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Background: Durvalumab, an anti-PD-L1 immune checkpoint inhibitor, after radio-chemotherapy (RCT) has changed the management of locally advanced non-small cell lung cancer (LA NSCLC). A series of retrospective studies have investigated different cut-off of lymphocyte count (LyC) and neutrophil-to-lymphocyte ratio (NLR) to predict survival in LA NSCLC. None of these studies has validated their threshold in an independent group of patients. We wanted to assess the OS prognostic value of NLR and LyC in patients with LA NSCLC treated by RCT and durvalumab, with threshold determination and their validation in an external cohort., Methods: Patients were enrolled in four institutions between Oct. 2017 and Jan. 2022. Pre durvalumab LyC, neutrophils count (NC) and NLR were collected. To define NLR and LyC cut-off value predicting survival event, time dependent Receiver Operating Characteristics (ROC) curves was performed. Survival outcomes were estimated by the Kaplan-Meier method and differences were compared using univariate and multivariate Cox proportional hazard models., Results: We included 76 patients in the training set and 85 in the test set. The best cut off were 2,94 for NLR and 0,61 G/l for LyC to predict OS in the training set. For patients with NLR > 2,94, univariate analysis showed no significant deterioration in OS in either the training set (p = 0,066) or the test set (p = 0,12). Patients with LyC > 0,61 G/L, in univariate analysis, had longer OS in training set (p = 0,030) and in test set (p = 0,0062). This OS increase was not found in multivariate analysis (p = 0,057) in training set but was confirmed in test set (0,039)., Conclusion: LyC > 0,61 G/l is associated with longer OS for LA NSCLC patient's treated with RCT and durvalumab in univariate analysis. In this context, a particular expectation for organs at risk sparing during RT to avoid lymphopenia seems important., Trial Registration: Retrospectively registered., (© 2024. The Author(s).)

Background: Combined treatment with anti-PD-1 and anti-CTLA-4 antibodies has shown superiority over chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC), but data for older patients (aged ≥70 years) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or those with an ECOG performance status of 2 are scarce. We aimed to test the superiority of the PD-1 antibody nivolumab and the CTLA-4 antibody ipilimumab over platinum-based doublet chemotherapy as first-line treatment in patients with NSCLC aged 70 years or older or with an ECOG performance status of 2., Methods: This open-label, multicentre, randomised, controlled, phase 3 trial was done at 30 hospitals and cancer centres in France. Eligible patients had stage IV histologically proven NSCLC, with no known oncogenic alterations, and were either aged 70 years or older with ECOG performance status of 0-2 or younger than 70 years with an ECOG performance status of 2. Patients were randomly assigned (1:1) centrally, using a computer-generated algorithm stratified by age (<70 vs ≥70 years), ECOG performance status (0-1 vs 2), and histology (squamous vs non-squamous) to receive nivolumab plus ipilimumab or platinum-based doublet chemotherapy (carboplatin [area under the curve ≤700 mg] plus pemetrexed [500 mg/m 2 intravenous infusion every 3 weeks] or carboplatin [on day 1; area under the curve ≤700 mg] plus paclitaxel [90 mg/m 2 as intravenous infusion on days 1, 5, and 15, every 4 weeks]). The primary endpoint was overall survival; secondary endpoints included progression-free survival and safety. All efficacy analyses were performed in the intention-to-treat population, which included all randomly assigned patients. Safety was analysed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study treatment and who had at least one safety follow-up. The trial is registered with ClinicalTrials.gov, NCT03351361., Findings: The trial was stopped early for futility on the basis of a pre-planned interim analysis after 33% of the expected events had occurred. Between Feb 12, 2018, and Dec 15, 2020, 217 patients were randomly assigned, of whom 216 patients were included in the final analysis, with 109 patients in the nivolumab plus ipilimumab group and 107 in the chemotherapy group; median age was 74 years (IQR 70-78). Median overall survival was 14·7 months (95% CI 8·0-19·7) in the nivolumab plus ipilimumab group and 9·9 months (7·7-12·3) in chemotherapy group (hazard ratio [HR] 0·85 [95% CI 0·62-1·16]). Among patients aged 70 years or older with an ECOG performance status of 0-1 (median age 76 years [IQR 73-79]), median overall survival was longer in the nivolumab plus ipilimumab group than the chemotherapy group: 22·6 months (95% CI 18·1-36·0) versus 11·8 months (8·9-20·5; HR 0·64 [95% CI 0·46-0·96]). Among patients with an ECOG performance status of 2 (median age 69 years [IQR 63-75]), median overall survival was 2·9 months (95% CI 1·4-4·8) in the nivolumab plus ipilimumab group versus 6·1 months (3·5-10·4) in the chemotherapy group (HR 1·32 [95% CI 0·82-2·11]). No new safety signals were reported. The most frequent grade 3 or worse adverse events were neutropenia (28 [27%] of 103 patients) in the chemotherapy group and endocrine disorders (five [5%] of 105 patients), cardiac disorders (ten [10%] patients), and gastrointestinal disorders (11 [11%] patients) in the nivolumab plus ipilimumab group., Interpretation: The study showed no benefit of nivolumab plus ipilimumab combination in the overall study population. As a result of early stopping, the trial was underpowered for primary and secondary endpoints; however, the finding of better survival with nivolumab plus ipilimumab compared with platinum doublet in the subgroup of older patients with NSCLC with an ECOG performance status of 0-1 warrants further study., Funding: Bristol-Myers Squibb., Competing Interests: Declaration of interests HL reports support for attending meetings or travel from Roche, Sanofi, Amgen, Takeda, and Pfizer; and participation on a data safety monitoring board or advisory board for Roche, MSD, Sanofi, Takeda, Daiichi, Amgen, and Pfizer. LG reports grants or contracts to their institution from Bristol-Myers Squibb, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly, and Novartis; payment or honoraria for lectures or presentations from Bristol-Myers Squibb, MSD, Takeda, Pfizer, Roche, Amgen, Sanofi, Janssen, Lilly and Novartis; support for attending meetings or travel from Pfizer, MSD, AstraZeneca, Takeda, and Amgen; and participation on a data safety monitoring board or advisory board for InhaTarget Therapeutics. OB reports consulting fees from Roche, Takeda, and AstraZeneca; and honoraria for lectures and presentations from MSD, Bristol-Myers Squibb, and Janssen. IM reports honoraria for educational events from Regeneron; and support for attending meetings or travel from Pfizer and MSD. AV reports consulting fees from Pierre Fabre, Amgen, and MSD; support for attending meetings or travel from Pierre Fabre and Amgen; and participation on a data safety monitoring board or advisory board for MSD, AstraZeneca, Sanofi, Amgen, and Pierre Fabre. PD reports support for attending meetings or travel from Takeda and Accord Healthcare; and participation on a data safety monitoring board or advisory board for Bristol-Myers Squibb. FG reports consulting fees from Roche, Takeda, and AstraZeneca; honoraria for lectures or presentations from MSD, Bristol-Myers Squibb, and Janssen; and congress travel expenses from AstraZeneca and MSD. RC reports meeting presentations and participation on boards for Bristol-Myers Squibb. CCh reports consulting fees from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, Bristol-Myers Squibb, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, and Amgen; and support for attending meetings or travel from AstraZeneca, Boehringer Ingelheim, GSK, Roche, Sanofi Aventis, Bristol-Myers Squibb, MSD, Lilly, Novartis, Pfizer, Takeda, Bayer, and Amgen. CR reports consulting fees from Roche, Takeda, MSD, Bristol-Myers Squibb, Janssen, and Sanofi; honoraria for lectures or presentations from Sanofi, Takeda, and AstraZeneca; and support for attending meetings or travel from MSD and Sanofi. CCr, CAV, LF, MG, SH, and CL declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The KBP studies are real-life nationwide, prospective, multicenter cohort studies of patients diagnosed with primary lung cancer that have been conducted in French non-academic public hospitals each decade since 2000., Methods: Patients were analyzed in three prospective cohorts using the same methodology. In this study, we describe and compare the characteristics and outcomes of patients with small cell lung cancer (SCLC), with a focus on treatments in the 2020 cohort., Findings: 8999 patients with lung cancer were included in the 2020 cohort, of whom 1137 had SCLC. From 2000 to 2010 and 2020, the proportion of patients with SCLC decreased from 16.4 % to 13.5 % and 12.6 % respectively. Between 2000 and 2020, the proportion of women increased from 15.5 % to 35.7 %. 15.4 % of patients with SCLC had limited-stage (LS) disease and 84.6 % of patients had extensive-stage (ES) disease. The 1-year overall survival (OS) rate for all patients with SCLC increased from 34.4 % in 2000 to 38.4 % in 2020. For ES-SCLC, multivariate analysis weighted with "entropy balancing" by including age, sex, performance status, number of metastatic sites, and brain metastases indicated an improvement in median OS from 8.1 months in patients receiving chemotherapy only to 11.1 months in patients receiving chemotherapy plus immunotherapy (HR 0.62, p < 0.001)., Interpretation: The proportion with SCLC has decreased over time, but the proportion of women has increased. The 1-year OS rates have improved over 20 years. The KBP-2020 cohort suggests a benefit of immunotherapy on OS in patients with ES-SCLC in the real-life setting., 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 © 2024 Elsevier Ltd. All rights reserved.)

Background: Management of stage-III-N2 non-small-cell lung cancer (NSCLC) based on a multimodal strategy (surgery or radiotherapycombined with systemic drugs) remains controversial. Patients are treated with a curative intent, and available data suggestprolonged survival after complete resection. However, no consensual definition of "tumor resectability" exists. This study aimed to analyze the concordanceamong French tumor board meeting (TBM)-emittedtherapeutic decisions forstage-III-N2 NSCLC., Methods: Six patients with stage-III-N2 NSCLC discussed at Saint-Etienne University Hospital'sthoracic TBMs were selected, anonymouslyreported, and submitted to the participating TBMs. The primary goal of this multicenter, prospective, observational study was to assess the consistency of TBMpanel decisions for each case. The secondary endpointwas identifying the demographic or technical factors that potentiallyaffected decision-making., Results: Twenty-seven TBMs from university hospitals, a cancer center, general hospitals, and a private hospitalparticipated in this study. None of their decisions for the six cases were unanimous.The decisions were homogenous for three cases (78%, 85%, and 88% TBMs opted for medical treatment, respectively),andmore ambivalent for the other three (medical versus surgical strategies were favored by 44%/56%, 46%/54%, and 58%/42% TBMs, respectively). Interestingly, decisions regarding chemoradiationand perioperative chemotherapyinthe medical and surgical strategies, respectively, were also discordant. Hospital type, specialist participation in TBMs, and activity volumes were not significantly associated with therapeutic decisions., Conclusion: The results of this study highlight substantial disparities amongFrench TBMs regarding therapeutic management of stage-III-N2 NSCLC. The decisions were not associated with local conditions., 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 © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Studies have shown improvement in overall survival with anti-PD1/PD-L1 molecules in combination with cisplatin/carboplatin and etoposide as a first-line treatment for Small Cell Lung Cancer (SCLC). However, first-line efficacy remains limited and well below that observed in Non-Small Cell Lung Cancer (NSCLC). Etoposide may have a detrimental effect on lymphocyte activation, which could explain the limited benefit of immunotherapy in the first line and the lack of benefit in the second line for patients previously exposed to high levels of etoposide., Methods: We initiated a multicenter, single-arm, open-label phase II study of a chemotherapy regimen with durvalumab, combined with carboplatin and paclitaxel for extensive disease SCLC. Eligible patients will receive durvalumab plus carboplatin and paclitaxel every 3 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. A total of 67 patients will be enrolled in this study, with a 12-month enrollment period and 36-month follow-up. The primary endpoint is Overall Survival (OS) rate at 12 months. Secondary endpoints are best response rate, OS, OS at 24- and 36 months, progression free survival (PFS), duration of response, quality of life and safety., Results: This study aims to establish the efficacy of durvalumab combined with carboplatin and paclitaxel in patients with extensive disease Small Cell Lung Cancer., Clinical Trial Registration: EU CT: 2023-504670-38-00., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: French intergroup IFCT reports financial support was provided by AstraZeneca Pharmaceuticals LP. Denis Moro-Sibilot reports a relationship with ASTRA ZENECA that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Denis Moro-Sibilot reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Denis Moro-Sibilot reports a relationship with MSD France SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Denis Moro-Sibilot reports a relationship with Roche that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with Roche that includes: funding grants, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with MSD France SAS that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with ASTRA ZENECA that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Virginie Westeel reports a relationship with Bristol Myers Squibb Co that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. If there are other authors, they 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 © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: We designed this study based on both a physician practice survey and real-world patient data to: (1) evaluate clinical management practices in extensive-stage small cell lung cancer (ES-SCLC) among medical centers located across France; and (2) describe first-line treatment patterns among patients with ES-SCLC following the introduction of immunotherapy into clinical practice., Methods: A 50-item questionnaire was completed by physicians from 45 medical centers specialized in SCLC management. Responses were collected from June 2022 to January 2023. The survey questions addressed diagnostic workup of ES-SCLC, chemoimmunotherapy in first-line and second-line settings, and use of prophylactic cranial irradiation (PCI) and radiotherapy. In parallel, using a chart review approach, we retrospectively analyzed aggregated information from 548 adults with confirmed ES-SCLC receiving first-line treatment in the same centers., Results: In ES-SCLC, treatment planning is based on chest computed tomography (CT) (as declared by 100% of surveyed centers). Mean time between diagnosis and treatment initiation was 2-7 days, as declared by 82% of centers. For detection of brain metastases, the most common imaging test was brain CT (84%). The main exclusion criteria for first-line immunotherapy in the centers were autoimmune disease (87%), corticosteroid therapy (69%), interstitial lung disease (69%), and performance status ≥ 2 (69%). Overall, 53% and 36% of centers considered that patients are chemotherapy-sensitive if they relapse within ≥ 3 months or ≥ 6 months after first-line chemoimmunotherapy, respectively. Among the 548 analyzed patients, 409 (75%) received chemoimmunotherapy as a first-line treatment, 374 (91%) of whom received carboplatin plus etoposide and 35 (9%) cisplatin plus etoposide. Overall, 340/548 patients (62%) received maintenance immunotherapy. Most patients (68%) did not receive radiotherapy or PCI., Conclusions: There is an overall alignment of practices reflecting recent clinical guidelines among medical centers managing ES-SCLC across France, and a high prescription rate of immunotherapy in the first-line setting., (© 2024. The Author(s).)

Background: Few epidemiological data are available on surgically treated Caucasian patients with non-small-cell lung cancers (NSCLCs) harboring epidermal growth factor receptor ( EGFR ) mutations. The main objective of this study was to describe, in the real-world setting, these patients' incidence, clinical, and tumoral characteristics., Methods: The participating centers included all consecutive localized non-squamous NSCLC patients undergoing surgery between January 2018 and December 2019 in France. EGFR status was determined retrospectively when not available before surgery., Results: The study includes 1391 no squamous NSCLC patients from 16 centers; EGFR status was determined before surgery in 692 (49.7%) of the cases and conducted as part of the study for 699 (50.3%); 171 (12.3%) were EGFR mutated; median age: 70 (range: 36-88) years; female: 59.6%; never smokers: 75.7%; non-squamous histology 97.7%, programmed death ligand-1 expression 0%/1-49%/⩾50 in 60.5%/25.7%/13.8%, respectively. Surgery was predominantly lobectomy (81%) or segmentectomy (14.9%), with systematic lymph node dissection in 95.9%. Resection completeness was R0 for 97%. Post-surgery staging was as follows: IA: 52%, IB: 16%, IIA: 4%, IIB: 10%, IIIA: 16%, and IIIB: 0.05%; EGFR mutation exon was Del19/exon 21 ( L858R )/20/18 in 37.4%/36.8%/14%, and 6.4% of cases, respectively; 31 (18%) patients received adjuvant treatment (chemotherapy: 93%, EGFR tyrosine kinase inhibitor: 0%, radiotherapy: 20%). After a median follow-up of 31 (95% confidence interval: 29.6-33.1) months, 45 (26%) patients relapsed: 11/45 (24%) locally and 34 (76%) with metastatic progression. Median disease-free survival (DFS) and overall survival were not reached and 3-year DFS was 60%., Conclusion: This real-world analysis provides the incidence and outcomes of resected EGFR -mutated NSCLCs in a European patient cohort., Competing Interests: J-BA: In the last 5 years, J-BA has received honoraria for attending scientific meetings, speaking, organizing research, or consulting, from Boehringer Ingelheim, Hoffman-Roche, Takeda, BMS, MSD, Astra Zeneca, Amgen, and Pfizer., (© The Author(s), 2024.)

Background: Small cell lung cancer (SCLC) has a tendency towards recurrence and limited survival. Standard-of-care in 1st-line is platinum-etoposide chemotherapy plus atezolizumab or durvalumab,based on landmarkclinical trials., Methods: IFCT-1905 CLINATEZO is a nationwide, non-interventional, retrospectivestudy of patients with extensive-SCLC receivingatezolizumab plus chemotherapy as part of French Early Access Program. Objectives were to analyse effectiveness,safetyand subsequent treatments., Results: The population analyzed included 518 patients who received atezolizumabin 65 participating centers. There were 66.2% male,mean age was 65.7 years; 89.1% had a performance status (PS) 0/1 and 26.6% brain metastases. Almost all(95.9%) were smokers. Fifty-five (10.6%) received at least 1 previous treatment. Median number of atezolizumab injections was 7.0 (range [1.0-48.0]) for a median duration of 4.9 months (95% CI 4.5-5.1). Atezolizumab was continued beyond progression in 122 patients (23.6%) for a median duration of 1.9 months (95% CI: [1.4-2.3]). Best objective response was complete and partialin 19 (3.9%) and 378 (77.1%)patients. Stable diseasewas observed in 50 patients (10.2%). Median follow-up was30.8 months (95% CI: [29.9-31.5]). Median overall survival (OS), 12-, 24-month OS rates were 11.3 months (95% CI: [10.1-12.4]), 46.7% (95% CI [42.3-50.9]) and 21.2% (95% CI [17.7-24.8]). Median real-world progression-free survival, 6-, 12-month rates were 5.2 months (95% CI [5.0-5.4]), 37.5% (95% CI [33.3-41.7]) and 15.2% (95% CI [12.2-18.6]). For patients with PS 0/1, median OS was 12.2 months (95% CI [11.0-13.5]). For patients with previous treatment, median OS was 14.9 months (95% CI [10.1-21.5]). Three-hundred-and-twenty-six patients(66.4%) received subsequent treatment and27 (5.2%) were still underatezolizumabat date of last news., Conclusions: IFCT-1905 CLINATEZO shows reproductibility, in real-life,ofIMpower-133survival outcomes, possibly attributed to selection of patients fit for this regimen, adoption of pragmatic approaches,including concurrent radiotherapy and treatment beyond progression., 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 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib., Objective: This study aimed to describe the clinical characteristics of these long-term responders., Patients and Methods: This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint., Results: A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively., Conclusions: Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Outside clinical trials, few data are available on the effect of long-term first-line pembrolizumab in patients with advanced non-small-cell lung cancers with ≥50% of tumor cells expressing programmed cell death ligand 1 (PD-L1). This French, multicenter study included consecutive advanced patients with non-small-cell lung cancer given first-line pembrolizumab alone between May 2017 (authorization date for this indication) and November 2019 (authorization date for pembrolizumab-chemotherapy combination). Information was collected from patients' medical files, with a local evaluation of the response and progression-free survival (PFS). Overall survival (OS) was calculated from pembrolizumab onset using the Kaplan-Meier method. The analysis concerned 845 patients, managed in 33 centers: median age: 65 (range: 59-72) years, 67.8% men, 78.1% Eastern Cooperative Oncology Group performance status 0/1, 38.9%/51.5%/6.6% active, ex or never-smokers, respectively, 10.9%/16.8% taking or recently took corticosteroids/antibiotics, 69.6% nonsquamous histology, 48.9% ≥75% PD-L1-positive, and 20.8% had brain metastases at diagnosis. After a median (95% CI) follow-up of 45 (44.1-45.9) months, respective median (95% CI) PFS and OS lasted 8.2 (6.9-9.2) and 22 (8.5-25.9) months; 3-year PFS and OS rates were 25.4% and 39.4%, respectively. Multivariate analysis retained never-smoker status, adenocarcinoma histology, Eastern Cooperative Oncology Group performance status ≥2, and neutrophil/lymphocyte ratio >4 as being significantly associated with shorter survival, but not brain metastases at diagnosis or <75% PD-L1 tumor-cell expression. These long-term results of pembrolizumab efficacy based on a nationwide "real-world" cohort reproduced those obtained in clinical trials., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: MET-targeted tyrosine kinase inhibitors (TKIs) demonstrated efficacy in advanced non-small cell lung cancer (aNSCLC) with MET exon14 skipping mutations (METexon14); yet, data on the management of these patients in clinical practice is sparse., Objective: The aim of this study was to describe the management of METexon14 aNSCLC patients., Patients and Methods: This real-life, retrospective study analyzed the management of METexon14 aNSCLC. The primary endpoint was the median overall survival (mOS). Secondary endpoints were to assess investigator-progression-free survival (PFS) and mOS in different subgroups: patients treated with (a) crizotinib, regardless of treatment line; (b) anti-MET TKIs (crizotinib, tepotinib, capmatinib); and (c) immunotherapy., Results: A total of 118 patients were included between December 2015 and January 1, 2020 in 13 centers. Median age was 73 years, 62.7% were female, 83.9% had adenocarcinoma, 92.4% at stage IV, and 27% had more than three metastatic sites. The majority of the patients (106, 89.8%) received at least one systemic treatment; 73% received at least one anti-MET TKI: crizotinib (68.6%), tepotinib (16%), capmatinib (10%). Only 10% received two anti-MET TKIs in their treatment sequences. With a median follow-up of 16 months (95% CI 13.6-29.7), mOS was 27.1 months (95% CI 18-31.4). There was no significant difference between mOS of patients treated and never treated with crizotinib, 19.7 (95% CI 13.6-29.7) and 28 (95% CI 16.4-NR) months, respectively (p = 0.16); mOS of the TKI cohort and of the TKI-naïve patient cohort were 27.1 (95% CI 18-29.7) and 35.6 (95% CI 8.6-NR) months respectively, with no significant difference (p = 0.7)., Conclusions: In this real-life study, there was no evidence of benefit in mOS with anti-MET TKIs., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Few real-world data are available in patients with advanced metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy, particularly in those with brain metastases at treatment initiation., Methods: This was a national, retrospective, multicenter study that consecutively included all patients with PD-L1-positive (tumor proportion score ≥ 50%) advanced NSCLC who initiated first-line treatment with pembrolizumab as a single agent between May 2017 (date of availability of pembrolizumab in this indication in France) to November 22, 2019 (approval of the pembrolizumab-chemotherapy combination). Data were collected from medical records with local response assessment., Results: The cohort included 845 patients and 176 (20.8%) had brain metastases at diagnosis. There were no significant differences in outcomes for patients with and without brain metastases: 9.2 (95% CI 5.6-15) and 8 (95% CI 6.7-9.2, p = 0.3) months for median progression-free survival (PFS) and, 29.5 (95% CI 17.2-NA) and 22 (95% CI 17.8-27.1, p = 0.3) months for median overall survival (OS), respectively. Overall response rates were 47% and 45% in patients with and without cerebral metastases. In multivariate analysis, performance status 2-4 vs. 0-1 and neutrophil-to-lymphocyte ratio ≥ 4 vs. < 4 were the main independent negative factors for OS; brain metastasis was not an independent factor for OS., Conclusion: In this large multicenter cohort, nearly 20% of patients initiating pembrolizumab therapy for advanced NSCLC had cerebral metastases. There was no significant difference in response rates, PFS and OS between patients with and without brain metastases., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Long-term changes in lung cancer (LC) patients are difficult to evaluate. We report results from the French KBP-2020 real-life cohort., Methods: KBP-2020 was a prospective cohort that included all patients diagnosed with LC in 2020, in nonacademic public hospital in France. Patient and tumour characteristics were described and compared with similarly designed cohorts in 2000 and 2010., Findings: In 2020, 82 centers included 8,999 patients diagnosed with LC. The proportion of women increased: 34·6% (3114/8999) compared to, 24·3% (1711/7051) and 16·0% (904/5667) in 2010 and 2000 ( p< 0·0001). The proportion of non-smokers was higher in 2020 (12·6%, 1129/8983) than in previous cohorts (10·9% (762/7008) in 2010; 7·2% (402/5586) in 2000, p< 0·0001). In 2020, at diagnosis, 57·6% (4405/7648) of patients had a metastatic/disseminated stage non-small-cell lung cancer (NSCLC) (58·3% (3522/6046) in 2010; 42·6% (1879/4411) in 2000, p< 0·0001). Compared with 2000 and 2010 data, early survival improved slightly. In 2020, 3-month mortality of NSCLC varied from 3·0% [2·2 - 3·8] for localized to 9·6% [8·1 - 11·0] for locally advanced to 29·2% [27·8 - 30·6] for metastatic and was 24·8% [22·3 - 27·3] for SCLC., Interpretation: To our knowledge KBP cohorts have been the largest, prospective, real-world cohort studies involving LC patients conducted in worldwide. The trend found in our study shows an increase in LC in women and still a large proportion of patients diagnosed at metastatic or disseminated stage., Funding: The study was promoted by the French College of General Hospital Pulmonologists with financial support of industrials laboratories., Competing Interests: The authors have no financial and personal relationship with other people or organization that could inappropriately bias this work. The scientific committee was fully independent from industrial sponsors., (© 2022 The Authors.)

Introduction: Systemic nocardiosis is an infectious disease that is rarely associated with mediastinal lymph nodes., Case Report: We report the case of a 72-year-old male patient treated with a high dose of oral corticosteroids for rheumatoid polyarthritis. This patient presented with rapid overall deterioration associated with mediastinal lymph nodes. Endobronchial ultrasound enabled us to establish a diagnosis of systemic nocardiosis. The patient recovered after having received suitable antibiotic treatment for four months., Conclusion: This work reports on a rare clinical presentation of systemic nocardiosis associated with mediastinal lymphadenopathies and highlights the key role of endobronchial ultrasound in diagnosing mediastinal lymph nodes, especially in differential diagnosis for lung cancer., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Patients with thoracic malignancies are at increased risk for mortality from coronavirus disease 2019 (COVID-19), and a large number of intertwined prognostic variables have been identified so far., Methods: Capitalizing data from the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry, a global study created with the aim of describing the impact of COVID-19 in patients with thoracic malignancies, we used a clustering approach, a fast-backward step-down selection procedure, and a tree-based model to screen and optimize a broad panel of demographics and clinical COVID-19 and cancer characteristics., Results: As of April 15, 2021, a total of 1491 consecutive eligible patients from 18 countries were included in the analysis. With a mean observation period of 42 days, 361 events were reported with an all-cause case fatality rate of 24.2%. The clustering procedure screened 73 covariates in 13 clusters. A further multivariable logistic regression for the association between clusters and death was performed, resulting in five clusters significantly associated with the outcome. The fast-backward step-down selection procedure then identified the following seven major determinants of death: Eastern Cooperative Oncology Group-performance status (ECOG-PS) (OR = 2.47, 1.87-3.26), neutrophil count (OR = 2.46, 1.76-3.44), serum procalcitonin (OR = 2.37, 1.64-3.43), development of pneumonia (OR = 1.95, 1.48-2.58), C-reactive protein (OR = 1.90, 1.43-2.51), tumor stage at COVID-19 diagnosis (OR = 1.97, 1.46-2.66), and age (OR = 1.71, 1.29-2.26). The receiver operating characteristic analysis for death of the selected model confirmed its diagnostic ability (area under the receiver operating curve = 0.78, 95% confidence interval: 0.75-0.81). The nomogram was able to classify the COVID-19 mortality in an interval ranging from 8% to 90%, and the tree-based model recognized ECOG-PS, neutrophil count, and c-reactive protein as the major determinants of prognosis., Conclusions: From 73 variables analyzed, seven major determinants of death have been identified. Poor ECOG-PS was found to have the strongest association with poor outcome from COVID-19. With our analysis, we provide clinicians with a definitive prognostication system to help determine the risk of mortality for patients with thoracic malignancies and COVID-19., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: FRESC reanalyzed extensive-stage small-cell lung cancer (ES-SCLC) patient data from the French KBP-2010 cohort to describe the characteristics and therapeutic management of ES-SCLC and provide real-world estimates of survival., Methods: A target population of first line (1L) ES-SCLC was identified at initial diagnosis in KBP-2010 (KBP population, N = 796). A KBP-2010 subpopulation was defined as patients who also met the IMpower133 clinicaltrial PS ≤ 1 inclusion criteria (KBP-PS&#95;0/1 population, N = 394). Subgroups were defined according to the 1L ES-SCLC chemotherapy regimens: carboplatin or cisplatin with etoposide (Carb-E or Cisp-E subgroups)., Results: The vast majority of KBP populations exhibited stage IV ES-SCLC (84.9%) at initial diagnosis. Median age was 66 years; patients were mostly male and smokers. Patients receiving Cisp + Eto were younger (median age 61 years [55.0-67.0]) and fitter (25.5% had PS ≥ 2) than those receiving Carb + Eto (71 years [62.5-77.5]; 44.1%had PS ≥ 2). Median overall survival (OS) of chemotherapy-treated 1L ES-SCLC patients varied from 7.0 months [95% CI, 6.1; 7.8] in the KBPCarb-Esubgroups to 9.6 months [95% CI, 8.4;10.8] in the KBP Cisp-E subgroup. KBP-PS&#95;0/1 population showed better median OS, especially for the Cisp-E subgroup (10 months [95% CI, 8.7; 11.3])., Conclusion: In the KBP-PS&#95;0/1 population, median OS was close to the one that was found in the IMpower133 control arm. Although this needs to be confirmed by further research, it suggests the transposability of the IMpower133 results to real-life conditions., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients., Methods: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score., Results: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65)., Conclusion: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE., Competing Interests: All participants have received fees from LEO Pharma for this research, either personally and/or to support the local organization of the research. Anne Lamblin is an employee of LEO Pharma., (Thieme. All rights reserved.)

Introduction: Advanced non-squamous non-small cell lung cancer (NsqNSCLC) progressing at the induction of a first-line of platin-based chemotherapy is a subgroup of patients with poor prognosis and few second-line treatment options., Materials and Methods: This single-stage phase II prospective multicenter open-label trial performed in platin-based refractory (i.e. progressing during induction phase of first-line platin-based chemotherapy) advanced NsqNSCLC assessed the efficacy of the nintedanib-docetaxel combination in second-line treatment. The primary endpoint was progression-free survival (PFS) rates at 12 weeks with a cut-off at 30% for ineffectiveness and 50% for minimal efficacy., Results: A total of 59 patients from 23 centers were included (mean age, 58.5 years; male gender, 73.6%; performance status 0-1, 100%; former/current smokers, 92.5%; adenocarcinoma, 92.5%, median platin-based first-line chemotherapy, 2). Nintedanib-docetaxel combination was administered for a median of 4 cycles. The rate of PFS at 12 weeks was 39.6% (95% CI, 28.2-56.8). Median PFS was 2.7 (95% CI, 1.4-4.1) months and one-year PFS was 11.8% (95% CI, 4.8-22.2). Median overall survival (OS) was 6.9 (95% CI, 4.3-8.2) months and 12-month OS was 32.1% (95% CI, 19.8-45.0); 18-month OS was 27.6% (95% CI, 16,1-40.4). Twenty-nine (53.7%) patients reported at least one serious treatment-related adverse events leading to permanent discontinuation of at least one study drug in 12 (22.2%) patients., Conclusion: The predefined minimal efficacy was not demonstrated. However, a number of NsqNSCLC patients refractory to first-line platin-based chemotherapy appeared to benefit from this combination., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Objectives: Few data are available about anticoagulation management beyond 6 months in patients with cancer associated thrombosis (CAT). Our objective was to describe anticoagulant treatment modalities up to 12 months., Methods: The management of the anticoagulant treatment beyond 6 months was described in this initially retrospective non-interventional French multicenter study in patients treated with low-molecular-weight heparins (LMWH) still alive at the end of an initial 6-month treatment period. Clinical outcomes, including venous thromboembolism, recurrence, bleeding and deaths have been published previously., Results: Among the 432 patients (mean age 66.5±12.7 years) included in the study, 332 were followed up to 12 months while 96 patients deceased before study end and 4 patients were lost-to-follow-up. At 6 months, anticoagulant therapy was stopped in 74 patients, 56 were switched to vitamin K antagonists (VKA) (16.1% [95%CI, 12.4%-20.4]), 30 to direct oral anticoagulants (DOAC) (8.6% [95%CI, 5.9%-12.1]). LMWHs were maintained in 256 patients (73.6% [95%CI, 68.6-78.1]). During the follow-up, LMWHs were definitively discontinued in 86 patients (33.7%), the main reason being a favorable course of the cancer (16 patients, 18.6%), or the thromboembolic disease (11 patients, 12.8%), whereas concern about bleeding risk was low (2 patients, 2.3%)., Conclusion: Anticoagulation beyond 6 months and up to 12 months was in accordance with clinical practice guidelines suggesting that treatment should be continued as long cancer is active or in the absence of bleeding risk. Anticoagulant treatment discontinuation beyond 6 months was influenced by the favorable courses of both malignancy and thromboembolic disease, as well as patient's preference., Competing Interests: Conflict of Interest Disclosures L. Plaisance, B. Planquette, L. Falchero, I.Mahé, S.Djennaoui: nothing to disclose. C. Chapelle: personal fees from LEO-PHARMA. I. Mahé: grants from LEO-PHARMA, during the conduct of the study; grants, personal fees and non-financial support from BMSPfizer, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from Leo-Pharma, outside the submitted work. S. Laporte: grants from LeoPharma, grants and personal fees from Bayer HealthCare, personal fees from Pfizer, outside the submitted work. L. Bertoletti: personal fees and other from Bayer, personal fees and other from BMS, personal fees and other from Pfizer, personal fees and other from Léo-Pharma, non-financial support from Sanofi, outside the submitted work. F. Couturaud: grants from Pfizer, personal fees from Bayer, other from Boeringher, grants, personal fees and other from BMS, other from Daiichi, personal fees and other from Aztra zeneca, other from GSK, personal fees from leopharma, other from actelion, outside the submitted work. N. Falvo: personal fees from BMS, personal fees from Bayer, personal fees from Leo-Pharma, outside the submitted work.

Background: The role and timing of whole or stereotaxic brain radiotherapy (BR) in patients with advanced non-small cell lung cancer (aNSCLC) and asymptomatic brain metastases (aBMs) are not well established. This study investigates whether deferring BR until cerebral progression was superior to upfront BR for patients with aNSCLC and aBM., Methods: This open-label, multicenter, phase III trial, randomized (1:1) aNSCLC patients with aBMs to receive upfront BR and chemotherapy: platin-pemetrexed and bevacizumab in eligible patients, followed by maintenance pemetrexed with or without bevacizumab, BR arm, or the same chemotherapy with BR only at cerebral progression, chemotherapy (ChT) arm. Primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), global, extra-cerebral and cerebral objective response rate (ORR), toxicity, and quality of life [ClinicalTrials.gov identifier: NCT02162537]., Results: The trial was stopped early because of slow recruitment. Among 95 included patients, 91 were randomized in 24 centers: 45 to BR and 46 to ChT arms (age: 60 ± 8.1, men: 79%, PS 0/1: 51.7%/48.3%; adenocarcinomas: 92.2%, extra-cerebral metastases: 57.8%, without differences between arms.) Significantly more patients in the BR-arm received BR compare with those in the ChT arm (87% versus 20%; p  < 0.001); there were no significant differences between BR and ChT arms for median PFS: 4.7, 95% confidence interval (CI):3.4-7.5 versus 4.8, 95% CI: 2.4-6.5 months, for median OS: 8.5, 95% CI:.6-11.1 versus 8.3, 95% CI:4.5-11.5 months, cerebral and extra-cerebral ORR (27% versus 13%, p  = 0.064, and 30% versus 41%, p  = 0.245, respectively). The ChT arm had more grade 3/4 neutropenia than the BR arm (13% versus 6%, p  = 0.045); others toxicities were comparable., Conclusion: The significant BR rate difference between the two arms suggests that upfront BR is not mandatory in aNSCLC with aBM but this trial failed to show that deferring BR for aBM is superior in terms of PFS from upfront BR., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

Oxysterols are products of enzymatic and/or chemical cholesterol oxidation. While some of the former possess broad antiviral activities, the latter mostly originate from the deterioration of the nutritional value of foodstuff after exposure to heat, light, radiation and oxygen, raising questions about their potential health risks. We evaluated the presence of selected oxysterols in bovine colostrum and monitored the evolution of their cholesterol ratio throughout an entire industrial-scale milk production chain and after industrially employed storage procedures of milk powders. We report here for the first time the presence of high levels of the enzymatic oxysterol 27-hydroxycholesterol (27OHC) in concentrations of antiviral interest in bovine colostrum (87.04 ng mL -1 ) that decreased during the first postpartum days (56.35 ng mL -1 ). Of note, this oxysterol is also observed in milk and milk products and is not negatively affected by industrial processing or storage. We further highlight an exponential increase of the non-enzymatic oxysterols 7β-hydroxycholesterol (7βOHC) and 7-ketocholesterol (7KC) in both whole (WMPs) and skimmed milk powders (SMPs) during prolonged storage, confirming their role as reliable biomarkers of cholesterol oxidation over time: after 12 months, 7βOHC reached in both SMPs and WMPs amounts that have been found to be potentially toxic in vitro (265.46 ng g -1 and 569.83 ng g -1 , respectively). Interestingly, industrial processes appeared to affect the generation of 7βOHC and 7KC differently, depending on the presence of fat in the product: while their ratios increased significantly after skimming and processing of skimmed milk and milk products, this was not observed after processing whole milk and milk cream.

Dabrafenib plus trametinib combination is approved in Europe for BRAF V600E-mutant metastatic non-small-cell lung cancer (NSCLC). The objective of this study was to assess efficacy and safety of this combination in a real-world setting. This retrospective multicentric study included 40 patients with advanced NSCLC harboring BRAF V600E mutation and receiving dabrafenib plus trametinib. The median progression-free survival (PFS) and overall survival (OS) were 17.5 (95% CI 7.1-23.0) months and 25.5 (95% CI 16.6-not reached) months in the entire cohort, respectively. For the 9 patients with first-line treatment, median PFS was 16.8 (95% CI 6.1-23.2) months and median OS was 21.8 (95% CI 1.0-not reached) months; for the 31 patients with second-line or more treatments, median PFS and OS were 16.8 (95% CI 6.1-23.2) months and 25.5 (95% CI 16.6-not reached) months, respectively. Adverse events led to permanent discontinuation in 7 (18%) patients, treatment interruption in 8 (20%) and dose reduction in 12 (30%). In conclusion, these results suggest that efficacy and safety of dabrafenib plus trametinib combination in patients with BRAF V600E metastatic NSCLC are comparable in a real-world setting and in clinical trials for both previously untreated and treated patients.

Introduction: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC., Methods: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate., Results: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%., Conclusions: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer., Methods: In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0-2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m 2 from day 1 to day 3]) or oral topotecan (2·3 mg/m 2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02738346., Findings: Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0-37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9-5·5 vs 2·7 months, 2·3-3·2; stratified hazard ratio 0·57, 90% CI 0·41-0·73; p=0·0041). The most frequent grade 3-4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group., Interpretation: Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer., Funding: Amgen and the French Lung Cancer Group (Groupe Français de Pneumo-Cancérologie)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: extended anticoagulant therapy beyond the initial 6 months is suggested in patients with cancer-associated thrombosis (CAT) and active cancer. Few data are available on patient management and outcomes on the period between 6 and 12 months after the venous thromboembolism (VTE) event., Objectives: our objective was to document patient management and outcomes beyond 6 months and up to 12 months in CAT patients initially treated for 6 months with tinzaparin., Methods: adult CAT patients with a cancer still alive at the end of an initial 6-month treatment period were eligible to participate in this retrospective non-interventional French multicenter study., Results: a total of 432 patients aged 66.5 ± 12.7 years were available to participate in this study. Out of the patients included in the study, the anticoagulant treatment was maintained in 348 of 422 documented patients (82.5%) while it was discontinued in 74 (17.5%) patients (before the end or at the end of the initial 6-month treatment period). Between 6 and 12 months, 24 patients (5.7%) experienced VTE recurrence, while 21 (5.1%) patients had clinically relevant bleeding, 11 patients (2.7%) had major bleeding and 96 patients (22.3%) died, mostly from cancer. VTE recurrence was more frequent in patients with lung (14.3%) and colorectal cancer (6.0%) while major bleeding was more frequent in patients with colorectal cancer (6.0%)., Conclusion: clinical outcomes were consistent with previous observations and variable according to the type of cancer. Further clinical research is required to orient the management of patients with CAT beyond 6 months based on cancer-specific treatment strategies.

Introduction: Immune-checkpoint inhibitor (ICI) efficacy in patients with NSCLC harboring molecular alterations remains poorly elucidated. This study was undertaken to determine ICI efficacy against BRAF-, HER2-, MET-, and RET-NSCLC in a real-world setting., Methods: In this retrospective, multicenter study in ICI-treated BRAF-, HER2-, MET- or RET-NSCLCs, we analyzed clinical characteristics and outcomes: ICI-treatment duration, progression-free survival (PFS), objective response rate, duration of response, and overall survival (OS)., Results: There were 107 patients with NSCLC (mean age, 65.5 y) included from 21 centers: 37% were never-smokers, 54% were men, and 93% had adenocarcinoma. Among them, 44 had BRAF mutation (V600: 26), 23 had HER2 mutation, 30 had MET mutation, and nine had RET translocation. Programmed cell death ligand 1 (PD-L1) status was known for 70 patients and was greater than or equal to 1% in 34 patients. Before ICI, patients had received a median of one treatment line. Median duration of response, PFS, and OS were 15.4 (95% confidence interval [CI]: 12.6-not reached [NR]) months, 4.7 (95% CI: 2.3-7.4) months, and 16.2 (95% CI: 12.0-24.0) months, respectively, for the entire cohort. The response rates for BRAF-V600, BRAF-non-V600, HER2, MET, and RET-altered NSCLC were 26%, 35%, 27%, 36%, and 38%, respectively. For patients who were PD-L1 negative and those who were PD-L1 positive, PFS was 3.0 (95% CI: 1.2-NR) and 4.3 (95% CI: 2.1-8.5) months, respectively, and OS was 11.7 (95% CI: 4.1-NR) and 35.8 (95% CI: 9.0-35.2) months, respectively. Toxicities were reported in 28 patients (26%), including 11 patients (10%) with a grade greater than or equal to three., Conclusions: In this real-world setting, ICI efficacy against patients with BRAF-, HER2-, MET-, or RET-NSCLC seemed close to that observed in unselected patients with NSCLC. Large prospective studies on these subsets of patients are needed., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have been approved as second-line therapy for advanced non-small cell lung cancers (NSCLCs) progressing after platinum-based chemotherapy. However, some patients' disease progressed rapidly and sometimes exhibited explosive tumor progression. This descriptive, prospective study aimed to assess the characteristics of nonresponders with rapid progression (RP), defined as progression-free survival (PFS) ≤2 or 2-4 months under ICIs., Methods: This analysis included all consecutive ICI-treated (second-or-more line) patients with RP ≤4 months from 1 September 2016 to 31 August 2017 and compared the clinical characteristics, treatments, and outcomes (overall survival [OS]; responses; PFS, according to treatment line) of NSCLCs that progressed after ≤2 vs 2-4 months on ICIs., Results: Comparisons of the 224 (70.2%) patients with ≤2-month and 95 (29.8%) with 2- to 4-month RP revealed the former had less frequent nonsmokers and ECOG PS = 0, more frequent stage IV disease and higher neutrophil/lymphocyte ratio. Their respective ICI PFS rates were: 1.6 [95% CI: 0.1-2] and 2.7 [2.0-4.2] months, with 16.5% and 11.6% having partial responses to first- and second-line therapies post-ICI chemotherapy. Their respective median OS rates were 6.0 and 9.0 months (P ≤ .009). Multivariate analysis retained only PFS of the first-line therapy pre-ICI and neutrophil/lymphocyte ratio at ICI onset as being significantly associated with ≤2-month RP., Conclusion: In the real-life setting, NSCLC RP on ICI remains a challenge. New descriptive and analytic studies are needed to identify factors predictive of RP., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Mutation of human receptor tyrosine kinase epidermal growth factor receptor-2 (HER2) is a rare event, found in approximately 1% non-small cell lung cancers (NSCLC). The objective was to investigate the clinical characteristics and management of HER2-mutated NSCLCs in a real-life setting., Methods: This multicenter study described NSCLCs harboring HER2 mutations diagnosed between January 2012 and December 2014, according their clinical characteristics, management, and outcomes: response rate (RR), progression-free survival (PFS), and overall survival (OS)., Results: Thirty patients were included: 66.7% women; median age 65.2 ± 12 years; never or former smokers 73.3%. Of the stage IV patients (n = 23), 86% received first-line platin doublet chemotherapy: RR 61.5% and PFS 6.7 (95% CI 5.9-9.5) months; 52.1% received a second-line therapy: RR 18.2% and PFS 4.9 (95% CI 2.5-11.9) months. Median OS of stage IV was 10.7 months and 2-year OS was 27.2% (95% CI 11.7-63.2). All patients with stage I-III NSCLCs were alive at 2 years., Conclusion: The rarity of HER2-mutated NSCLCs requires specific studies.

Background: The non-interventional ASSESS study (NCT01785888) evaluated the utility of circulating free tumor-derived DNA (ctDNA) from plasma for epidermal growth factor receptor ( EGFR ) mutation testing in patients with advanced non-small-cell lung cancer (NSCLC), in a real-world setting across 56 centers in Europe and Japan. The high mutation status concordance between 1162 matched tissue/cytology and plasma samples (89%, sensitivity =46%, specificity =97%) suggested that ctDNA is a feasible sample for EGFR mutation analysis. We report data for the French subset of patients (pre-planned analysis)., Methods: Eligible patients (stage IIIA/B/IV locally advanced/metastatic treatment-naive advanced NSCLC) provided diagnostic tissue/cytology and plasma samples. DNA extracted from tissue/cytology samples was subjected to EGFR mutation testing as per local practice; a designated laboratory performed ctDNA extraction/mutation testing of plasma samples. The primary outcome was EGFR mutation status concordance between matched tumor and plasma samples., Results: Of the 1,311 patients enrolled in the ASSESS trial, 145 were recruited from 9 centers in France. Tumor samples from 130 patients were collected and 126 were evaluable for EGFR mutation analysis. Activating EGFR mutations were identified in 13 of the 126 patient tumor samples ( EGFR mutation frequency 10.3%). For plasma testing, 10 of the 145 samples tested were positive for EGFR mutations ( EGFR mutation frequency 6.9%). EGFR mutation rate was significantly higher in never- versus ever-smokers (stepwise logistic regression: tumor, P<0.0001; plasma, P=0.0008). Mutation status concordance between 126 matched patient samples was 96.0% [121/126; 95% confidence intervals (CI), 91.0-98.7]. Of the 113 EGFR mutation-negative patient tissue samples, one tested plasma-positive; reanalysis of plasma via two different techniques confirmed the presence of a L858R mutation, indicating a tissue false-negative result. Based on these data, sensitivity of plasma testing was 64.3% (9/14; 95% CI, 35.1-87.2%) and its specificity was 100.0% (112/112; 95% CI, 96.8-100.0%)., Conclusions: Data confirm ctDNA as an alternative sample for EGFR mutation analysis in patients with advanced NSCLC., Competing Interests: Conflicts of Interest: MG Denis: grants/research support/consultant for AstraZeneca, BMS, Boehringer Ingelheim, Merck, Qiagen, Roche Pharma, and Takeda. G Le Garff: clinical trials for AstraZeneca, Lilly, and Roche; all financial contributions except MUTACT study (AstraZeneca) paid by clinical research unit; board member for Novartis; invitation to congress from Air Santé, Altana, AstraZeneca (before 2012), Boehringer Ingelheim, GSK, LFB, Lilly, MSD, Pierre Fabre, and Roche. C Locher: membership on advisory board for AstraZeneca, BMS, Boehringer Ingelheim, Pfizer, and Roche; medical conferences for Novartis. M Licour: employee of AstraZeneca. N Normanno: grants/research support/consultant for AstraZeneca, Qiagen, and Roche Diagnostics. M Reck: member of the speaker’s bureau for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Hoffmann-La Roche, Lilly, and Pfizer; consultant for AstraZeneca, BMS, Boehringer Ingelheim, Daiichi Sankyo, Hoffmann-La Roche, Lilly, MSD, and Pfizer. All other authors have declared no conflicts of interest.

Background: Although improved during the last decades, the prognosis of lung cancer is poor. In 2000, the French College of general hospital respiratory physicians, conducted KBP-2000-CPHG, a prospective multicenter epidemiological study including all volunteer adult patients diagnosed for primary lung cancer; with the five-year survival as primary endpoint. The primary objective of KBP-2010-CPHG was to compare overall five-year survival data with KBP-2000-CPHG ones., Material and Methods: All consecutive patients≥18 years of age with primary lung cancer diagnosed between 1st January and 31st December 2010 were included. The KBP-2010-CPHG protocol was approved by the advisory committee on research information processing in the health field (CCTIRS) on November 19, 2009., Results: Respectively, 5667 and 7051 patients were included in KBP-2000-CPHG and KBP-2010-CPHG. Five-year survival was improved: 12.7% [11.9%-13.5%] in 2010 versus 10.0% [9.2%-10.9%] in 2000 (P<0.001). Non-small-cell lung cancer showed improvement (13.8% [13.0%-14.8%] in 2010 versus 11.4% [10.5%-12.4%] in 2000; P<0.001); but not small-cell lung cancer (5.7% [4.4%-7.4%] in 2010 versus 3.3% [2.3%-4.7%] in 2000; P=0.56). The KBP-2010-CPHG study showed an overall 6% reduction in risk of death (HR=0.94 [0.89-0.98]; P=0.004)., Conclusions: Survival of patients with lung cancer improved over a 10-year period. This improvement was slight and limited to non-small-cell lung cancer, possibly partly because of 2010 advances in diagnosis and targeted therapy., (Copyright © 2019 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Objectives The efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR T790 M resistance mutation was demonstrated in clinical trials. However, data on efficacy of osimertinib in real world remain rare. Materials and methods This retrospective multicentric study analyzed T790M-positive advanced NSCLC patients enrolled in French early access program for osimertinib. Patients were pretreated with first- or second-generation EGFR tyrosine-kinase inhibitor and for a majority with chemotherapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. Results 205 patients (mean age, 69.5 years; female, 68.8%; adenocarcinoma, 97.5%, never-smokers, 71.5%) were analyzed. Osimertinib was used in second and third line in 18.0% and 82.0% of patients, respectively. Median PFS was 12.4 (95% CI, 10.1-15.1) months. In patients with and without cerebral metastasis, PFS was 9.7 (7.7-13.5) and 15.1 (12.0-17.1) months (p = 0.21), respectively. PFS in second and third line or more was 12.6 (6.7-17.5) and 12.4 (9.7-15.3) months, respectively. Median PFS in patients with EGFR exon 19 deletion and exon 21 mutation was 13.5 (10.1-16.0) and 9.7 (7.4-13.2) months, respectively (p = 0.049). Median OS since osimertinib initiation was 20.5 (16.9-24.3) months: 23.1 (18.6-27.8) and 18.0 (12.2-22.2) months in patients without and with cerebral metastasis (p = 0.11); 17.5 (11.6-27.8) and 21.7 (17.3-24.3) months as second or third line of treatment or more (p = 0.46), respectively. Median OS in patients with EGFR exon 19 deletion and exon 21 mutation was 23.1 (18.6-25.7) and 15.3 (11.6-21.7) months, respectively (p = 0.03). Osimertinib dosage was modified in 8.0% of patients and definitively discontinued for adverse events in 5.9%. Fifty patients benefited from rebiopsy (persistence of T790 M mutation, 44.7%; C797S mutation, 21.1%; cMET amplification, 8.0%). Conclusion In pretreated patients with T790M-mutated advanced NSCLC, the efficacy of osimertinib appears similar in real-world setting to that of clinical trials., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Mutations in BRAF are rare oncogene mutations, found in 2% of non-small-cell lung cancers (nsclcs). Little information is available about the management of patients with BRAF- mutated nsclc, except for those included in clinical trials. We undertook the present study to assess the clinical characteristics, management, and outcomes of those patients in a real-life setting., Methods: This retrospective multicentre observational study included all patients with BRAF- mutated nsclc diagnosed between January 2012 and December 2014., Results: Patients ( n = 59) from 24 centres were included: 57.6% men; mean age: 64.5 ± 14.5 years; 82% with a performance status of 0-1 at diagnosis; smoking status: 40.3% current, 32.6% former; 93% with adenocarcinoma histology; 75% stage iv; 78% with V600E mutations; 2 with EGFR and 2 with ALK co-mutations. Of the stage iv patients, 79% received first-line therapy (14.2% anti -BRAF) , and 48% received second-line treatment (23.8% anti -BRAF). Response rate and progression-free survival were, respectively, 51.7% and 8.7 months [95% confidence interval (ci): 6.4 months to 15.2 months] for first-line therapy and 35.3% and 4.1 months (95% ci: 2 months to 10.9 months) for second-line treatments. The 2-year overall survival was 58.5% (95% ci: 45.8% to 74.8%). Outcomes in patients with stage iv nsclc harbouring BRAF V600E mutations ( n = 32) did not differ significantly from those of patients with other BRAF mutations., Conclusions: In this real-world analysis, most nsclc patients with a BRAF mutation were men and current or former smokers. Survival appears to be better in these BRAF- mutated patients than in nsclc patients without an oncogenic driver., Competing Interests: CONFLICT OF INTEREST DISCLOSURES In the past 5 years, JBA, AV, and CC received fees for attending scientific meetings, speaking, organizing research, or consulting from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche, Sanofi Aventis, Bristol–Myers Squibb, Merck Sharp and Dohme, Lilly, Novartis, and Amgen. The others authors declare that they have no conflicts to disclose.

In this study, proton transfer reaction-mass spectrometry (PTR-MS), coupled with a time-of-flight mass analyzer and a multipurpose automatic sampler, was evaluated as a rapid and nondestructive tool for the quality control of anhydrous milk fat. Anhydrous milk fats packed in cardboard and bag-in-box were compared during refrigerated shelf life at 4°C for 9 months. Anhydrous milk fat samples were taken at 120, 180, and 240 days and measured by PTR-MS during storage at 50°C for 11 days. Univariate and multivariate data analysis were performed in order to classify samples according to the packaging type and compare aromatic profiles. Markers related to both packaging and storage duration were identified, and all stored samples were clearly distinguishable from reference fresh samples. Significant differences in some key butter aroma compounds such as 2-pentanone, 2-heptanone, 2/3-methylbutanal, acetoin, and butanoic acid were observed between different types of packaging. During the refrigerated storage, differences related to packaging are more evident, while during the storage at 50°C, the fat oxidation induced by the high temperature becomes the most relevant phenomenon independently of the packaging type. These results indicate the importance of avoiding anhydrous milk fat storage at 50°C for long times during industrial production processes. All together data demonstrated the viability of PTR-MS as a rapid and high-sensitivity tool in agroindustry quality control program., (© 2018 John Wiley & Sons, Ltd.)

Objectives: The aim of this study was to describe the characteristics of patients receiving bevacizumab plus first-line metastatic chemotherapy for non-squamous advanced non-small cell lung cancer (aNSCLC), with or without brain metastases, in routine clinical practice. Other objectives were to describe treatment efficacy, modalities of use, and safety., Methods: For this non-interventional, prospective, national, multicentre study, data were collected every 3 months over 18 months., Results: Of the 407 patients analysed, 84 (21%) with brain metastases at bevacizumab initiation had poorer general health than patients with no brain metastases (Eastern Cooperative Oncology Group [ECOG] performance status score = 2: 16 vs. 11%). All but 2 patients received bevacizumab (7.5 or 15 mg/kg/3 weeks in 99% of patients) in combination with doublet chemotherapy. Median progression-free survival and overall survival did not differ significantly between patients with or without brain metastases (6.5 months, 95% CI 5.7-8.1 vs. 6.9 months, 95% CI 5.9-7.6, p = 0.57; 14.5 months, 95% CI 10.0 vs. 12.5 months, 95% CI 10.1-14.7, p = 0.33). In 30 and 32% of the patients, respectively, at least one serious adverse event was reported, with a causal relationship to bevacizumab in 20 and 21% of the patients., Conclusion: This study confirmed in a real-life setting the safety profile and survival benefits of first-line chemotherapy with bevacizumab in aNSCLC patients with brain metastases., (© 2017 S. Karger AG, Basel.)

Objectives: The aim of this study was to describe the demographic and clinico-pathological characteristics of lung cancer in patients younger than 40 years., Materials and Methods: This was a prospective study performed within the Groupe Français de Pneumo-Cancérologie. Consecutive patients diagnosed with lung cancer before the age of 40 years were eligible. Data on demographics, medical history, clinico-pathological characteristics, treatment and overall survival were analysed., Results: In total, 146 patients were included from January 2011 to December 2013. Median age was 38 years (IQR: 34-40). Women accounted for 41%. Main histological type was adenocarcinoma (77%). Only 3% had a prior history of cancer, but a family history (first- or second-degree relatives) of cancer was reported in 80 (55%) patients; 85 and 50% were current or past smokers of tobacco and cannabis, respectively; 82% had stage IIIB/IV at diagnosis. Median overall survival was 15.3 (95% CI: 8.1-24.0) months in the whole population, 10.3 (95% CI: 12.5-14.2) months in stage IV and 15 (95% CI: 8.7-35.2) months in stage III. One- and two-year overall survival rates were 57% (95 CI: 49-65) and 31.5% (95 CI: 27-43), respectively. Compared to smokers, non-smokers were significantly younger and more often females. Median overall survival was not statistically different between smokers and non-smokers., (© 2018 S. Karger AG, Basel.)

Introduction: The EOLE cohort aimed to describe, in routine clinical practice, the characteristics and management of patients receiving bevacizumab in combination with first-line metastatic chemotherapy for advanced metastatic or recurrent non squamous non-small cell lung cancer (nsNSCLC), as well as its efficacy and safety., Methods: A total of 423 patients were enrolled in this prospective, national, multicenter study. Data were collected every 3 months over an 18-month period., Results: Amongst the 407 patients analyzed (mean age 60±10 years, male 68%, ECOG-PS≤1 88%, smokers or former smokers 87%, cardiovascular comorbidities 40%), all except for 2 patients received bevacizumab (7.5 or 15mg/kg/3 weeks in 99% of patients) in combination with doublet chemotherapy. A total of 160 (60%) patients who completed induction received bevacizumab maintenance therapy. Median progression-free survival was 6.9 months (95% CI=[6.0-7.5]). Median overall survival (12.8 months [10.4-14.7]) was longer in patients with ECOG-PS≤1 (14.4 months [12.3-15.9] versus 4.9 months [3.4-8.3] if ECOG-PS=2). A total of 131 (32%) patients experienced at least one serious adverse event (SAE), and 51 (12%) at least one bevacizumab-related SAE., Conclusion: EOLE confirms the efficacy and safety of bevacizumab in aNSCLC patients, in current medical practice., (Copyright © 2016 SPLF. Published by Elsevier Masson SAS. 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.)

Purpose: Comprehensive geriatric assessment (CGA) is recommended to assess the vulnerability of elderly patients, but its integration in cancer treatment decision making has never been prospectively evaluated. Here, in elderly patients with advanced non-small-cell lung cancer (NSCLC), we compared a standard strategy of chemotherapy allocation on the basis of performance status (PS) and age with an experimental strategy on the basis of CGA., Patients and Methods: In a multicenter, open-label, phase III trial, elderly patients ≥ 70 years old with a PS of 0 to 2 and stage IV NSCLC were randomly assigned between chemotherapy allocation on the basis of PS and age (standard arm: carboplatin-based doublet if PS ≤ 1 and age ≤ 75 years; docetaxel if PS = 2 or age > 75 years) and treatment allocation on the basis of CGA (CGA arm: carboplatin-based doublet for fit patients, docetaxel for vulnerable patients, and best supportive care for frail patients). The primary end point was treatment failure free survival (TFFS). Secondary end points were overall survival (OS), progression-free survival, tolerability, and quality of life., Results: Four hundred ninety-four patients were randomly assigned (standard arm, n = 251; CGA arm, n = 243). Median age was 77 years. In the standard and CGA arms, 35.1% and 45.7% of patients received a carboplatin-based doublet, 64.9% and 31.3% received docetaxel, and 0% and 23.0% received best supportive care, respectively. In the standard and CGA arms, median TFFS times were 3.2 and 3.1 months, respectively (hazard ratio, 0.91; 95% CI, 0.76 to 1.1), and median OS times were 6.4 and 6.1 months, respectively (hazard ratio, 0.92; 95% CI, 0.79 to 1.1). Patients in the CGA arm, compared with standard arm patients, experienced significantly less all grade toxicity (85.6% v 93.4%, respectively P = .015) and fewer treatment failures as a result of toxicity (4.8% v 11.8%, respectively; P = .007)., Conclusion: In elderly patients with advanced NSCLC, treatment allocation on the basis of CGA failed to improve the TFFS or OS but slightly reduced treatment toxicity., (© 2016 by American Society of Clinical Oncology.)

Objectives: In advanced non-small cell lung cancer (NSCLC), maintenance therapy has emerged as a novel therapeutic reference for patients with non-progressive disease after platinum-based induction chemotherapy. However, the use of double maintenance (DM) with pemetrexed and bevacizumab is still being evaluated in terms of its clinical benefits and safety profile. The objective of this retrospective study was to describe the reasons for DM discontinuation in a real-world setting., Materials and Methods: Patients with advanced non-squamous NSCLC were eligible if they had received at least 4 cycles of induction chemotherapy, followed by at least 1 cycle of DM. They were identified by using the oncology pharmacy database of 17 French centers., Results: Eighty-one patients who began a DM after induction chemotherapy were identified from September 2009 to April 2013. Among the 78 patients who had stopped DM at the time of the analysis, the main reasons for discontinuation were disease progression (42%), adverse events (33%), and personal preference (8%). The most frequent toxicity responsible for DM discontinuation was renal insufficiency (54%)., Conclusion: For patients with advanced NSCLC eligible for DM therapy, a particular attention should be paid to potential renal failure. Kidney function should be monitored carefully before and during DM to detect and manage early this adverse event., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

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.)

Background: No reference second-line treatment of small-cell lung cancer is available. The aim of the present phase II randomized trial (Groupe Français de Pneumo-Cancérologie 0501) was to compare, in patients with progressive small-cell lung cancer after first-line platinum-based chemotherapy, oral multidrug chemotherapy (lomustine, cyclophosphamide, etoposide) and intravenous therapy with cyclophosphamide, doxorubicin, and vincristine (CAV) in terms of efficacy and tolerance. The primary endpoint was overall survival. The secondary endpoints were progression-free survival, response rate, and tolerance., Patients and Methods: The study randomized 131 patients (76.7% male; median age, 61 ± 8.1 years, 85.5% with a performance status of 0-1), 65 to oral therapy and 66 to the CAV arm. No statistically significant differences were found in the baseline patient characteristics., Results: The OS and PFS was 6.1 and 3 months for the oral arm and 5.8 and 3.1 months for the CAV arm, respectively. The control disease rate was 61.6% and 45.5% in oral and CAV arms, respectively. No unexpected adverse events occurred, and no statistically significant difference was found between the 2 arms in terms of toxicity (grade 4 hematologic adverse events in 32.3% and 31.8% of patients in the oral and CAV arms, respectively)., Conclusion: Compared with CAV, oral therapy in this setting appears as feasible as, but not superior to, the efficacy in the CAV arm., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The IFCT-GFPC 0502 phase III study reported prolongation of progression-free survival with gemcitabine or erlotinib maintenance vs. observation after cisplatin-gemcitabine induction chemotherapy for advanced non-small-cell lung cancer (NSCLC). This analysis was undertaken to assess the incremental cost-effectiveness ratio (ICER) of these strategies for the global population and pre-specified subgroups., Methods: A cost-utility analysis evaluated the ICER of gemcitabine or erlotinib maintenance therapy vs. observation, from randomization until the end of follow-up. Direct medical costs (including drugs, hospitalization, follow-up examinations, second-line treatments and palliative care) were prospectively collected per patient during the trial, until death, from the primary health-insurance provider's perspective. Utility data were extracted from literature. Sensitivity analyses were conducted., Results: The ICERs for gemcitabine or erlotinib maintenance therapy were respectively 76,625 and 184,733 euros per quality-adjusted life year (QALY). Gemcitabine continuation maintenance therapy had a favourable ICER in patients with PS = 0 (52,213 €/QALY), in responders to induction chemotherapy (64,296 €/QALY), regardless of histology (adenocarcinoma, 62,292 €/QALY, non adenocarcinoma, 83,291 €/QALY). Erlotinib maintenance showed a favourable ICER in patients with PS = 0 (94,908 €/QALY), in patients with adenocarcinoma (97,160 €/QALY) and in patient with objective response to induction (101,186 €/QALY), but it is not cost-effective in patients with PS =1, in patients with non-adenocarcinoma or with stable disease after induction chemotherapy., Conclusion: Gemcitabine- or erlotinib-maintenance therapy had ICERs that varied as a function of histology, PS and response to first-line chemotherapy.

Background: Concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective., Objective: To assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC., Methods: In an open-label phase II trial, patients with advanced NSCLC, EGFR wild-type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150 mg/d (day 2-16)+docetaxel (75 mg/m(2) d1) (arm ED) or docetaxel (75 mg/m(2) d1) alone (arm D) (21-day cycle). The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15). Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages., Results: 147 patients were randomized (median age: 60±8 years, PS 0/1/2: 44/83/20 patients; males: 78%). The ED strategy was rejected, with only 18 of 73 patients achieving PFS15 in arm ED at the end of stage 2 and 17 of 74 patients in arm D. In arms ED and D, respectively, median PFS was 2.2 and 2.5 months and median OS was 6.5 and 8.3 months., Conclusion: Sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild-type or unknown EGFR status., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Maintenance therapy in advanced non-small-cell lung cancer (NSCLC) might lead to resistance to subsequent treatments. IFCT-GFPC 0502 study showed a progression-free survival (PFS) benefit with gemcitabine or erlotinib maintenance compared with observation after cisplatin-gemcitabine chemotherapy. The trial included a pre-defined pemetrexed second-line therapy, allowing post-hoc assessment of its efficacy according to previous maintenance treatment or treatment-free interval., Methods: Stage IIIB/IV NSCLC patients were randomized after four cycles of cisplatin-gemcitabine chemotherapy to either observation or to receive maintenance therapy with gemcitabine or erlotinib. Pemetrexed was given as second-line treatment on disease progression in all arms. PFS and overall survival (OS) were assessed from the beginning of pemetrexed therapy according to randomization arm., Results: Of the 464 randomized patients, 360 (78 %) received second-line pemetrexed (130 [84%], 114 [74%], and 116 [75%] in observation, gemcitabine, and erlotinib arm, respectively). Median number of pemetrexed cycles was 3 (1-40) in all arms. Median PFS did not differ between gemcitabine and observation arms (4.2 versus 3.9 months, hazard ratio [HR] [95% confidence interval [CI] 0.81 [0.62-1.06]) or between erlotinib and observation arms (4.2 versus 3.9 months, HR 0.83 [0.64-1.09]). OS data showed a non-significant improvement with gemcitabine arm versus observation arm (8.3 versus 7.5 months, HR 0.81 [0.61-1.07]) or erlotinib arm versus observation arm (9.1 versus 7.5 months, HR 0.80 [0.61-1.05]). Results were similar for non-squamous patients. Grade 3 to 4 treatment-related adverse events (AEs) were comparable in all arms., Conclusions: Maintenance therapy with gemcitabine continuation or erlotinib does not seem to impair efficacy of second-line pemetrexed comparatively to administration after a treatment-free interval.

Background: A large proportion of elderly patients (>70 years) with newly diagnosed NSCLC are shown to be frail by a comprehensive geriatric assessment. This population is more vulnerable to adverse effects of chemotherapy and might thus benefit more from targeted therapy. The objective of this study was to assess the cost-effectiveness of erlotinib followed by chemotherapy after progression, compared with the reverse strategy, in frail elderly patients with advanced NSCLC participating in a prospective randomized phase II trial (GFPC 0505)., Materials and Methods: Outcomes (progression-free survival and overall survival) and costs (limited to direct medical costs, from the third-party payer perspective) were collected prospectively until second progression. Costs after progression and health utilities (based on disease states and grade 3-4 toxicities) were derived from the literature., Results: Median overall survival, QALYs, and total costs for the erlotinib-first strategy were 3.9 months, 0.33, and €15,233, respectively, compared with 4.4 months, 0.35, and €15,363 for the chemotherapy-first strategy. There was no significant difference between the 2 strategies in term of cost-effectiveness (respectively €47,381 and €44,350 per QALY)., Conclusion: No difference in cost-effectiveness was found between an erlotinib-first strategy and a chemotherapy-first strategy in frail elderly patients with NSCLC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: This phase III study investigated whether continuation maintenance with gemcitabine or switch maintenance with erlotinib improves clinical outcome compared with observation in patients with advanced non-small-cell lung cancer (NSCLC) whose disease was controlled after cisplatin-gemcitabine induction chemotherapy., Patients and Methods: Four hundred sixty-four patients with stage IIIB/IV NSCLC without tumor progression after four cycles of cisplatin-gemcitabine were randomly assigned to observation or to gemcitabine (1,250 mg/m(2) days 1 and 8 of a 3-week cycle) or daily erlotinib (150 mg/day) study arms. On disease progression, patients in all three arms received pemetrexed (500 mg/m(2) once every 21 days) as predefined second-line therapy. The primary end point was progression-free survival (PFS)., Results: PFS was significantly prolonged by gemcitabine (median, 3.8 v 1.9 months; hazard ratio [HR], 0.56; 95% CI, 0.44 to 0.72; log-rank P < .001) and erlotinib (median, 2.9 v 1.9 months; HR, 0.69; 95% CI, 0.54 to 0.88; log-rank P = .003) versus observation; this benefit was consistent across all clinical subgroups. Both maintenance strategies resulted in a nonsignificant improvement in overall survival (OS); patients who received second-line pemetrexed or with a performance status of 0 appeared to derive greater benefit. Exploratory analysis showed that magnitude of response to induction chemotherapy may affect the OS benefit as a result of gemcitabine maintenance. Maintenance gemcitabine and erlotinib were well tolerated with no unexpected adverse events., Conclusion: Gemcitabine continuation maintenance or erlotinib switch maintenance significantly reduces disease progression in patients with advanced NSCLC treated with cisplatin-gemcitabine as first-line chemotherapy. Response to induction chemotherapy may affect OS only for continuation maintenance.

Background: The aim of this randomized phase II trial was to evaluate the feasibility and activity of weekly gemcitabine (G) followed by erlotinib at disease progression (arm A) versus erlotinib followed by G at progression (arm B) in vulnerable elderly patients with advanced non small-cell lung cancer (NSCLC), selected on the basis of a comprehensive geriatric assessment (CGA)., Methods: Vulnerable elderly chemotherapy-naive patients with stage IIIB/IV NSCLC were selected after a CGA (socioeconomic, cognitive and emotional status, depression, nutritional status, ADL and IADL assessments). The primary endpoint was the time to second progression (TTP2). Overall survival (OS), time to first progression (TTP1) and safety were secondary endpoints., Results: Between May 2006 and January 2010, 21 centers enrolled 100 patients, of whom 94 were eligible. TTP2 was 4.3 and 3.5 months in arm A and arm B, respectively; TTP1 was 2.5 and 2.2 months; and the median OS time was 4.4 and 3.9 months. The respective one-year survival rates were 27.3% and 20%. There was no major unexpected toxicity., Conclusion: In vulnerable elderly patients with NSCLC not selected for EGFR expression, both strategies were feasible but had modest efficacy. Further studies are needed to identify elderly patients who should receive palliative care only., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)