disparities have been in focus during the last few years due to concerns regarding subjective care variations and poor quality of care. Given the high mortality rate and disease burden of lung cancer, end-of-life care quality is particularly crucial for this disease. This study uses previously validated measures and examines racial-ethnic disparities in lung cancer end-of-life care quality. Methods This study involves retrospective analysis of patients ≥66 years, who were diagnosed with stage I–IV lung cancer, and who died on or before December 31, 2013, using the Surveillance Epidemiology and End Result-Medicare data from 1991–2013. Poor quality of care was measured using three themes: (1) potentially preventable medical encounters, (2) delayed hospice referral, and (3) aggressive chemotherapy provision during end-of-life. The patients were analyzed as two separate cohorts of NSCLC and SCLC patients. Logistic regression analyses were performed to estimate racial-ethnic disparities in the adjusted odds of receiving poor quality end-of-life care. Results The study found considerable racial-ethnic disparities in end-of-life care quality. The racial-ethnic minorities had higher odds of experiencing potentially preventable medical encounters in the last month of life as compared with non-Hispanic whites. Odds of delayed hospice referral and aggressive chemotherapy provision during end-of-life were lower in non-Hispanic blacks as compared with non-Hispanic whites. Conclusions The study findings highlight the continued lack of access and care disparity among the minorities, which could precipitate potentially preventable utilizations, and limit access to hospice care during end-of-life. The study suggests the need to develop educational, patient navigational and other interventions that could potentially reduce aggressive utilizations and improve appropriate hospice care provision during end-of-life.
Revised Modified RECIST Criteria for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1) J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-09 Samuel G. Armato III, Anna K. Nowak
Malignant pleural mesothelioma poses unique difficulties in tumor measurement and response assessment; however, robust and reproducible assessment of response is critically important in the conduct, interpretation, and reporting of clinical trials. The current de-facto standard for the assessment of mesothelioma tumor response, “modified RECIST” (Response Evaluation Criteria in Solid Tumors), was published in 2004 as a research paper. Practical application of the modified RECIST guidelines has suffered from varied interpretations, resulting in inaccuracies and inconsistencies in tumor response assessment across and within mesothelioma clinical trials. The presented “modified RECIST 1.1 for mesothelioma” response assessment guidelines provide a much-needed update that incorporates recommendations from RECIST 1.1 and approaches to other practical issues, including: (1) definition of minimally measurable disease; (2) definition of measurable lesions; (3) acceptable measurement location; (4) non-pleural disease considerations; (5) characterization of non-measurable pleural disease; (6) assessment of pathological lymph nodes; (7) establishing progressive disease; and (8) accommodations for bilateral pleural disease. These modified RECIST 1.1 guidelines for mesothelioma tumor response collate and apply research published since the development of modified RECIST, align modified RECIST with RECIST 1.1, address those aspects of tumor measurement that were neglected or not well characterized in the modified RECIST paper, and clarify ambiguous or difficult measurement issues that have been highlighted through the subsequent decade of clinical trials research. Adoption of the modified RECIST 1.1 guidelines for mesothelioma is recommended to harmonize the application of tumor measurement and response assessment across the next generation of clinical trials in this disease.
Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-08 Jordi Codony-Servat, Silvia García-Roman, Miguel Ángel Molina-Vila, Jordi Bertran-Alamillo, Ana Giménez-Capitán, Santiago Viteri, Andrés F. Cardona, Erik d’Hondt, Niki Karachaliou, Rafael Rosell
Introduction Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant non-small cell lung cancer (NSCLC) is of particular interest. Immunization against EGF has demonstrated efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations. Methods The EGFR-mutant, NSCLC cell lines H1975 and PC9, together with several gefitinib and osimertinib-resistant cells derived from PC9, were treated with anti-EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs). Cell viability was analyzed by proliferation assays, cell cycle by fluorescence-activated cell sorting analysis and levels of RNA and proteins by quantitative retro-transcription PCR and Western blotting. Results Anti-EGF VacAbs generated in rabbits suppressed EGF-induced cell proliferation and cycle progression and inhibited downstream EGFR signaling in EGFR-mutant cells. Sera from patients immunized with an EGF vaccine were also able to block activation of EGFR effectors. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of all TKIs tested, suppressed Erk1/2 phosphorylation, blocked the activation of signal transducer and activator of transcription 3 (STAT3) and downregulated the expression of AXL. Finally, anti-EGF VacAbs significantly delayed the emergence in vitro of EGFR TKI resistant clones. Conclusions EGFR-mutant patients can derive benefit from immunization against EGF, particularly if combined with EGFR TKIs. A Phase I trial of an EGF vaccine in combination with afatinib has been initiated.
Sarcopenia in resected non-small cell lung cancer: Effect on postoperative outcomes J. Thorac. Oncol. (IF 10.336) Pub Date : 2018-05-08 Ryota Nakamura, Yoshihisa Inage, Rika Tobita, Satoshi Yoneyama, Takeshi Numata, Kyoko Ota, Hidetoshi Yanai, Takeo Endo, Yukinori Inadome, Shingo Sakashita, Hiroaki Satoh, Kenji Yuzawa, Toru Terashima
Background Skeletal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor for poor outcomes in various malignancies. However, the prognostic significance of sarcopenia in patients with non-small cell lung cancer (NSCLC) following surgery has not been adequately determined. This study investigated the impact of sarcopenia in patients undergoing pulmonary resection for lung cancer. Methods This retrospective study consisted of 328 patients with pathologically confirmed NSCLC who underwent curative resection between January 2005 and April 2017. Preoperative computed tomography (CT) imaging at the third lumbar vertebrae level was assessed to measure the psoas muscle mass index (PMI, cm2/m2). Sarcopenia was defined as a cutoff value of PMI less than 6.36 cm2/m2 for males and 3.92 cm2/m2 for females, based on PMI values from “healthy” subjects. Results The median patient age was 71 years and 59% were male. Sarcopenia was present in 183 (55.8%) and was significantly related with increasing age (p<0.001), being male (p<0.001), smoking habit (p<0.001), lower body mass index (p<0.001), and postoperative major complication (Clavien Dindo grade ≥3, p=0.036). The prevalence of sarcopenia was higher in men than in women, and the prevalence increased with age in men, whereas the prevalence did not increase in females above 70 years. The five-year survival rate was 61% in patients with sarcopenia and 91% in those without. Multivariate analysis revealed that sarcopenia was an independent unfavorable prognostic factor (p=0.019). Conclusion Sarcopenia as determined using preoperative CT could be used to predict postoperative major complication and prognosis in patients with resected NSCLC. Our results may provide some important information for preoperative management.
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