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Background: Capmatinib has previously shown activity in treatment-naive and previously treated patients with non-small-cell lung cancer (NSCLC) and a MET exon 14-skipping mutation (METex14). Here, we report the final outcomes from the phase 2 GEOMETRY mono-1 study with an aim to provide further evidence for the activity of capmatinib., Methods: In this non-randomised, multi-cohort, open-label, phase 2 trial conducted in 152 centres and hospitals in 25 countries, with patients treated in 95 centres in 20 countries, eligible patients (aged ≥18 years) with MET-dysregulated, EGFR wild-type, and ALK rearrangement-negative advanced NSCLC (stage IIIB/IV) and an Eastern Cooperative Oncology Group performance status of 0 or 1 were assigned to cohorts (1a, 1b, 2, 3, 4, 5a, 5b, 6 and 7) based on their MET status (METex14 or MET amplification) and previous therapy lines. Patients received capmatinib (400 mg orally twice daily) in 21-day treatment cycles. The primary endpoint was overall response rate by blinded independent central review per Response Evaluation Criteria in Solid Tumours version 1.1 and was performed on the full analysis set (all patients who received at least one dose of capmatinib). Previous reports of this study had published interim or primary data for cohorts 1-7. Here, we report the final clinical outcomes from all METex14 cohorts (4, 5b, 6, and 7) and safety from all study cohorts (1-7). The trial is registered with ClinicalTrials.gov, NCT02414139, and has been completed., Findings: Of 373 treated patients enrolled from June 11, 2015, to March 12, 2020, 160 (97 [61%] female) patients had METex14 NSCLC and were enrolled in four cohorts: 60 treatment-naive (cohorts 5b and 7) and 100 previously treated (cohorts 4 and 6). The overall median study follow-up was 46·4 months (IQR 41·8-65·4) for the treatment-naïve patients and 66·9 months (56·7-73·9) for previously treated patients, respectively. Overall responses were recorded in 41 (68%; 95% CI 55·0-79·7) of 60 treatment-naive patients and 44 (44%; 95% CI 34·1-54·3) of 100 previously treated patients. In all 373 treated patients, the most common treatment-related adverse events were peripheral oedema (n=174; 47%), nausea (n=130; 35%), increased blood creatinine (n=78; 21%), and vomiting (n=74; 20%). Grade 3-4 serious adverse events occurred in 164 (44%) patients, dyspnoea being the most common (18 patients [5%]). Treatment-related deaths occurred in four (1%) patients (one each of cardiac arrest, hepatitis, organising pneumonia, and pneumonitis). No new safety signals were reported., Interpretation: These long-term results support METex14 as a targetable oncogenic driver in NSCLC and add to the evidence supporting capmatinib as a targeted treatment option for treatment-naive and previously treated patients with METex14 NSCLC., Funding: Novartis Pharmaceuticals., Competing Interests: Declaration of interests JW reports research grant support (to their institution) from Bristol Myers Squibb, Janssen Pharmaceutica, Novartis, and Pfizer; and consulting fees or honoraria for lectures and for attending meetings from Amgen, AstraZeneca, Bayer, Blueprint, Bristol Myers Squibb, Boehringer-Ingelheim, Chugai, Daiichi Sankyo, Janssen, Lilly, Loxo, Merck, Mirati, MSD, Novartis, Nuvalent, Pfizer, Pierre Fabre, Roche, Seattle Genetics, Takeda, and Turning Point. MH declares personal honoraria for lectures and presentations from Boehringer Ingelheim, AstraZeneca, Takeda, Amgen, MSD, and Roche. J-YH reports research grants from Pfizer, Takeda, and ONO; consulting fees or honoraria for lectures and presentations from AstraZeneca, Jassen, Amgen, Oncobix, Daiichi Sankyo, Merck, Norvatis, Abion, Takeda, Pfizer, and Yuhan; participation in data safety monitoring board for AstraZeneca, Jassen; and a leadership role for National Cancer Drug Assessment Committee. NR declares research grants from Artidis, MSD, Amgen, and Roche; honoraria for lectures and presentations from Amgen, AstraZeneca, Bristol Myers Squibb, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron; support for attending the meetings from Takeda, Regeneron, and Roche; and participation in a data safety monitoring and advisory board for AbbVie, Amgen, AstraZeneca, Bayer, Boehringer, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, Takeda, and Regeneron. P-JS reports the research grants received (to their institution) from AstraZeneca, Bristol Myers Squibb, Genentech, and Gilead; and consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, Pfizer, and Takeda. EFS reports consulting fees support to their institution from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche, Sanofi, Takeda, and Merck; honoraria for lectures and presentations for self from Boehringer Ingelheim and Daiichi Sankyo; and participation in a data safety monitoring and advisory board for Daiichi Sankyo and Taiho for institution. JV declares consulting fees received from Bristol Myers Squibb, Janssen, and PDCline; honoraria for lectures and presentations from AstraZeneca, Daiichi Sankyo, and Merck; and participation in a data safety monitoring and advisory board for AstraZeneca, Boehringer, and Transgene. MN reports honoraria received for lectures and presentations from Ono Pharmaceuticals, Chugai Pharmaceutical, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi Sankyo, Lilly, AstraZeneca, MSD, AbbVie, Takeda Pfizer, Boehringer, Ingelheim, Novartis, Nippon, Kayaku, Merck, and Janssen; and support for attending meetings from Novartis. WA declares research grants received from Bristol Myers Squibb, AstraZeneca, Bioatla, Imugene, Astride, BridgeBio, AbbVie, and Novocure; and participation in data safety monitoring and advisory board for Lilly. EBG reports research grants received (to their institution) from ABL-Bio, Arrivent, AstraZeneca, Bristol Myers Squibb, Daiichi, Sanko, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Prelude, Regeneron, and Synthekine; consulting fees from AbbVie, Arcus, AstraZeneca, Arrivent, Atreca, BridgeBio, Bristol Myers Squibb, EMD Serono, Eli Lilly, Gilead, GlaxoSmithKline, Hookipa, LianBio, Merckl Merus, Novartis, Nuvalent, Personalis, Regeneron, Sanofi, Seagan, Sensei, Sumitomo, Strata, Summit, Synthekine, Xilio, and Zymeworks; support for attending meetings from A2 and Novartis; patents issued (to their institution); and other financial support for independent medical education from Daiichi Sankyo and Ipsen. DSWT reports research grants support to their institution from ACM Biolabs, Amgen, AstraZeneca, Bayer, and Pfizer, outside of the submitted work; consulting fees from Amgen, AstraZeneca, Bayer, Boehringer, Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, and Takeda; honoraria for lectures and presentations from Amgen, Bayer, Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, Takeda, BeiGene, Regeneron, and Zymeworks; and support for attending meetings from Bayer, Merck, Pfizer, Regeneron, and Zymeworks. TS declares honoraria for lectures from Amgen, AnHeart Therapeutics, AstraZeneca, Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, GlaxoSmithKline, MSD, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Takeda Pharmaceutical, and Towa Pharmaceutical. GMF declares the stocks and shareholder for Roche. AR, MC, SLM, CB, YY, LJ, LF, and AY are employees of Novartis. AB reports stocks and stock options from Novartis and Daiichi Sankyo. RSH declares research grants received to their institution for clinical trials from AbbVie, Agios, Corvus, Daichii Sankyo, Erasca, Lilly, Mirati, Mythic, Novartis, and Turning Point; and consulting fees for self from AbbVie, Astrazeneca, Biohaven, Claim Therapeutics, Daichii Sankyo, EMD Serono, Lilly, Merck, Novartis, Regeneron, and Sanofi. SVO, HJMG, and MJ declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: We evaluated the disease and patient characteristics, treatment, and MET testing patterns, predictive biomarkers and survival outcomes in patients with MET-dysregulated metastatic non-small-cell lung cancer (NSCLC) in a real-world setting., Patients and Methods: This was a multinational, retrospective, noninterventional chart review study. Data from medical records of patients with advanced/metastatic EGFR wild-type, MET-dysregulated NSCLC (December 2017-September 2018) were abstracted into electronic data collection forms., Results: Overall, 211 patient charts were included in this analysis; 157 patients had MET exon 14 skipping mutations (METex14; with or without concomitant MET amplification) and 54 had MET amplification only. All patients were tested for METex14, whereas MET amplification was evaluated in 168 patients. No overlap was reported between MET dysregulation and ALK, ROS1 or RET rearrangements, or HER2 exon 20 insertions. Overall, 56 of 211 patients (26.5%) received MET inhibitor (METi) therapy in any treatment-line setting (31.2% in the METex14 cohort; 13% in the MET-amplified only cohort). In the METex14 cohort, median OS in patients receiving METi was 25.4 months versus 10.7 months in patients who did not (HR [95% CI]: 0.532 [0.340-0.832]; P = .0055). In the MET-amplified only cohort, median OS was 20.6 months in patients treated with METi compared with 7.6 months in those without METi (HR [95% CI]: 0.388 [0.152-0.991]; P = .0479)., Conclusions: MET alterations in NSCLC typically occur in the absence of other oncogenic driver mutations and are associated with poor survival outcomes. Notably, METi therapies are associated with improved survival outcomes in patients with MET-dysregulated NSCLC., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: The objective of this study was to assess the cost-effectiveness of atezolizumab versus best supportive care (BSC) as adjuvant treatment following resection and platinum-based chemotherapy for patients with stage II-IIIA non-small cell lung cancer (NSCLC) whose tumours have a programmed death-ligand 1 (PD-L1) expression ≥ 50% of tumour cells and excluding those with ALK/EGFR mutations, from a French collective perspective., Material and Methods: A five state Markov model over a 20-year time horizon was considered, including disease-free survival (DFS 1 ) from IMpower010 trial, three progression states (locoregional recurrence, first and second-line metastatic recurrence) and death. Utilities, quality-adjusted life year (QALY) decrements associated to adverse events, costs, resource use, and transition probabilities were considered in the model. These inputs were sourced from IMpower010 trial, literature, and clinical experts' opinion. Model uncertainty was assessed through deterministic, probabilistic sensitivity analyses and scenario analyses., Results: Atezolizumab was associated with a QALY gain of 1.662, mainly driven by additional time spent in the DFS state, and a life-year gain of 2.112 years. The incremental cost-effectiveness ratio (ICER) for atezolizumab versus BSC was €21,348/QALY gained. The sensitivity analyses highlighted that uncertainty within the model had limited impact on results. Changing the DFS survival curves to other plausible distributions produced ICERs below €20,000/QALY. Introducing an increasing proportion of cured patients (91.5%) from year two to year five reduced the ICER to €13,083/QALY, while including a loss of efficacy at year two in the atezolizumab treatment arm increased the ICER to €33,755/QALY., Discussion: Atezolizumab as adjuvant treatment in stage II-IIIA NSCLC resected patients with PDL1 ≥ 50% and without ALK/EGFR mutations has a lower ICER than other oncology drugs in France and a similar ICER to other adjuvant treatment in oncology., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Ingrid Plessala, Hélène Cawston and Justine Cortes are employees of Amaris Consulting, which received professional fees from Roche SAS France for the study, and which has also received fees for projects outside the present study. Roula Ajjouri and Katell Le Lay are employees of Roche SAS France. Roche SAS France provided professional fees to Amaris Consulting for the project, including preparation of the manuscript. Pierre-Jean Souquet and, Christos Chouaid received fees for this project and provided clinical advice to Roche SAS France, as clinical experts. They also participated to advisory boards, to the manuscript development and its review]., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation., Case Report: We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m 2 and pembrolizumab 200 mg intravenously every 3 weeks. The patient presented neglected celiac disease, resulting in malabsorption syndrome with iron and folic acid deficiency. The question was how to administer folic acid supplementation during the pemetrexed-based chemotherapy., Management and Outcomes: Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin-tazobactam was started, and then switched to amoxicillin-clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia., Discussion/conclusion: This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed - antifolate-based chemotherapy.

Background and Objectives: Cancer patients undergoing cytotoxic chemotherapies exhibit a series of adverse side effects including smell and taste alterations, which can have a significant impact on their food behavior and quality of life. Particularly, olfactory alterations are often underestimated, although declared as frequent by cancer patients. In the present study, we set out to examine loss of smell in lung cancer patients undergoing chemotherapy and its relationship to food habits., Material and Methods: Forty-four bronchial cancer patients receiving cisplatin and 44 controls age and gender matched participants were tested for olfactory and gustatory functions using the European Test of Olfactory Capabilities and the Taste Strips test. Participants reported their food and dietary habits by filling a self-administered questionnaire. Patients were tested under two different sessions: i) before the beginning of the treatment, and ii) 6 weeks later, after 2 cycles of chemotherapy. Controls were tested under the same protocol with two sessions separated by 6 weeks., Results and Conclusions: The results highlighted decreased smell and taste abilities in almost half of the lung patients' group even before the exposition to Cisplatin. On a perceptual level, patients rated typical food odors as less edible compared to controls. Moreover, within the patients' group, hyposmics reported using more condiments, possibly as a compensatory mechanism to their decreased sensory abilities. Taken together, these findings showed that loss of smell is prevalent in lung cancer patients and is related to changes in dietary practices including seasoning. Future studies will provide a better understanding of these sensory compensation mechanisms associated with olfactory loss and their effects on food pleasure in this patient population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown., Patients and Methods: SAFIR02-Lung/IFCT 1301 was an open-label, randomized, phase II trial, involving 33 centers in France. We investigated eight TT (substudy-1) and one ICB (substudy-2), compared with standard-of-care as a maintenance strategy in patients with advanced EGFR, ALK wild-type (wt) NSCLC without progression after first-line chemotherapy, based on high-throughput genome analysis. The primary outcome was progression-free survival (PFS)., Results: Among the 175 patients randomized in substudy-1, 116 received TT (selumetinib, vistusertib, capivasertib, AZD4547, AZD8931, vandetanib, olaparib, savolitinib) and 59 standard-of-care. Median PFS was 2.7 months [95% confidence interval (CI), 1.6-2.9] with TT versus 2.7 months (1.6-4.1) with standard-of-care (HR, 0.97; 95% CI, 0.7-1.36; P = 0.87). There were no significant differences in PFS within any molecular subgroup. In substudy-2, 183 patients were randomized, 121 received durvalumab and 62 standard-of-care. Median PFS was 3.0 months (2.3-4.4) with durvalumab versus 3.0 months (2.0-5.1) with standard-of-care (HR, 0.86; 95% CI, 0.62-1.20; P = 0.38). Preplanned subgroup analysis showed an enhanced benefit with durvalumab in patients with PD-L1 tumor proportion score (TPS) ≥1%, (n = 29; HR, 0.29; 95% CI, 0.11-0.75) as compared with PD-L1 <1% (n = 31; HR, 0.71; 95% CI, 0.31-1.60; Pinteraction = 0.036)., Conclusions: Molecular profiling can feasibly be implemented to guide treatment choice for the maintenance strategy in EGFR/ALK wt NSCLC; in this study it did not lead to substantial treatment benefits beyond durvalumab for PD-L1 ≥ 1 patients., (©2022 American Association for Cancer Research.)

Background: Even after resection of early-stage non-small-cell lung cancer (NSCLC), patients have a high risk of developing recurrence and second primary lung cancer. We aimed to assess efficacy of a follow-up approach including clinic visits, chest x-rays, chest CT scans, and fibre-optic bronchoscopy versus clinical visits and chest x-rays after surgery for resectable NSCLC., Methods: In this multicentre, open-label, randomised, phase 3 trial (IFCT-0302), patients aged 18 years or older and after complete resection of pathological stage I-IIIA NSCLC according to the sixth edition of the TNM classification were enrolled within 8 weeks of resection from 122 hospitals and tertiary centres in France. Patients were randomly assigned (1:1) to CT-based follow-up (clinic visits, chest x-rays, thoraco-abdominal CT scans, and fibre-optic bronchoscopy for non-adenocarcinoma histology) or minimal follow-up (visits and chest x-rays) after surgery for NSCLC, by means of a computer-generated sequence using the minimisation method. Procedures were repeated every 6 months for the first 2 years and yearly until 5 years. The primary endpoint was overall survival analysed in the intention-to-treat population. Secondary endpoints, also analysed in the intention-to-treat population, included disease-free survival. This trial is registered with ClinicalTrials.gov, NCT00198341, and is active, but not enrolling., Findings: Between Jan 3, 2005, and Nov 30, 2012, 1775 patients were enrolled and randomly assigned to a follow-up group (888 patients to the minimal follow-up group; 887 patients to the CT-based follow-up group). Median overall survival was not significantly different between follow-up groups (8·5 years [95% CI 7·4-9·6] in the minimal follow-up group vs 10·3 years [8·1-not reached] in the CT-based follow-up group; adjusted hazard ratio [HR] 0·95, 95% CI 0·83-1·10; log-rank p=0·49). Disease-free survival was not significantly different between follow-up groups (median not reached [95% CI not estimable-not estimable] in the minimal follow-up group vs 4·9 [4·3-not reached] in the CT-based follow-up group; adjusted HR 1·14, 95% CI 0·99-1·30; log-rank p=0·063). Recurrence was detected in 246 (27·7%) of 888 patients in the minimal follow-up group and in 289 (32·6%) patients of 887 in the CT-based follow-up group. Second primary lung cancer was diagnosed in 27 (3·0%) patients in the minimal follow-up group and 40 patients (4·5%) in the CT-based follow-up group. No serious adverse events related to the trial procedures were reported., Interpretation: The addition of thoracic CT scans during follow-up, which included clinic visits and chest x-rays after surgery, did not result in longer survival among patients with NSCLC. However, it did enable the detection of more cases of early recurrence and second primary lung cancer, which are more amenable to curative-intent treatment, supporting the use of CT-based follow-up, especially in countries where lung cancer screening is already implemented, alongside with other supportive measures., Funding: French Health Ministry, French National Cancer Institute, Weisbrem-Benenson Foundation, La Ligue Nationale Contre Le Cancer, and Lilly Oncology., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests VW reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bristol Myers Squibb (BMS), Merck Sharpe and Dohme, Pfizer, and Roche outside the submitted work; support for attending meetings or travel from AstraZeneca, BMS, and Sanofi outside the submitted work; and participation on a data safety monitoring board or advisory board from MSD and Takeda outside the submitted work. JT reports support for attending meetings or travel from Roche and BMS, outside the submitted work. EQ reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Chugai and BMS, outside the submitted work; and support for attending meetings or travel from BMS, Roche, and Takeda, outside the submitted work. GZ reports grants or contracts from Fondation Roche, Takeda, and BMS outside the submitted work; consulting fees from BMS and AstraZeneca, outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from BMS, AstraZeneca, Pfizer, and MDS, outside the submitted work; support for attending meetings or travel from BMS, AstraZeneca, and AbbVie, outside the submitted work. FB reports payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F Hoffmann–La Roche, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda, outside the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Concerns about the proper schedule for discontinuing immunotherapy have been raised by many clinicians, as well as the minimal check-up required to assess residual disease before stopping immunotherapy. In fact, there currently exist no recommendations concerning immunotherapy prescription and optimal assessment in the event of persistent oncological response in cases of metastatic non-small cell lung cancer (NSCLC)., Methods: We conducted an online survey among board-certified French Thoracic Oncologists belonging to two professional associations. The survey included multiple-choice questions that either stood alone or were included in case reports., Results: The survey was sent to 490 physicians, of whom 88 responded. For minimal residual disease assessment after 2 years of immunotherapy, PET-scan is prescribed by 92% of respondents and cerebral MRI by 59%. In the event of complete response after 2 years of treatment, 83% of physicians stop prescribing pembrolizumab and 70% discontinue nivolumab. In the event of partial response, 88% of respondents continue immunotherapy. In this case, only 33% use a complementary locoregional treatment such as radiotherapy., Conclusion: Our survey highlights a pronounced tendency to stop immunotherapy in the event of complete oncological response. In the event of partial morphologic response, on the other hand, there is a tendency to continue immunotherapy. However, the use of locoregional treatments remains more heterogeneous., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Background: Immunotherapy using inhibitors targeting immune checkpoint programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) is currently the standard of care in patients with advanced non-small-cell lung cancer (NSCLC)., Materials and Methods: We carried out a nationwide cohort retrospective study of consecutive patients with advanced, refractory NSCLC who received nivolumab as second to later lines of treatment as part of the expanded access program. Key objectives were to assess the efficacy and safety of nivolumab and the efficacy of first post-nivolumab treatment., Results: Nine hundred and two patients were enrolled: 317 (35%) with squamous cell carcinoma and 585 (65%) with non-squamous cell carcinoma. Median age was 64 years; there were 630 (70%) men, 795 (88%) smokers, 723 (81%) patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0/1, 197 (22%) patients with brain metastases, and 212 (27%) with liver metastases. Best response was partial response for 16.2% and stable disease (SD) for 30.5%. Progression-free survival and overall survival (OS) rates at 2, 3, and 5 years were 8% and 25%, 6% and 16%, and 4% and 10%, respectively. At multivariate analysis, ECOG PS ≥2 [hazard ratio (HR) = 2.13, 95% confidence interval (95% CI) 1.78-2.55, P < 0.001], squamous histology (HR = 1.17, 95% CI 1.01-1.36, P = 0.04), and presence of central nervous system metastases (HR = 1.29, 95% CI 1.08-1.54, P = 0.005) were significantly associated with lower OS. Four hundred and ninety-two patients received at least one treatment after discontinuation of nivolumab, consisting of systemic therapies in 450 (91%). Radiation therapy was delivered to 118 (24%) patients., Conclusion: The CLINIVO cohort represents the largest real-world evidence cohort with the use of immune checkpoint inhibitor in advanced, metastatic NSCLC after failure of first-line chemotherapy, with long-term follow-up and analysis of subsequent therapies. Our data confirm the efficacy of nivolumab in a cohort larger than that reported in landmark clinical trials and identify prognostic factors, which reinforces the need for accurate selection of patients for treatment with immune checkpoint inhibitors. Our data indicate that oligoprogression is frequent after nivolumab exposure and provide a unique insight into the long-term survival., Competing Interests: Disclosure OM reports personal fees from AstraZeneca, Takeda, BMS, MSD, Novartis, and AMGEN. NG reports research/grant support from MSD, AstraZeneca, AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, MSD, Novartis, Pfizer, Sivan, and Trizell, and consultative services for Bristol Myers Squibb, AstraZeneca, AbbVie, Amgen, Boehringer Ingelheim, Eli Lilly, Hoffmann-La Roche, Janssen, Merck, MSD, Novartis, Pfizer, Sanofi, and Sivan. BB reports grants from AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, and Tolero Pharmaceuticals. FB reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, ß. Hoffmann-La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre, Pfizer, and Takeda. CA-V reports personal fees and non-financial support from Roche, BMS, MSD, AstraZeneca, AbbVie, Pfizer, and Takeda. SF reports support for attending meetings and/or travel from Boehringer Ingelheim France, BMS, Leo Pharma, Sandoz, and Novartis Pharma SAS. JM reports personal fees from Roche, AstraZeneca, Pierre Fabre, Takeda, BMS, MSD, Hengrui, BLUEPRINT, DAIICHI, and Novartis and grants from Roche, AstraZeneca, Pierre Fabre, and BMS. JC reports consulting fees from AstraZeneca, Boehringer Ingelheim, BMS, Jansen, MSD, Pfizer, Roche, and Takeda. WH reports payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from BMS and Astellas and support for attending meetings and/or travel from Astellas, Pfizer, and Janssen. DM-S reports grants or contracts from Roche, AstraZeneca, Amgen, AbbVie, Pfizer, Takeda, and Lilly; consulting fees from Roche, AstraZeneca, Amgen, AbbVie, Pfizer, Takeda, and Lilly; payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from Roche, AstraZeneca, Amgen, AbbVie, Pfizer, Takeda, Lilly, and BMS; and support for attending meetings and/or travel from Roche, AstraZeneca, Amgen, AbbVie, Pfizer, Takeda, Lilly, and BMS. VW reports honoraria from Roche, AstraZeneca, BMS, and MSD and non-financial support from Roche and Pfizer. PJS reports consulting fees, support for attending meetings and/or travel, payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing, or educational events from BMS and participated on a data safety monitoring board or advisory board for BMS. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Benefit from maintenance in advanced non-squamous non-small cell lung cancer (NS-NSCLC) might favor switch maintenance after disease stabilization (SD) and continuation after objective response (OR). This trial assessed a maintenance strategy conditioned by response to cisplatin-gemcitabine (CG) with G continuation for patients with OR or switch to pemetrexed (P) for patients with SD as compared with a control arm based on the Paramount regimen., Methods: Eligibility criteria: age 18-70 years, ECOG PS 0-1, untreated stage IV NS-NSCLC without EGFR or ALK alteration, ineligibility to bevacizumab. Patients were randomized 1:1 to receive either CG (4 cycles) followed by G maintenance in case of OR followed by P at progression, or switch to P for patients with SD, or 4 cycles of CP followed by P (control arm). Primary endpoint: overall Survival., Results: Between 2012 and 2016, 932 patients were randomized (CG: 467, CP: 465) with well-balanced characteristics. 257 patients (56.7%) in the CG arm received maintenance (G: 142, P: 113) versus 277 patients (59.7%) in the CP arm. Median number of maintenance cycles was 5 for G and P (CG induction) and 4 for P (CP induction). OS adjusted HR was 0.97 (95% CI 0.84, 1.13; p = 0.71) with a median of 10.9 months (CG) versus 10.4 (CP). HR for PFS was 0.95 (95% CI 0.83, 1.09; p = 0.45) with a median of 4.8 months for CG versus 4.5 for CP. Safety profile was as expected., Conclusions: Adapting maintenance strategy according to response to induction chemotherapy does not improve patient outcome., Clinical Trial Information: NCT01631136., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Dabrafenib plus trametinib was found to have robust antitumor activity in patients with BRAF V600E-mutant metastatic NSCLC (mNSCLC). We report updated survival analysis of a phase 2 study (NCT01336634) with a minimum of 5-year follow-up and updated genomic data., Methods: Pretreated (cohort B) and treatment-naive (cohort C) patients with BRAF V600E-mutant mNSCLC received dabrafenib 150 mg twice daily and trametinib 2 mg once daily. The primary end point was investigator-assessed overall response rate per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points were duration of response, progression-free survival, overall survival, and safety., Results: At data cutoff, for cohorts B (57 patients) and C (36 patients), the median follow-up was 16.6 (range: 0.5-78.5) and 16.3 (range: 0.4-80) months, overall response rate (95% confidence interval [CI]) was 68.4% (54.8-80.1) and 63.9% (46.2-79.2), median progression-free survival (95% CI) was 10.2 (6.9-16.7) and 10.8 (7.0-14.5) months, and median overall survival (95% CI) was 18.2 (14.3-28.6) and 17.3 (12.3-40.2) months, respectively. The 4- and 5-year survival rates were 26% and 19% in pretreated patients and 34% and 22% in treatment-naive patients, respectively. A total of 17 patients (18%) were still alive. The most frequent adverse event was pyrexia (56%). Exploratory genomic analysis indicated that the presence of coexisting genomic alterations might influence clinical outcomes in these patients; however, these results require further investigation., Conclusions: Dabrafenib plus trametinib therapy was found to have substantial and durable clinical benefit, with a manageable safety profile, in patients with BRAF V600E-mutant mNSCLC, regardless of previous treatment., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Context: Residents in respiratory medicine are often confronted with breaking bad news to patients. In communication skill training, a recurring question is whether to use standardized or peer-played patients for simulation METHODS: In this prospective single-center crossover study in pulmonology residents, a range of scenarios were performed during training sessions using standardized or peer-played patients. The aim was to assess whether patient type did alter the quality of the role-play. The residents completed post-scenario questionnaires about the role-play of each scenario, but also pre- and post-session questionnaires about their perception of the effectiveness of both modalities, and pre- and post-testing questionnaires about the psychological impact of the training., Results: Collectively, 4 scenarios were performed 52 times and evaluated 208 times by 52 residents. The use of standardized patients appeared to improve the quality of the patient role (8.8 ± 1.0 vs. 8.3 ± 1.1; p = 0.001) and the general quality of role-play (8.8 ± 1.0 vs. 8.2 ± 0.9; p = 0.008), without affecting the quality of the physician role played by the resident. There were no significant differences between standardized and peer-played patients regarding learning interest or psychological impact. Regardless of the modality, the training sessions did appear to significantly affect the residents' evaluations of their ability to break bad news to patients (5.7 ± 1.1 vs. 7.4 ± 1.1; p < 10-4)., Conclusion: Our results did not point to a superiority of either of these modalities for learning how to break bad news. Both may be used, depending on the local resources., Competing Interests: Conflict of interests Dr. DARRASON reports personal fees from Bristol Meyers Squibb, personal fees from CCC Congres Colloques Conventions, outside the submitted work. Dr COURAUD reports reports grants and personal fees from Amgen, grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from Boehringer Ingelheim, grants, personal fees and non-financial support from Chugai, grants and personal fees from Laidet, grants and personal fees from Lilly, grants and personal fees from MSD, grants from Pfizer, non-financial support from Sysmex Inostics, grants, personal fees and non-financial support from Takeda, non-financial support from Vitalaire, grants from Bayer, grants, personal fees and non-financial support from Astra Zeneca, grants, personal fees and non-financial support from Roche, outside the submitted work. Dr SOUQUET reports no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 SPLF and Elsevier Masson SAS. All rights reserved.)

Background: To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up., Patients and Methods: Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs., Results: With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation., Conclusions: With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer., Competing Interests: Disclosure MR reports advisory/consulting fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Mirati Therapeutics, MSD Oncology, Novartis, Pfizer, Roche/Genentech, and Samsung Bioepis; speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Merck Serono, Mirati Therapeutics, MSD Oncology, Novartis, Pfizer, and Roche/Genentech. TEC reports advisory/consulting fees and travel, accommodation, and expenses from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Janssen, Merck Sharp & Dohme (MSD), Novartis/GlaxoSmithKline, Pfizer, Roche, Sanofi, and Servier. MS reports research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Clovis, Eli Lilly, Gilead Sciences, GlaxoSmithKline, MSD, Novartis, Pfizer/EMD Serono, Regeneron, Roche, and Tesaro; travel, accommodation, and expenses from Bristol Myers Squibb. BZ reports research funding from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Janssen-Cilag, MSD, and Roche. JB reports advisory/consulting fees and honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Roche, and Servier; travel, accommodation, and expenses from AstraZeneca and Roche. EF reports advisory fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Blue Print Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Medical Trends, Merck KGaA, MSD, Novartis, Peptomyc, Pfizer, Puma Biotechnology, Regeneron, Roche, Sanofi Genzyme, Syneos Health, Takeda; independent board member of Grifols; research funding from Grant for Oncology Innovation and Fundación Merck Salud; speaker fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Medscape, MSD, Novartis, PeerVoice, Pfizer, Prime Oncology, Roche, Springer, Takeda, Touch Medical, and CME Outfitters. OJV reports advisory/consulting fees from Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD, Roche/Genetech, and Takeda; honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche/Genentech; research funding from AstraZeneca Spain; speaker fees from Roche/Genentech; travel, accommodation, and expenses from Boehringer Ingelheim, Bristol Myers Squibb, MSD, and Roche/Genentech. AA reports advisory/consulting fees from Boehringer Ingelheim Pharmaceuticals Inc and Roche; expert testimony fees for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche, and Sanofi; speaker fees from Bristol Myers Squibb, Novartis, and Sandoz; travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche, and Sanofi. HS reports research funding from AstraZeneca, Bristol Myers Squibb, Chugai Pharma, Merck KGaA, MSD K.K, Ono Pharmaceutical, and Taiho Pharmaceutical; speaker fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb Japan, Chugai Pharma, MSD K.K, Ono Pharmaceutical, and Taiho Pharmaceutical. FR reports consulting and speaker fees from Novartis; travel, accommodation, and expenses from Roche. PJS reports non-financial support from AstraZeneca, Bristol Myers Squibb, MSD, and Roche; personal fees from AstraZeneca, Bristol Myers Squibb, Novartis, and Roche; research funding from AstraZeneca, Bristol Myers Squibb, Novartis, MSD, and Roche. CM reports advisory and speaker fees from AstraZeneca, Bristol Myers Squibb, and MSD. MP reports advisory fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, MSD, Novartis, Pfizer, Roche, and Takeda; research funding from AstraZeneca, Boehringer Ingelheim, Chugai, Roche, and Takeda; speaker fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, MSD, Pfizer, Roche, and Takeda; travel support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, MSD, Pfizer, Roche, and Takeda. AS reports expert testimony fees from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche; research funding from Bristol Myers Squibb; speaker fees from AstraZeneca/MedImmune; travel, accommodation, and expenses from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche. SL reports advisory/consulting fees from AstraZeneca, Boehringer Ingelheim, Hutchison MediPharma, Roche, and Simcere; research funding from AstraZeneca, Bristol Myers Squibb, Hutchison MediPharma, Heng Rui, and Roche; speaker fees from AstraZeneca, Hanseng, and Roche. LPA reports honoraria from Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly, Merck Serono, Mirati Therapeutics, MSD, Novartis, Pfizer, PharmaMar, Roche/Genentech, Sanofi, Servier, and Takeda; leadership fees from Genomica and ALTUM Sequencing; research funding from AstraZeneca, Bristol Myers Squibb, Kura Oncology, PharmaMar, and MSD; speaker fees from Bristol Myers Squibb, Eli Lilly, Merck Serono, MSD Oncology, Pfizer, Roche/Genentech; travel, accommodation, and expenses from AstraZeneca, Bristol Myers Squibb, MSD, Pfizer, Roche, and Takeda. DPC reports advisory/consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Bristol Myers Squibb Japan, Curio Science, Daiichi Sankyo, Eli Lilly, EMD Serono, Flame Biosciences, G1 Therapeutics (Intellisphere), Geneplus, GlaxoSmithKline, Gloria Biosciences, Incyte, Inivata, Inovio Pharmaceutical, Janssen, Johnson & Johnson, Kyowa Hakko Kirin, Loxo, Merck, Merck KGaA, MSD, Novartis, Novocure, Oncocyte, OncoHost, Pfizer, Piper Sandler, Roche/Genentech, Sanofi, and Takeda; employment with James Cancer Center; honoraria from AstraZeneca and Nexus Pharmaceutical; research funding from Bristol Myers Squibb. AM is an employee of and has stock ownership in Bristol Myers Squibb. SM is an employee of and has stock ownership in Bristol Myers Squibb; was employed as a contractor by Sanofi (Rangam Consultants Inc); reports travel, accommodation, and expenses from Bristol Myers Squibb. XZ is an employee of Bristol Myers Squibb. PT is an employee of and has stock ownership in Bristol Myers Squibb. TJ reports advisory/consulting fees from AstraZeneca, AstraZeneca/MedImmune, Boehringer Ingelheim, Bristol Myers Squibb, Ignyta, Merck KGaA, MSD Oncology, Novartis, Pfizer, and Roche/Genentech; honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, MSD Oncology, and Roche/Genentech; travel, accommodation, and expenses from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, and Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Tumor mutation screening is standard of care for patients with stage IV NSCLC. Since a couple of years, widespread NGS approaches used in routine diagnostics to detect driver mutations such as EGFR, KRAS, BRAF or MET allows the identification of other alterations that could modulated the intensity or duration of response to targeted therapies. The prevalence of co-occurring alterations that could affect response or prognosis as not been largely analyzed in clinical settings and large cohorts of patients. Thanks to the IFCT program "Biomarkers France", a collection of samples and data at a nation-wide level was available to test the impact of co-mutations on first line EGFR TKI in patients with EGFR mutated cancers., Materials and Methods: Targeted NGS was assessed on available (n = 208) samples using the Ion AmpliSeq™ Cancer Hotspot Panel v2 to screen for mutations in 50 different cancer genes., Results: This study showed that PTEN inactivating mutations, ATM alterations, IDH1 mutations and complex EGFR mutations were predictors of short PFS in patients with a stage 4 lung adenocarcinoma receiving first line EGFR TKI and that PTEN, ATM, IDH1 and KRAS mutations as well as alterations in the MAPK pathway were related to shorter OS., Conclusion: These findings may lead to new treatment options in patients with unfavorable genotypes to optimize first line responses., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Maintenance chemotherapy is a reasonable choice for patients with metastatic non-small cell lung carcinoma (NSCLC) not progressing after induction therapy with a platinum-based doublet. Nevertheless, there have been no studies dedicated to elderly patients., Patients and Methods: We conducted a randomised trial in patients aged 70-89 years, with advanced NSCLC (with neither EGFR mutation nor ALK rearrangement), who had not progressed after four cycles of monthly carboplatin and weekly paclitaxel in order to compare maintenance with either pemetrexed (500 mg/m 2 d1, 22) in patients with non-squamous cell carcinoma or gemcitabine (1,150 mg/m 2 d1, 8, 22) in squamous cell carcinoma to simple observation. The patients were required to have a performance status (PS) 0-2, mini-mental score >23, and creatinine clearance ≥45 mL/min. The primary end-point was overall survival (OS)., Results: 632 patients were enrolled from May 2013 to October 2016. Of the 328 (52.3%) patients randomised after induction therapy, 166 patients were assigned to the observation arm, versus 162 to the switch maintenance arm, 119 of whom received pemetrexed and 43 gemcitabine. The median OS from randomisation was 14.1 months (95% confidence interval [CI]: 12.0-17.0) in the observation arm and 14 months (95% CI: 10.9-16.9) in the maintenance arm (p = 0.72). The median progression-free survival (PFS) from randomisation was 2.7 months (95% CI: 2.6-3.1) in the observation arm versus 5.7 months (95% CI: 4.8-7.1) in the maintenance arm (p < 0.001)., Conclusion: Switch maintenance therapy significantly prolonged PFS but not OS and, thus, should not be proposed to elderly patients with advanced NSCLC., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation., Methods: We conducted a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET -dysregulated advanced NSCLC. Patients were assigned to cohorts on the basis of previous lines of therapy and MET status ( MET exon 14 skipping mutation or MET amplification according to gene copy number in tumor tissue). Patients received capmatinib (400-mg tablet) twice daily. The primary end point was overall response (complete or partial response), and the key secondary end point was response duration; both end points were assessed by an independent review committee whose members were unaware of the cohort assignments., Results: A total of 364 patients were assigned to the cohorts. Among patients with NSCLC with a MET exon 14 skipping mutation, overall response was observed in 41% (95% confidence interval [CI], 29 to 53) of 69 patients who had received one or two lines of therapy previously and in 68% (95% CI, 48 to 84) of 28 patients who had not received treatment previously; the median duration of response was 9.7 months (95% CI, 5.6 to 13.0) and 12.6 months (95% CI, 5.6 to could not be estimated), respectively. Limited efficacy was observed in previously treated patients with MET amplification who had a gene copy number of less than 10 (overall response in 7 to 12% of patients). Among patients with MET amplification and a gene copy number of 10 or higher, overall response was observed in 29% (95% CI, 19 to 41) of previously treated patients and in 40% (95% CI, 16 to 68) of those who had not received treatment previously. The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2., Conclusions: Capmatinib showed substantial antitumor activity in patients with advanced NSCLC with a MET exon 14 skipping mutation, particularly in those not treated previously. The efficacy in MET -amplified advanced NSCLC was higher in tumors with a high gene copy number than in those with a low gene copy number. Low-grade peripheral edema and nausea were the main toxic effects. (Funded by Novartis Pharmaceuticals; GEOMETRY mono-1 ClinicalTrials.gov number, NCT02414139.)., (Copyright © 2020 Massachusetts Medical Society.)

Purpose: The incidence of lung cancer has dramatically increased in women. Preclinical data have suggested that combining EGFR-tyrosine kinase inhibitor (TKI) with an antiestrogen may overcome resistance to EGFR-TKI., Patients and Methods: The IFCT-1003 LADIE trial was a 2 × 2 arms parallel open-label randomized phase II trial. EGFR-TKI-naïve postmenopausal women with advanced lung cancer were treated with gefitinib (G) versus gefitinib + fulvestrant (G+F) in the EGFR-mutated group (EGFR + ) or with erlotinib (E) versus erlotinib + fulvestrant (E+F) in the EGFR wild-type group (EGFR-WT). The primary objective was progression-free survival (PFS) at 3 and 9 months for EGFR-WT and EGFR + patients., Results: Overall, 204 patients (gefitinib 104 and G+F 100) and 175 patients (erlotinib 87 and E+F 88) were enrolled in the EGFR + and EGFR-WT cohorts. In the EGFR + cohort, the primary endpoint was reached, with 58% of the G+F group patients being nonprogressive at 9 months. Adding fulvestrant to gefitinib was not associated with improved PFS (9.9 vs 9.4 months) or overall survival (OS; 22.1 vs 28.6 months). In the EGFR-WT cohort, the primary endpoint was also achieved (33.7% of the patients were nonprogressive at 3 months). Adding fulvestrant to erlotinib was not associated with improved outcome (PFS 1.8 vs 2.0 and OS 10.3 vs 7.3 months). No PFS difference was observed regarding estrogen receptor alpha expression. The tolerance was as expected with no treatment-related death., Conclusions: Adding fulvestrant to EGFR-TKI is feasible, but not associated with prolonged PFS regardless of EGFR status. The lack of benefits while combining fulvestrant to EGFR-TKI does not support its future development in an unselected population., (©2020 American Association for Cancer Research.)

Background: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort., Patients and Methods: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS)., Results: Of the 118 patients enrolled, 101 presented with a BRAF V600 mutation and 17 with BRAF nonV600 mutations; the median follow-up was 23.9 months. In the BRAF nonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAF V600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications., Conclusion: Routine biomarker screening of NSCLC should include BRAF V600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAF V600 -mutated NSCLC but not those with BRAF nonV600 mutations., Trial Registration: ClinicalTrials.gov identifier: NCT02304809., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: An international consensus proposed in 2011 a definition and classification system for cachexia (CAX), mainly based on weight loss, sarcopenia [skeletal muscle mass (SMM) loss], inflammation, and anorexia. The aim of this study was to stage CAX in non-small-cell lung cancer (NSCLC) patients by using a classification based on the Fearon criteria and supported by quantifiable parameters., Methods: This was a cross-sectional and non-interventional multicentre study. SMM was assessed by analysing L3 computed tomography-scan images. Patients completed the anorexia/CAX subscale of the Functional Assessment of Anorexia/Cachexia Therapy, EORTC QLQ-C30 quality of life (QoL) and International Physical Activity Questionnaire (IPAQ)., Results: Patients were recruited in 56 sites. The analysis population comprised 531 patients, and SMM was assessed in 312 patients. Male patients were 66.5%, with a mean (SD) age of 65.2 (10.0) years, 79.9% were PS 0-1, and the tumour stage was mainly IIIB-IV (87.3%). Overall, 38.7% of patients had CAX, 33.8% pre-CAX, and 0.9% refractory CAX. Molecular tumour profiles were significantly associated with the presence of CAX: 23.9% in EGFR, ALK, ROS1, BRAF, or HER2+ patients, 41.4% in K-RAS+, and 43.2% in patients with no molecular abnormality (P = 0.003). The more advanced the CAX stage, the poorer the scores of functional items of the QoL (P < 0.001) and International Physical Activity Questionnaire (P < 0.001). Sarcopenia was present in 66.7% of CAX and 68.5% of pre-CAX patients. Overall, 43.8% of pre-CAX patients had only sarcopenia with limited weight loss (≤2%) and no anorexia., Conclusions: This is the first study to show the distribution of CAX in a population of NSCLC patients and an association between molecular abnormality in NSCLC and CAX. The original Fearon classification for CAX stages was supported by the associated functional QoL scores and physical activity levels, resulting in a clinically relevant system for detection of early stages of CAX., (© 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Introduction: Patients with stage IV non-small-cell lung cancer (NSCLC) and BRAF V600 mutations may benefit from targeted therapies. Chemotherapy outcomes are little known in this population., Methods: The French Cooperative Thoracic Intergroup (IFCT) Biomarkers France study was a national prospective cohort study aiming to describe the molecular characteristics and clinical outcome of all consecutive NSCLC patients (N = 17,664) screened for molecular alterations. We used this data set to set up a case-control analysis. Cases had stage IV BRAF-mutated (BRAF-MT) NSCLC, whereas controls had NSCLC that was wild-type for EGFR, KRAS, HER2, BRAF, PIK3CA and ALK. Each case was matched for sex, age at diagnosis and smoking status to two controls randomly selected., Results: Overall, 83 cases with BRAF mutant disease (66.3% V600E) were matched to 166 controls. Five cases received tyrosine kinase inhibition in the first-line and 16 in the second-line. All others were treated with standard chemotherapy. There was no significant difference in first-line and second-line progression-free survival (PFS) between the groups, as well as in the disease control rate, BRAF mutation was not found to be prognostic of overall survival. We found no significant difference in outcome between the treatment types used in first-line or second-line in patients with BRAF-MT disease compared with controls nor between BRAF V600E or non-V600E compared with controls., Conclusions: BRAF mutation is not a strong prognostic factor in NSCLC. Although taxan-based therapy shows poorest PFS in first-line, no chemotherapy regimen was associated with prognosis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Cell-free plasma DNA (cfDNA) and mimicking circulating tumor cells (mCTCs) have demonstrated tremendous potential for molecular diagnosis of cancer and have been rapidly implemented in specific settings. However, widespread clinical adoption still faces some obstacles. The purpose was to compare the performance of a BEAMing (beads, emulsion, amplification, and magnetics) assay (OncoBEAM™-epidermal growth factor receptor [EGFR] [Sysmex Inostics]) and a next-generation sequencing assay (NGS; 56G Oncology panel kit, Swift Bioscience) to detect the p.T790M EGFR mutation in cfDNA of non-small cell lung cancer (NSCLC) patients. CfDNA samples (n = 183) were collected within our hospital from patients having a known EGFR sensitizing mutation, and presenting disease progression while under first-line therapy. EGFR mutations were detected using NGS in 42.1% of samples during progression in cfDNA. Testing using the OncoBEAM™-EGFR assay enabled detection of the p.T790M EGFR mutation in 40/183 NSCLC patients (21.8%) versus 20/183 (10.9%), using the NGS assay. Samples that were only positive with the OncoBEAM™-EGFR assay had lower mutant allelic fractions (Mean = 0.1304%; SD ± 0.1463%). In addition, we investigated the detection of p.T790M in mCTCs using H1975 cells. These cells spiked into whole blood were enriched using the ClearCellFX1 microfluidic device. Using the OncoBEAM™-EGFR assay, p.T790M was detected in as few as 1.33 tumoral cells/mL. Overall, these findings highlight the value of using the OncoBEAM™-EGFR to optimize detection of the p.T790M mutation, as well as the complementary clinical value that each of the mutation detection assay offers: NGS enabled the detection of mutations in other oncogenes that may be relevant to secondary resistance mechanisms, whereas the OncoBEAM™-EGFR assay achieved higher sensitivity for detection of clinically actionable mutations., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aim: We performed a clinical audit of the management of patients with EGFR mutations, 1 year after the introduction of EGFR tyrosine kinase inhibitor ( EGFR -TKI) in first-line treatment. Methods: Compliance was defined by tumor molecular profiling for stage IIIB and IV non-small-cell lung cancer and first-line treatment as recommended by the French guidelines. Results: Among the 169 EGFR -mutated patients, compliance was 76.4%. The most common noncompliance criterion was chemotherapy given in first-line treatment instead of EGFR -TKI. No dedicated multidisciplinary meeting and type of institutions were independent unfavorable predictors for compliance. Compliance to guidelines was significantly correlated with time-to-first subsequent treatment improvement (2.5 vs 9.1 months; p < 0.0001). Conclusion: Implementation of new standards of care is challenging. Our results reinforce the role of multidisciplinary meetings to provide a better access to innovating therapeutics.

Introduction: This randomized phase II trial aimed at evaluating the engineered programmed cell death ligand 1 (PD-L1) antibody atezolizumab in SCLC progressing after first-line platinum-etoposide chemotherapy., Methods: Patients were randomized 2:1 to atezolizumab (1200 mg intravenously every 3 weeks) until progression or unacceptable toxicity, or conventional chemotherapy (up to 6 cycles of topotecan or re-induction of initial chemotherapy). Patients were not selected based on PD-L1 tissue expression. The primary endpoint was objective response rate at 6 weeks. A two-stage design with 2:1 randomization and O'Brien-Fleming stopping rules was used. The null hypothesis was rejected if more than 12 of 45 patients were responders., Results: Overall, 73 patients were randomized (atezolizumab n = 49; chemotherapy n = 24). At 6 weeks, 1 of 43 eligible atezolizumab patients achieved an objective response (2.3%, 95% confidence interval [CI]: 0.0-6.8), whereas 8 others had stable disease (20.9% disease control rate; 95% CI: 8.8-33.1). Among eligible chemotherapy patients (n = 20), 10% achieved an objective response (65% disease control rate). Median progression-free survival was 1.4 months (95% CI: 1.2-1.5) with atezolizumab and 4.3 months (95% CI: 1.5-5.9) with chemotherapy. Overall survival did not significantly differ between groups. Median overall survival was 9.5 months versus 8.7 months for the atezolizumab and the chemotherapy group, respectively (adjusted hazard ratio atezolizumab : 0.84, 95% CI: 0.45-1.58; p = 0.60). Two atezolizumab patients (4.2%) experienced grade 3 fatigue, and two others grade 1 dysthyroidism. Among 53 evaluable specimens, only 1 (2%) had positive immunohistochemical PD-L1 staining (SP142 clone)., Conclusions: Atezolizumab monotherapy in relapsed SCLC failed to show significant efficacy. No unexpected safety concerns were observed., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Bone is the third metastatic site after liver and lungs. Bone metastases occur in one out of three lung cancers and are usually of osteolytic aspect. Osteolytic bone metastases are responsible of long bone and vertebral fractures leading to restricted mobility, surgery and medullar compression that severely alter quality of life and that have a huge medico-economic impact. In the recent years, Bone Metastatic Multidisciplinary Tumour Board (BM 2 TB) have been developed to optimize bone metastases management for each patient in harmony with oncology program. In this review, we will go through all the different aspects of bone metastases management including diagnosis and evaluation (CT scan, Tc 99m-MDP bone scan, 18 FDG-PET scan and biopsy for molecular diagnosis), systemic bone treatments (zoledronic acid and denosumab) and local treatments (interventional radiology and radiotherapy). Surgical strategies will be discussed elsewhere. Based on the last 2017-Lung Cancer South East French Guidelines, we present a practical decision tree to help the physicians for decision making in order to reach a personalized locomotor strategy for every patient., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To assess how physicians and surgeons carried out malnutrition screening and follow-up for patients with lung cancer. Materials and methods: We carried out an expert opinion survey in France using an anonymous self-administered online questionnaire. Results: In 2017, 206 practitioners responded, of which 60.7% were pulmonologists, 17.4% thoracic surgeons, 11.2% oncologists, and 10.7% radiotherapists. At initial diagnosis, 79.3% of practitioners recorded patients' percentage of weight loss. During follow-up examinations, 67.5% recorded this data for patients at risk of malnutrition and 70.4 % for malnourished patients. Food intake was evaluated by 21.7% of practitioners at initial diagnosis. Surgeons assessed percentage of weight loss and food intake significantly less often than pulmonologists did, they were less likely to request serum albumin tests and waited for a greater percentage of weight loss before referring patients to a nutrition professional. All practitioners were well aware of the prevalence of malnutrition among lung cancer patients and its consequences. The main factors preventing optimal nutritional assessment reported by practitioners were a lack of time and limited specialized knowledge. Conclusion: Nutritional assessment remained suboptimal, especially for surgical patients. The importance granted to malnutrition needs to be increased for patients with lung cancer, especially in surgical departments. Highlights Physicians and thoracic surgeons are well aware of the prevalence and consequences in lung cancer patients. Thoracic surgeons seemed to be less sensitized to malnutrition screening than pulmonologists. Lack of time and limited specialized knowledge were reported as the main factors preventing optimal nutritional assessment.

Background: Territorial differences in the access to innovative anticancer drugs have been reported from many countries. The objectives of this study were to evaluate access to innovative treatments for metastatic lung cancer in France, and to assess whether socioeconomic indicators were predictors of access at the level of the municipality of residence., Methods: All incident cases of metastatic lung cancer hospitalised for a chemotherapy in public hospitals in 2011 were identified from the French National Hospital discharge database. Information on prescription of innovative drugs from an associated database (FICHCOMP) was crossed with the population density of the municipality and a social deprivation index based on national census data., Results: Overall, 21,974 incident cases of metastatic lung cancer were identified, all of whom were followed for 2 years. Of the 11,486 analysable patients receiving chemotherapy in the public sector, 6959 were treated with a FICHCOMP drug at least once, principally pemetrexed. In multivariate analysis, prescription of FICHCOMP drugs was less frequent in patients ≥66 years compared to those ≤55 years (odds ratio: 0.49 [0.44-0.55]), in men compared to women (0.86 [0.79-0.94]) and in patients with renal insufficiency (0.55 [0.41-0.73]) and other comorbidities. Prescription rates were also associated with social deprivation, being lowest in the most deprived municipalities compared to the most privileged municipalities (odds ratio: 0.82 [0.72-0.92]). No association was observed between the population density of the municipality and access to innovative drugs., Conclusion: Although access to innovative medication in France seems to be relatively equitable, social deprivation is associated with poorer access. The reasons for this need to be investigated and addressed.

Purpose: This systematic review with network meta-analysis compared the efficacy and safety of currently licensed second-line treatments in patients with late stage non-small cell lung cancer (NSCLC)., Methods: Randomised controlled trials (RCTs) of participants with advanced/metastatic NSCLC receiving second/third line treatments were screened. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 to July, 2017. Two reviewers screened bibliographic records, extracted data, and assessed risk of bias of included studies. The outcomes were overall survival (OS), progression-free survival (PFS), and drug-related grade 3-5 adverse-events (AEs). We pooled study-specific hazard ratios (HR; for OS and PFS) and risk ratios (RR; for AEs) using conventional and network-meta-analyses, and ranked interventions by the surface under the cumulative ranking curve., Findings: We included 11 RCTs (7,581 participants) comparing nine drugs. All drugs except for erlotinib significantly improved OS compared to docetaxel. Nivolumab was the highest ranking drug followed by atezolizumab and pembrolizumab. There was no significant difference in OS across these three drugs (HR = 0.98, 95% CI 0.79, 1.21 for nivolumab vs atezolizumab; HR = 0.98, 95% CI 0.77, 1.25 for nivolumab vs pembrolizumab). For PFS, ramucirumab + docetaxel and nivolumab were the drugs with the highest ranking. All interventions except ramucirumab + docetaxel had a reduced risk for severe drug-related AEs vs. docetaxel. Of the drugs with the highest ranking on AEs, nivolumab was significantly safer compared to atezolizumab (RR = 0.55, 95% CI 0.38, 0.79) or pembrolizumab (RR = 0.52, 95% CI 0.34, 0.81)., Implications: Nivolumab, pembrolizumab and atezolizumab exhibited superior benefit/risk balance compared to other licensed drugs used late stage NSCLC. Our results indicate that the use of immunotherapies in people diagnosed with non-specific late stage NSCLC should be promoted. The use of docetaxel may now be judged irrelevant as a comparator intervention for approval of new drugs for second line treatment of NSCLC., Study Registration Number: PROSPERO CRD42017065928., Competing Interests: XA, AT, MC, PR, GJMT, AC: none to declare. PJS reports grants from Bristol Myers Squibb, Roche, and MSD outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Introduction: The National Lung Screening Trial found that, in a selected population with a high risk of lung cancer, an annual low-dose CT-scan decreased lung cancer mortality by 20% and overall mortality by 7% compared to annual chest X-Ray. In France, a work group stated that individual screening should be considered in this setting. However, the economic impact of an organized and generalized (to all eligible individuals) screening in France was never reported., Methods: This is a modeling study using French population demographic data and published data from randomized screening trials. We used the same selection criteria as NLST: 55-74-year-old smokers for at least 30 pack-years, current smoker or quit less than 15 years. We computed a second model including also 50-54-year-old individuals. Then, we used different participation rates: 65%, 45%, and 32%., Results: According to the considered model, there would be 1,650,588 to 2,283,993 subjects eligible to screening in France. According to the model and participation rate, lung cancer screening would diagnose 3600 to 10,118 stages 1/2 lung cancer each year. There would be 5991 to 16,839 false-positives, of whom 1416 to 3981 would undergo unnecessary surgery. Screening policy would cost 105 to 215 € million per year. However, increasing the price of a cigarette pack by 0.05 to 0.10 € would fully cover the screening costs., Conclusion: Participation rate is a key point for screening impact. Screening could be easily funded by a small increase in cigarette prices., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

The French healthcare system is a universal healthcare system with no financial barrier to access to health services and cancer drugs. The objective of the study is to investigate associations between, on the one hand, incidence and survival of patients diagnosed with lung cancer in France and, on the other, the socioeconomic deprivation and population density of their municipality of residence. A national, longitudinal analysis using data from the French National Hospital database crossed with the population density of the municipality and a social deprivation index based on census data aggregated at the municipality level. For lung cancer diagnosed at the metastatic stage, one-year and two-year survival was not associated with the population density of the municipality of residence. In contrast, mortality was higher for people living in very deprived, deprived and privileged areas compared to very privileged areas (hazard ratios at two years: 1.19 [1.13-1.25], 1.14 [1.08-1.20] and 1.10 [1.04-1.16] respectively). Similar associations are also observed in patients diagnosed with non-metastatic disease (hazard ratios at two years: 1.21 [1.13-1.30], 1.15 [1.08-1.23] and 1.10 [1.03-1.18] for people living in very deprived, deprived and privileged areas compared to very privileged areas). Despite a universal healthcare coverage, survival inequalities in patients with lung cancer can be observed in France with respect to certain socioeconomic indicators.

In the Intergroupe Francophone de Cancérologie Thoracique 0501 trial the carboplatin-paclitaxel chemotherapy increased toxicity (most frequent, decreased neutrophil count, asthenia). We longitudinally compared health-related quality of life (HRQoL) of the two treatment arms.In total, 451 patients aged 70-89 years with advanced non-small cell lung cancer (NSCLC) were randomly assigned to receive carboplatin plus paclitaxel or vinorelbine or gemcitabine. HRQoL was assessed by means of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire at baseline, week 6 and week 18.Using a five-point decrease as the minimal clinically important difference, patients treated with the chemotherapy doublet exhibited a significant longer time until definitive deterioration (TUDD) for two HRQoL dimensions: physical functioning (median TUDD: 2.04 for the doublet versus 1.71 months for monotherapy; log-rank p=0.01) and nausea and vomiting (median: not reached versus 4.83, respectively; log-rank p=0.046). Cox multivariate analysis revealed the carboplatin and paclitaxel arm to be independently associated with longer TUDD for these two HRQoL dimensions. In addition, TUDD didn't significantly differ between the two arms for all the other HRQoL dimensions.The chemotherapy doublet did not reduce TUDD in elderly patients with advanced NSCLC. Moreover, TUDD was prolonged for two HRQoL dimensions, namely physical functioning and nausea and vomiting., (Copyright ©ERS 2016.)

Background: BRAF mutations act as an oncogenic driver via the mitogen-activated protein kinase (MAPK) pathway in non-small cell lung cancer (NSCLC). BRAF inhibition has shown antitumour activity in patients with BRAF(V600E)-mutant NSCLC. Dual MAPK pathway inhibition with BRAF and MEK inhibitors in BRAF(V600E)-mutant NSCLC might improve efficacy over BRAF inhibitor monotherapy based on observations in BRAF(V600)-mutant melanoma. We aimed to assess the antitumour activity and safety of dabrafenib plus trametinib in patients with BRAF(V600E)-mutant NSCLC., Methods: In this phase 2, multicentre, non-randomised, open-label study, we enrolled adult patients (aged ≥18 years) with pretreated metastatic stage IV BRAF(V600E)-mutant NSCLC who had documented tumour progression after at least one previous platinum-based chemotherapy and had had no more than three previous systemic anticancer therapies. Patients with previous BRAF or MEK inhibitor treatment were ineligible. Patients with brain metastases were allowed to enrol only if the lesions were asymptomatic, untreated (or stable more than 3 weeks after local therapy if treated), and measured less than 1 cm. Enrolled patients received oral dabrafenib (150 mg twice daily) plus oral trametinib (2 mg once daily) in continuous 21-day cycles until disease progression, unacceptable adverse events, withdrawal of consent, or death. The primary endpoint was investigator-assessed overall response, which was assessed by intention to treat in the protocol-defined population (patients who received second-line or later treatment); safety was also assessed in this population and was assessed at least once every 3 weeks, with adverse events, laboratory values, and vital signs graded according to the Common Terminology Criteria for Adverse Events version 4.0. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT01336634., Findings: Between Dec 20, 2013, and Jan 14, 2015, 59 patients from 30 centres in nine countries across North America, Europe, and Asia met eligibility criteria. Two patients who had previously been untreated due to protocol deviation were excluded; thus, 57 eligible patients were enrolled. 36 patients (63·2% [95% CI 49·3-75·6]) achieved an investigator-assessed overall response. Serious adverse events were reported in 32 (56%) of 57 patients and included pyrexia in nine (16%), anaemia in three (5%), confusional state in two (4%), decreased appetite in two (4%), haemoptysis in two (4%), hypercalcaemia in two (4%), nausea in two (4%), and cutaneous squamous cell carcinoma in two (4%). The most common grade 3-4 adverse events were neutropenia in five patients (9%), hyponatraemia in four (7%), and anaemia in three (5%). Four patients died during the study from fatal adverse events judged to be unrelated to treatment (one retroperitoneal haemorrhage, one subarachnoid haemorrhage, one respiratory distress, and one from disease progression that was more severe than typical progression, as assessed by the investigator)., Interpretation: Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAF(V600E)-mutant NSCLC., Funding: GlaxoSmithKline., Competing Interests: Declaration of interests DP acts as an advisor for AstraZeneca, Boehringer, Bristol-Myers Squibb, Clovis, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and Sanofi and has received research funding from Novartis unrelated to the current trial. BB’s institution received a grant from Novartis for this study. HJMG’s institution has received payments from Eli Lilly, Merck Sharp & Dohme, and Roche. P-JS has been involved in clinical trials for GlaxoSmithKline and Novartis. EQ has received personal fees from AbbVie, Bristol-Myers Squibb, Clovis, Lilly, Pfizer, and Roche, has received grants from Amgen, Boehringer, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Mundipharma, and Roche, and has received non-financial support from Boehringer. CSB’s institution received a grant for this study from Novartis and CSB has received personal fees from Novartis. FB has received personal fees from Novartis. SN has received personal fees from Boehringer, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, and Roche. AU, PZ, AD’A, and BM are currently employees of Novartis. AD’A and BM were employees of GlaxoSmithKline during a portion of the study. AD’A and BM own stock in GlaxoSmithKline and Novartis and BM owns stock in Incyte and AstraZeneca. BEJ has received personal fees from Amgen, AstraZeneca, Boehringer, Chugai Pharmaceuticals, Clovis, Genentech, KEW Group, Merck, and Novartis, and shares of post-market revenue for an EGFR genotyping patent. The other authors declare no competing interests., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this retrospective study was to analyse the efficacy of gemcitabine-oxaliplatin (gemox) or 5-fluorouracil-oxaliplatin (folfox) in the treatment of metastatic pulmonary carcinoid tumors., Patients and Methods: 45 patients were included in two tertiary referral centers between January 1999 and January 2013. Typical, atypical carcinoids or not otherwise specified carcinoids were diagnosed according to WHO criteria in 19%, 57%, and 24% of cases by two expert pathologists. Patients had synchronous (38%) or metachronous (62%) metastastic disease (median of 2 (1-5) metastatic sites). Seventy-nine percent had progressive disease before start of chemotherapy. Treatment consisted of: gemcitabine 1000mg/m(2) and oxaliplatin 100mg/m(2) every 2 weeks (gemox regimen, n=24) or 5-fluorouracil (5-FU) (400mg/m(2) in bolus injection and 5-FU 2400mg/m(2) in 46h-infusion) and oxaliplatin 85mg/m(2) (folfox regimen, n=21) every 2 weeks. Tumor response was assessed according to RECIST criteria every 8-12 weeks. Progression free survival and overall survival were assessed using Kaplan Meier curves., Results: Patients received oxaliplatin-based chemotherapy in first-line (20%), second-line (33%), or post-second-line (47%) systemic treatment. The median number of cycles was 8 (1-12). Nine (20%) stopped oxaliplatin before 8 cycles because of toxicity. Nine patients (20%) had a partial response and 29 (64%) had stable disease. Median progression free survival (PFS) was 15 (6-25) months. Median overall survival (OS) was 34 (21-49) months. No significant difference was observed in response and PFS between either regimens., Conclusions: Our results suggest that either gemcitabine-oxaliplatin or 5-fluorouracil-oxaliplatin combinations are attractive chemotherapy regimen in metastatic pulmonary carcinoid tumors., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Rash is a common epidermal growth factor receptor inhibitor-induced toxicity that can impair quality of life and treatment compliance., Objective: We sought to evaluate the efficacy of doxycycline in preventing erlotinib-induced rash (folliculitis) in patients with non-small-cell lung cancer., Methods: This open-label, randomized, prospective, phase II trial was conducted in 147 patients with locally advanced or metastatic non-small-cell lung cancer progressing after first-line chemotherapy, randomized for 4 months with erlotinib alone 150 mg/d per os (control arm) or combined with doxycycline 100 mg/d (doxycycline arm). Incidence and severity of rash, compliance, survival, and safety were assessed., Results: Baseline characteristics of the 147 patients were well balanced in the intent-to-treat population. Folliculitis occurred in 71% of patients in the doxycycline arm and 81% in the control arm (P = .175). The severity of folliculitis and other skin lesions was lower in the doxycycline arm compared with the control arm. Other adverse events were reported at a similar frequency across arms. There was no significant difference in survival between treatment arms., Limitations: The open-label design of the study and the duration of the treatment with doxycycline are limitations., Conclusion: Doxycycline did not reduce the incidence of erlotinib-induced folliculitis, but significantly reduced its severity., (Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Epidermal growth factor receptor gene (EGFR) mutation status has emerged as a crucial issue in lung cancer management. Availability and cost of tests and tyrosine kinase inhibitors (TKIs) may vary as a function of country development.We conducted a prospective specialist opinion survey to map EGFR test and EGFR-TKI availability and detect associations with the Human Development Index (HDI). A questionnaire was sent to specialists in thoracic oncology in all United Nations Member States.We obtained responses from 74 countries, comprising 78% of the worldwide population. Nonresponding countries had significantly lower HDI rank than responding countries. EGFR mutation analysis was routinely available in 57 countries (70% of the worldwide population). The cost of the test was

Background: Annual screening for lung cancer using low-dose CT-scans is associated with decreased mortality. A survey conducted in Rhône-Alpes area in France found that clinicians need education and information on this topic. Script concordance tests (SCT) are a tool for assessing clinical reasoning in situations of uncertainty. They have not previously been used in France in the context of continuing medical education., Method: We created a questionnaire with 5 multiple-choice questions (MCQ) and two SCT scenarios. The questionnaire was sent to all clinicians and residents who are members of French-Speaking Respiratory Society or the French Young Pulmonologist Association., Results: One hundred and ninety answers were analyzed. Seventy percent stated that decreasing mortality was the best criterion for assessing the effectiveness of a cancer screening policy, and 75% that low-dose CT scan was the best test to achieve this in lung cancer screening. Forty-five percent knew the eligibility criteria of the population, and 62% that low-dose CT scan should be performed annually. Participation in tumor boards and certification in oncology were significantly associated with a better score at MCQ and SCT. SCT and MCQ scores were significantly correlated (Spearman's Rho 0.339; P<0.0001)., Conclusion: SCT are feasible by electronic survey and seem relevant. Improving knowledge of clinicians on lung cancer screening is still critical., (Copyright © 2015 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Endobronchial ultrasound is a recent technique for the diagnosis and the lymph node staging in lung cancer. It also showed interest in non tumoral mediastinal lymph nodes diagnosis. This work relates the CHLS first three years' experience in terms of EEB practical use as a new diagnostic tool in this field., Methods: Retrospective study of consecutive cases patients having undergone endobronchial ultrasound from November 2008 till June 2011 in the CHLS., Results: On 65 endobronchial ultrasound, general anesthesia was practiced in 89 % of the cases, with a good tolerance in 81 % of the cases. In 77 % cases, EEB allowed diagnosis and avoided mediastinoscopy in 60.5 % of the cases. The respective sensibility, specificity, positive and negative predictive values were 74 %, 100 %, 100 % and 48 %., Conclusion: These data, reflect of a novice team experience, illustrate the results obtained in the current practice in terms of etiologic diagnosis. Endobronchial ultrasound seems destined to a bright future but requires the development of dedicated centers allowing pulmonologists training and specialized pathologists in this field., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Introduction: This retrospective study was undertaken to evaluate late results of lung cancer surgery in octogenerians., Methods: All patients 80years old or more who underwent a lung resection for cancer from 2000 to 2010 at Lyon University Hospital were included. No patients were treated with video-assisted surgery. Wedge resections were excluded., Results: Sixty-three patients (42 men, 21 women) were operated. The median age was 82years. Operative mortality was 4.7%. The rate of perioperative complications was 49%. The late survival was 34% at 5years. Five-year survival by nodal involvement was N0, 36%; N1, 29%; N2 20%, P<0.05. Patients with a squamous cell carcinoma (24) had a better long-term survival than patients with an adenocarcinoma (30), 33% and 25% respectively at 5years, P<0.05. The rate of recurrence was 33.9%., Conclusions: Surgical treatment of lung cancer in selected population of octogenerians is associated with satisfactory early and long-term results. Survival is influenced by nodal involvement and by the pathologic type of the cancer., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Introduction: Oral targeted therapies are a new option for lung cancer treatment. However, patient's belief about these drugs - which may interact with adherence - is poorly known in this setting., Method: Our study is a pilot prospective unicentric study. Inclusion criteria were: to have been diagnosed with a lung cancer; and to be prescribed with an oral targeted therapy in second line or more. The main objective was to assess patient's specific (SB) and general beliefs (GB) about these drugs according to the Beliefs about Medicines Questionnaire (BMQ). The declared adherence was assessed with the Morisky's test. All included patients underwent a semi-structured interview with a psychologist., Results: Fifthteen patients were included: 12 underwent erlotinib treatment and 3 a crizotinib treatment. The mean score (±standard deviation) at BMQ was 54/85 (±6) overall; 34/50 (±5) for specific belief and 19/35 (±3) for general belief about drugs. During interview, 47% believed in efficacy of targeted oral therapy; 93% reported concerns about their drug; 80% considered that the information given by the physician about the drug was comprehensive; but 40% still required additional information about it. The mean score at Morisky's test was 3/4 (±2) and 53% reported to have forgotten at least once their antineoplastic drug. No correlation was found between belief and adherence., Conclusion: Belief about t anti-cancer targeted oral therapy is relatively fair but adherence is moderate in this pilot study. Interview shows the need for additional information about the prescribed drug., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Purpose: The objective of this randomised phase II study was to evaluate the impact in terms of response and toxicities of induction or consolidation chemotherapy respectively before or after concurrent chemoradiotherapy in unresectable stage III non-small-cell lung cancer., Patients and Methods: In the induction arm, patients received induction chemotherapy with cisplatin (80 mg/m(2)) and paclitaxel (200 mg/m(2)) on days 1 and 29 followed by a concurrent chemoradiotherapy (66 Gy in 33 fractions, cisplatin 80 mg/m(2) days 1, 29 and 57, vinorelbine 15 mg/m(2) days 1, 8, 29, 36, 57 and 64). In consolidation arm, the same concurrent chemoradiotherapy began on day 1 followed by two cycles of cisplatin and paclitaxel., Results: One hundred twenty seven patients were randomised. The intent to treat response rates in induction and consolidation arms were 58% and 56% respectively. Median survival was 19.6 months in induction arm and 16.3 months in consolidation arm and 4-year survival rates were 21% and 30% respectively. Haematologic and non-haematologic toxicities were similar in both arms, except grade 3/4 oesophagitis, more frequent in consolidation arm than in induction arm (17% versus 10%)., Conclusion: Cisplatin-based chemotherapy as induction or consolidation with concurrent chemoradiotherapy can be administrated safely. Response rates were similar in both arms with a trend in favour for consolidation arm for long-term survival., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations are identified in approximately 2% of non-small cell lung cancer (NSCLC). Because of the rarity of those mutations, associated clinical features and prognostic significance have not been thoroughly described so far., Methods: Here we took advantage of the French National Cancer Institute Program of systematic molecular profiling of metastatic lung cancer, to collect clinical characteristics and analyze the outcome of consecutive patients with NSCLC harboring BRAF mutations at the Lyon University Hospital laboratory between February 2012 and October 2014. Especially, we compared those variables with that of patients with EGFR-, BRAF-, KRAS-, HER2-, PIK3CA- wild-type NSCLCs., Results: Among 2690 patients with genotyped NSCLC during the study period, BRAF mutations were identified in 80 (3%) cases, consisting of V600E substitution in 42 (53%) cases; non-V600E mutation were observed in 38 (48%) cases. Concurrent mutations were not observed in case of BRAF V600 mutation, and were identified in 5 patients with BRAF non-V600E mutations, in all cases consisting of KRAS mutations. Non-V600E mutations were more likely to be observed in smokers, as compared V600E mutations. There was no significant difference in age, histologic type, performance status, and stage at diagnosis between cases of V600E and non-V600E mutations. Overall survival did not significantly differ in BRAF wild-type, V600E, and non-V600E patients., Conclusion: This one of the largest series of patients with BRAF mutant NSCLC. Our clinical data suggest that BRAF mutations define specific subsets of patients with NSCLC; while their oncogenic nature is yet to be established in lung cancer, especially for non-V600E mutations, the value of BRAF mutations to predict the efficacy of targeted agents remains unclear., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Plasma circulating cell-free (cf)DNA is of interest in oncology because it has been shown to contain tumour DNA and may thus be used as liquid biopsy. In nonsmall cell lung cancer (NSCLC), cfDNA quantification has been proposed for the monitoring and follow-up of patients. However, available studies are limited and need to be confirmed by studies with larger sample sizes and including patients who receive more homogenous treatments. Our objective was to assess the predictive and prognostic value of plasma cfDNA concentration in a large series of patients with NSCLC and treated with a standard chemotherapy regimen.We included samples from lung cancer patients recruited into the Pharmacogenoscan study. The cfDNA of 218 patients was extracted and quantified by fluorometry before and after two or three cycles of platinum-based chemotherapy. The association between baseline and post-chemotherapy concentrations and treatment response, assessed by RECIST (response evaluation criteria in solid tumours) or patient survival was analysed.Patients with high cfDNA concentrations (highest tertile) at baseline had a significantly worse disease-free and overall survival than those with lower concentrations (lowest and middle tertiles) (median overall survival 10 months (95% CI 10.7-13.9) versus 14.2 months (95% CI 12.6-15.8), respectively; p=0.001). In multivariate analysis, increased baseline concentration of cfDNA was an independent prognostic factor. However, we did not find any association between cfDNA concentration and response to treatment.cfDNA may be a biomarker for the assessment of prognosis in NSCLC. However, total concentration of cfDNA does not appear to predict chemotherapy response., (Copyright ©ERS 2015.)

The IFCT-0504 phase II trial evaluated the efficacy of erlotinib versus carboplatin-paclitaxel (CP) as first-line treatment in 130 cases of advanced lepidic-predominant adenocarcinoma (ADC).The primary objective of the study was treatment efficacy, evaluated based on an end-point of disease control at 16 weeks.The primary objective was met, with a disease control in 35 (53%) out of 66 patients treated with CP and in 25 (39.1%) out of 64 patients treated with erlotinib. Median progression-free survival (PFS) for the total population was 3.6 months. The disease control rate did not differ between either the therapeutic arms or pathological subtypes, whereas there was a strong interaction between treatment arms and tumour pathological subtypes for PFS (p=0.009). Mucinous tumour patients treated with erlotinib exhibited an increased progression risk (hazard ratio 3.4, 95% CI 1.7-6.5; p≤0.001). The PFS for nonmucinous tumour patients was similar in both arms. Median overall survival was 20.1 months and did not differ between therapeutic arms. These findings were not further elucidated by molecular analyses and the toxicity profiles were as expected.Our study demonstrated the dominant role of CP alongside erlotinib in the management of advanced lepidic ADC. Based on these findings, erlotinib should not be administered in first-line therapy to patients with lepidic ADC in the absence of an epidermal growth factor receptor mutation., (Copyright ©ERS 2015.)

Introduction: This study compared the efficacy of docetaxel alone vs. docetaxel plus cisplatin/carboplatin in resected NSCLC patients relapsing after preoperative, adjuvant, or perioperative platinum-based chemotherapy., Materials and Methods: Patients were randomly assigned to receive docetaxel plus cisplatin/carboplatin (Arm A) or docetaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate at 6 weeks, toxicity, quality of life, and overall survival (OS)., Results: From November 2007 to August 2012, 88 patients were enrolled. Due to an unexpectedly slow accrual, the trial was prematurely stopped. Adding platinum to docetaxel caused a non-significant increase in PFS. Median PFS was 8.0 months (95% CI: 5.3-10.4) for Arm A vs. 5.6 months (95% CI: 4.0-7.3) for Arm B (HR: 0.71, 95% CI: 0.45-1.1, p=0.15). Median OS was 16.0 months (95% CI: 10.1-23.9) for Arm A vs. 12.4 months (95% CI: 8.2-19.6) for Arm B. In pre-planned subgroup analyses, a time to recurrence ≥12 months and non-squamous histology favorably influenced OS (HR: 0.51, 95% CI: 0.29-0.91, p=0.02 and HR: 0.54, 95% CI: 0.33-0.91, p=0.02, respectively). There were no unexpected adverse events, and Grade 3-4 toxicity was comparable in both groups., Conclusions: Our study failed to demonstrate significant PFS improvement with the docetaxel-platinum doublet compared to single-agent docetaxel. The 3.6-month improvement in OS with the cisplatin-based doublet proves, however, appealing and merits further investigation., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Specimens collected by CT scan-guided transthoracic core-needle biopsy (TTNB) are frequently used for the diagnosis of lung nodules, but the clinical value of negative results has not been sufficiently investigated. We sought to determine the negative predictive value (NPV) of TTNB specimens and investigate predictive factors of negative results., Methods: All consecutive TTNBs performed in three centers between 2006 and 2012 were included. The medical charts of patients with nonmalignant TTNB specimens were reviewed and classified as true or false negatives. Binary logistic regression was used for multivariate analysis., Results: Overall, findings from 980 TTNB specimens were included. Malignant disease was found in 79% (n = 777) of the cases, nonmalignant disease in 6% (n = 54), and "negative" results in 15% (n = 149). For the diagnosis of malignant disease, NPV was 51%. Estimated sensitivity, specificity, and accuracy were 89%, 99%, and 90%, respectively. The complication rate was 34% (life-threatening complication in 6%). In multivariate analysis, predictive factors for a false-negative result were radiologist experience (adjusted OR [AOR], 0.996; 95% CI, [0.994-0.998]), occurrence of a complication during the procedure (AOR, 1.958; 95% CI, [1.202-3.187]), and moderate to high maximum standardized uptake value on PET scan (AOR, 7.657; 95% CI, [1.737-33.763]). In 24 cases, a second TTNB was performed at the same target. The complication rate was 33%, and TTNB specimens provided diagnosis in 95% of cases with a 67% NPV., Conclusions: One-half of all "negative" TTNB specimen results were falsely negative for malignant diagnosis. Findings in tissue collected from a second TTNB at the same target provided a final diagnosis in most cases without increasing complication rates.

Objectives: We evaluated the impact of age in a randomized phase II trial that compared three first-line drugs in elderly patients with advanced non-small cell lung cancer (NSCLC) and a poor performance status (PS)., Materials and Methods: Patients with advanced NSCLC with a PS of 2 or 3 were enrolled into a multicenter randomized trial: arm A, gefitinib; arm B, gemcitabine; and arm C, docetaxel. We performed subgroup analyses according to age., Results: Between December 2004 and June 2007, 127 patients were enrolled. Analyses were performed between the two subgroups aged <70years (younger, n=56) and ≥70years (older, n=71). Patients mainly had adenocarcinoma (46% young vs. 51%: elderly), of which 62% vs. 75% had a PS of 2, respectively. Significantly more elderly patients were women and non-smokers, and there was a non-significant trend towards more PS-2 among the elderly. Progression-free survival (PFS) was 1.4months (95% CI: 1.1-1.9) for younger compared to 2.3months (95% CI: 2.1-2.9) for elderly patients. Overall survival (OS) was 2.0months (95% CI: 1.5-2.4) and 3.7months (95% CI: 2.4-4.8), respectively. Toxicity did not differ between younger and older patients. NSCLC was better controlled in elderly patients after three cycles of monotherapy compared to younger patients (p=0.034). When adjusted for stratification criteria, age was the main prognostic factor for PFS. Adjusted HRs for PFS was 0.57 (95% CI: 0.38-0.85) for the elderly compared to patients aged <70years (p=0.004)., Conclusions: Older patients had a decreased risk of progression/death compared to younger patients. Single-agent chemotherapy can be considered for patients aged ≥70years with a PS of 2., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Lung cancer in never-smokers (LCINS) (fewer than 100 cigarettes in lifetime) is considered as a distinct entity and harbours an original molecular profile. However, the epidemiological and molecular features of LCINS in Europe remain poorly understood. All consecutive newly diagnosed LCINS patients were included in this prospective observational study by 75 participating centres during a 14-month period. Each patient completed a detailed questionnaire about risk factor exposure. Biomarker and pathological analyses were also collected. We report the main descriptive overall results with a focus on sex differences. 384 patients were included: 65 men and 319 women. 66% had been exposed to passive smoking (significantly higher among women). Definite exposure to main occupational carcinogens was significantly higher in men (35% versus 8% in women). A targetable molecular alteration was found in 73% of patients (without any significant sex difference): EGFR in 51%, ALK in 8%, KRAS in 6%, HER2 in 3%, BRAF in 3%, PI3KCA in less than 1%, and multiple in 2%. We present the largest and most comprehensive LCINS analysis in a European population. Physicians should track occupational exposure in men (35%), and a somatic molecular alteration in both sexes (73%)., (Copyright ©ERS 2015.)

Background: This randomized phase II-III trial sought to evaluate the efficacy and safety of adding bevacizumab (Bev) following induction chemotherapy (CT) in extensive small-cell lung cancer (SCLC)., Patients and Methods: Enrolled SCLC patients received two induction cycles of CT. Responders were randomly assigned 1:1 to receive four additional cycles of CT alone or CT plus Bev (7.5 mg/kg), followed by single-agent Bev until progression or unacceptable toxicity. The primary end point was the percentage of patients for whom disease remained controlled (still in response) at the fourth cycle., Results: In total, 147 patients were enrolled. Partial response was observed in 103 patients, 74 of whom were eligible for Bev and randomly assigned to the CT alone group (n = 37) or the CT plus Bev group (n = 37). Response assessment at the end of the fourth cycle showed that disease control did not differ between the two groups (89.2% versus 91.9% of patients remaining responders in CT alone versus CT plus Bev, respectively; Fisher's exact test: P = 1.00). Progression-free survival (PFS) since randomization did not significantly differ, with a median PFS of 5.5 months [95% confidence interval (CI) 4.9% to 6.0%] versus 5.3 months (95% CI 4.8% to 5.8%) in the CT alone and CT plus Bev groups, respectively [hazard ratio (HR) for CT alone: 1.1; 95% CI 0.7% to 1.7%; unadjusted P = 0.82]. Grade ≥2 hypertension and grade ≥3 thrombotic events were observed in 40% and 11% of patients, respectively, in the CT plus Bev group. Serum vascular endothelial growth factor (VEGF) and soluble VEGF receptor titrations failed to identify predictive biomarkers., Conclusion: Administering 7.5 mg/kg Bev after induction did not improve outcome in extensive SCLC patients., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

EGFR and HER2 mutations and ALK rearrangement are known to be related to lung cancer in never-smokers, while KRAS, BRAF and PIK3CA mutations are typically observed among smokers. There is still debate surrounding whether never-smokers exposed to passive smoke exhibit a "smoker-like" somatic profile compared with unexposed never-smokers. Passive smoke exposure was assessed in the French BioCAST/IFCT-1002 never-smoker lung cancer cohort and routine molecular profiles analyses were compiled. Of the 384 patients recruited into BioCAST, 319 were tested for at least one biomarker and provided data relating to passive smoking. Overall, 219 (66%) reported having been exposed to passive smoking. No significant difference was observed between mutation frequency and passive smoke exposure (EGFR mutation: 46% in never exposed versus 41% in ever exposed; KRAS: 7% versus 7%; ALK: 13% versus 11%; HER2: 4% versus 5%; BRAF: 6% versus 5%; PIK3CA: 4% versus 2%). We observed a nonsignificant trend for a negative association between EGFR mutation and cumulative duration of passive smoke exposure. No association was found for other biomarkers. There is no clear association between passive smoke exposure and somatic profile in lifelong, never-smoker lung cancer., (Copyright ©ERS 2015.)

Purpose: The phase II prospective, noncomparative BRAIN study (NCT00800202) investigated efficacy and safety of bevacizumab in chemotherapy-naïve or pretreated patients with non-small cell lung cancer (NSCLC) and asymptomatic untreated brain metastases to provide data in this previously unexplored subgroup., Experimental Design: Patients with stage IV nonsquamous NSCLC, Eastern Cooperative Oncology Group performance status 0-1, and untreated, asymptomatic brain metastases received first-line bevacizumab (15 mg/kg) plus carboplatin (area under the curve ×6) and paclitaxel (200 mg/m(2)) every 3 weeks (B + CP), or second-line bevacizumab plus erlotinib (150 mg/d; B + E). Six-month progression-free survival (PFS) was the primary endpoint. The trial could be stopped if there were more than three (B + CP) or more than two (B + E) intracranial hemorrhages., Results: In first-line B + CP cohort (n = 67), 6-month PFS rate was 56.5% with a median PFS of 6.7 months [95% confidence interval (CI), 5.7-7.1] and median overall survival (OS) of 16.0 months. Investigator-assessed overall response rate (ORR) was 62.7%: 61.2% in intracranial lesions and 64.2% in extracranial lesions. Because of low enrolment (n = 24), efficacy results for the second-line B + E cohort were exploratory only; 6-month PFS rate was 57.2%, median PFS was 6.3 months (95% CI, 3.0-8.4), median OS was 12.0 months, and ORR was 12.5%. Adverse events were comparable with previous trials of bevacizumab. One grade 1 intracranial hemorrhage occurred and resolved without sequelae., Conclusions: The BRAIN study demonstrates encouraging efficacy and acceptable safety of bevacizumab with first-line paclitaxel and carboplatin in patients with NSCLC and asymptomatic, untreated brain metastases., (©2015 American Association for Cancer Research.)