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Purpose: The RAS/MEK signaling pathway is essential in carcinogenesis and frequently altered in non-small-cell lung cancer (NSCLC), notably by KRAS mutations (KRASm) that affect 25%-30% of non-squamous NSCLC. This study aims to explore the impact of KRASm subtypes on disease phenotype and survival outcomes., Patients and Methods: We conducted a retrospective analysis of the French Epidemiological Strategy and Medical Economics database for advanced or metastatic lung cancer from 2011 to 2021. Patient demographics, histology, KRASm status, treatment strategies, and outcomes were assessed., Results: Of 10 177 assessable patients for KRAS status, 17.6% had KRAS p.G12C mutation, 22.6% had KRAS non-p.G12C mutation, and 59.8% were KRASwt. KRASm patients were more often smokers (96.3%) compared with KRASwt (85.8%). A higher proportion of programmed death-ligand 1 ≥50% was found for KRASm patients: 43.5% versus 38.0% (P < 0.01). KRASm correlated with poorer outcomes. First-line median progression-free survival was shorter in the KRASm than the KRASwt cohort: 4.0 months [95% confidence interval (CI) 3.7-4.3 months] versus 5.1 months (95% CI 4.8-5.3 months), P < 0.001. First-line overall survival was shorter for KRASm than KRASwt patients: 12.6 months (95% CI 11.6-13.6 months) versus 15.4 months (95% CI 14.6-16.2 months), P = 0.012. First-line chemoimmunotherapy offered better overall survival in KRAS p.G12C (48.8 months) compared with KRAS non-p.G12C (24.0 months) and KRASwt (22.5 months) patients. Second-line overall survival with immunotherapy was superior in the KRAS p.G12C subgroup: 12.6 months (95% CI 8.1-18.6 months) compared with 9.4 months (95% CI 8.0-11.4 months) for KRAS non-p.G12C and 9.6 months (8.4-11.0 months) for KRASwt patients., Conclusion: We highlighted distinct clinical profiles and survival outcomes according to KRASm subtypes. Notably KRAS p.G12C mutations may provide increased sensitivity to immunotherapy, suggesting potential therapeutic implications for sequencing or combination of therapies. Further research on the impact of emerging KRAS specific inhibitors are warranted in real-world cohorts., Competing Interests: Disclosure QDT received honoraria from Amgen, AstraZeneca, and Sanofi and meeting/travel support from Amgen and Sanofi. CC received grants or contracts, consulting fees, personal/institutional honoraria, and meeting/travel support from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck Sharp & Dohme (MSD), Novartis, Pfizer, Roche, Sanofi, and Takeda. TF received personal/institutional honoraria from Janssen, Lilly, and Roche. JRM received grants or contracts from MSD, received payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or educational events from AstraZeneca, Edimark, Janssen, MSD, Sanofi, Roche, and Takeda and meeting/travel support from Ose-Immunotherapeutics. MP received consulting fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, Eisai, GlaxoSmithKline, Ipsen, Janssen, MSD, Novocure, Pfizer, Roche, and Takeda; payment or honoraria for lectures, presentations, speaker bureau, manuscript writing or educational events from Anheart Therapeutics, AstraZeneca, Bristol-Myers Squibb, Janssen, MSD, Pfizer, Sanofi, and Takeda; payment for expert testimony from AstraZeneca, Bristol-Myers Squibb, Janssen, and Roche; support for attending meetings and/or travel from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Roche, and Takeda; and participated on a data safety monitoring board or advisory board for Pharmamar and Roche. CAV received consulting fees or meeting/travel support from Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi Aventis, and Takeda; and participated in an advisory board for AbbVie, AstraZeneca, Bristol-Myers Squibb, Janssen, Lilly, MSD, Pfizer, Roche, and Sanofi. GJ received meeting/travel support from Sanofi. SH received personal/institutional honoraria from AstraZeneca, Bristol-Myers Squibb, Roche, Sanofi, and Takeda; and meeting/travel support from Novartis and Sanofi. AS received consulting fees from Exafield and Guidepoint; honoraria from Amgen, AstraZeneca, and MSD; meeting/travel support from Amgen and Roche; and is a board member of the SFFPO. EP received personal/institutional honoraria from Amgen, AstraZeneca, and MSD; meeting/travel support from Takeda and Amgen; and participated in an advisory board for Takeda. NG declared research grants/support from AbbVie, Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Gilead, Hoffmann-La Roche, Janssen, LEO Pharma, Lilly, Merk Serono, MSD, Novartis, Sanofi, Sivan; consultative services for AbbVie, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb, Daiichi-Sankyo, Gilead, Ipsen Hoffmann-La Roche, Janssen, LEO Pharma, Lilly, MSD, Mirati, Novartis, Pfizer, Pierre Fabre, Sanofi, Takeda; participation on a data safety monitoring board for Hoffmann-La Roche; and employment of a family member with AstraZeneca. PDR received meeting/travel support from Boehringer Ingelheim, Daiichi Sankyo, Summit Therapeutics, Sanofi, and Takeda; and participated in an advisory board for Sanofi and Takeda. All other authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Treatment of metastatic non-small cell lung cancer (mNSCLC) has been modified due to the development of immunotherapy. We assessed survival outcomes (overall [OS] and progression-free [rwPFS] survivals, time-to-next-treatment [TNT]) in mNSCLC patients after first-line immunotherapy and chemotherapy in real-life settings. Association between rwPFS and TNT, two candidate surrogate endpoints (SE), with OS was assessed. This retrospective multi-center study uses data from patients included in the Epidemio-Strategy Medico-Economic program with mNSCLC over 2015-2019. The impact of treatment on rwPFS/OS was evaluated with Cox models. Individual-level associations between SE and OS were estimated with an iterative multiple imputation approach and joint survival models. The population included 5294 patients (63 years median age). Median OS in immunotherapy group was 16.4 months (95%CI [14.1-NR]) and was higher than in chemotherapy group (11.6 months; 95%CI [11.0-12.2]). Improved OS was observed for the immunotherapy group after 3 months for subjects with performance status 0-1 (HR = 0.59; 95%CI [0.42-0.83], p < 0.01). The associations between rwPFS and TNT with OS were close ([Formula: see text]=0.57). Results emphasized a survival improvement with immunotherapy for patients in good health condition. There was moderate evidence of individual-level association between candidate SE and OS., (© 2023. The Author(s).)

Introduction: There is a great need for data based on clinical trials for the older population in order to improve treatment. Historically, the inclusion rate of older adults in clinical trials has been low, but the rate specific to lung cancer is unknown, as are the factors associated with enrolment., Materials and Methods: We used the national Epidemio-Strategy and Medical Economics Advanced or Metastatic Lung Cancer (AMLC) Data Platform, a multicentre real-life database. Inclusion criteria were patients with advanced or metastatic non-small cell lung cancer (AMNSCLC) aged 70 years or older, with at least one line of systemic treatment from 01 January 2015 to 31 December 2018. The primary objective was to evaluate the proportion of older adults enrolled in clinical trials. Secondary objectives were to identify factors associated with enrolment in clinical trials for older patients and to compare the overall survival of older adults included in trials versus those not included., Results: There were 3488 patients aged ≥70 years (median age at AMNSCLC 75 years). Among older patients, 234 (6.7%) were enrolled in a clinical trial in the first-line setting. Significant factors associated with enrolment in the multivariable analysis in older patients were: good Eastern Cooperative Oncology Group (ECOG) Performance Status (PS 0) (p < 0.001), de novo versus recurrent presentation at diagnosis (p < 0.001), and non-central nervous system (CNS) metastases versus advanced setting or CNS metastases (p < 0.001). Medical history was associated with fewer inclusions (odds ratio [OR] = 0.74, 95% confidence interval [CI] [0.56; 0.99]). Among older patients, being enrolled in a trial in the first-line setting was not associated with better overall survival (OS) (hazard ratio [HR] = 1.03; 95%CI 0.86-1.22) in the multivariable analysis., Discussion: In this large database, few older AMNSCLC patients were enrolled in a trial. Factors associated with enrolment were: good ECOG PS, absence of medical history, de novo AMNSCLC, and presentation with non-CNS metastases., Competing Interests: Declaration of Competing Interest All authors declare no potential conflict of interest relevant to the content of the manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.)

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months., Competing Interests: Disclosure AJS reports consulting/advising role to J&J and Perceptive Advisors. SJA reports consulting/advising role from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis; expenses from Bristol-Myers Squibb, Merck, CBMG, AstraZeneca, Memgen, RAPT, and Venn, Achilles Therapeutics, Celsius, Samyang Biopharma, Glaxo Smith Klein, Amgen, other from Bristol-Myers Squibb, Merck, Rapt, Achilles Therapeutics, Celsius, GlaxoSmithKline, Amgen, grants from Novartis. MMA reports grants and personal fees from Genentech, grants and personal fees from Bristol-Myers Squibb, personal fees from Merck, grants and personal fees from AstraZeneca, grants from Lilly, personal fees from Maverick, personal fees from Blueprint Medicine, personal fees from Syndax, personal fees from Ariad, personal fees from Nektar, personal fees from Gritstone, personal fees from ArcherDx, personal fees from Mirati, personal fees from NextCure, personal fees from EMD Serono. EF reports personal fees from AbbVie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Blue Print Medicines, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from GSK, personal fees from Janssen, personal fees from Medscape, personal fees from Merck KGaA, personal fees from Merck Sharp & Dohme, personal fees from Novartis, personal fees from Roche, personal fees from PeerVoice, personal fees from Pfizer, personal fees from prIME Oncology, personal fees from Puma Biotechnology, personal fees from Roche, personal fees from Sanofi Genzyme, personal fees from Springer, personal fees from Takeda, personal fees from TouchIME, grants from Grant for Oncology Innovation (GOI), grants from Fundación Merck Salud, outside the submitted work; and Grífols: Independent Member of the Board. JG reports grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech/Roche, personal fees from Takeda, grants and personal fees from Blueprint, grants and personal fees from Loxo, personal fees from Oncorus, personal fees from Regeneron, personal fees from Pfizer, personal fees from Incyte, grants and personal fees from Novartis, grants and personal fees from Merck, personal fees from Agios, personal fees from Amgen, grants from Array, grants from Tesaro, grants from Moderna, grants from Adaptimmune, grants from Alexo, personal fees from Ironwood Pharmaceuticals, personal fees from Gilead, personal fees from EMD Serono, personal fees from AstraZeneca, personal fees from Mirati. SNG reports personal fees and other from Bristol Myers Squibb, personal fees from Nektar, other from Genentech, other from Ariad/Takeda, other from Iovance Biotherapeutics, during the conduct of the study. FSH reports grants, personal fees and other from Bristol-Myers Squibb, personal fees from Merck, personal fees from EMD Serono, grants, personal fees and other from Novartis, personal fees from Surface, personal fees from Compass Therapeutics, personal fees from Apricity, personal fees from Aduro, personal fees from Sanofi, personal fees from Pionyr, personal fees from 7 Hills Pharma, personal fees from Verastem, personal fees from Torque, personal fees from Rheos, personal fees from Kairos, personal fees from Bicara, from Psioxus Therapeutics, other from Pieris Pharmaceutical, from Zumutor, from Corner Therapeutics, personal fees from Eisai, personal fees from Checkpoint Therapeutics, outside the submitted work; In addition, FSH has a patent Methods for Treating MICA-Related Disorders (#20100111973) with royalties paid, a patent Tumor antigens and uses thereof (#7250291) issued, a patent Angiopoiten-2 Biomarkers Predictive of Anti-immune checkpoint response (#20170248603) pending, a patent Compositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma using PD-L1 Isoforms (#20160340407) pending, a patent Therapeutic peptides (#20160046716) pending, a patent Therapeutic Peptides (#20140004112) pending, a patent Therapeutic Peptides (#20170022275) pending, a patent Therapeutic Peptides (#20170008962) pending, a patent Therapeutic Peptides Patent number: 9402905 issued, a patent Methods of using pembrolizumab and trebananib pending, a patent Vaccine compositions and methods for restoring NKG2D pathway function against cancers Patent number: 10279021 issued, a patent Antibodies that bind to MHC class I polypeptide-related sequence A Patent number: 10106611 issued, and a patent Anti- galectin antibody biomarkers predictive of anti-immune checkpoint and anti-angiogenesis responses. Publication number: 20170343552 pending. MLJ reports other from Achilles Therapeutics, grants and other from AstraZeneca, grants and other from Atreca, grants and other from Boehringer Ingelheim, grants and other from Calithera Biosciences, grants and other from EMD Serono, grants and other from Roche/Genentech, grants and other from GlaxoSmithKline, grants and other from Gritstone Oncology, grants and other from Guardant Health, grants and other from Incyte, grants and other from Janssen Research and Development, grants and other from Lilly, grants and other from Merck, grants and other from Mirati Therapeutics, grants and other from Novartis, grants and other from Pfizer, grants and other from Sanofi-Aventis, grants from AbbVie, grants from Acerta Pharma, grants from Adaptimmune, grants and other from Amgen, grants from Apexigen, grants from Array BioPharma, grants from BeiGene, grants from Checkpoint Therapeutics, grants from Corvus Pharmaceuticals, grants from CytomX, grants and other from Daiichi Sankyo, grants from Dynavax Technologies, grants from Genmab, grants from Genocea Biosciences, grants from Hengrui Therapeutics, grants from Immunocore, grants from Jounce Therapeutics, grants from Kadmon Pharmaceuticals, grants from Loxo Oncology, grants from Lycera, grants from Neovia Oncology, grants from OncoMed Pharmaceuticals, grants from Regeneron Pharmaceuticals, grants from Shattuck Labs, grants from Stem CentRx, grants from Syndax Pharmaceuticals, grants from Takeda Pharmaceuticals, grants from Tarveda, grants from University of Michigan, grants and other from WindMIL Therapeutics, grants from TCR2 Therapeutics, grants from Arcus Biosciences, grants and other from Ribon Therapeutics, grants from Seven and Eight Biopharmaceuticals, other from Bristol-Myers Squibb, personal fees from Astellas, personal fees from Otsuka, grants from BerGenBio, grants from Foundation Medicine, other from G1 Therapeutics, grants from Tmunity Therapeutics. NBL reports grants and personal fees for CME lectures from MSD and BMS. CML reports other from Cepheid, other from Syros, other from Foundation Medicine, other from Novartis, other from Astra Zeneca, other from Takeda, other from Amgen, other from Blueprints Medicine, other from Genentech, other from Eli Lilly/Loxo, other from Pfizer, other from Roche, other from Achilles, from null, outside the submitted work. TM reports personal fees from AbbVie, Inc., personal fees and other from ACEA Pharma, personal fees and other from Alpha Biopharma Co. Ltd., personal fees and other from Amgen, personal fees and other from Amoy Diagnostics Co. Ltd., grants, personal fees and other from AstraZeneca, personal fees and other from BeiGene, personal fees and other from Boehringer Ingelheim, grants, personal fees and other from Bristol-Myers Squibb, personal fees and other from Blueprint Medicines Corporation, personal fees and other from CStone Pharmaceuticals, personal fees and other from Daiichi Sankyo, personal fees and other from Eisai, personal fees and other from Fishawack Facilitate Ltd., other from geneDecode, personal fees and other from Gritstone Oncology Inc., personal fees and other from Guardant Health, personal fees and other from Hengrui Therapeutics, personal fees and other from Ignyta Inc., personal fees and other from IQVIA, personal fees and other from Incyte Corporation, personal fees from InMed Medical Communication, personal fees and other from Janssen, personal fees and other from Lilly, personal fees and other from Loxo-Oncology, personal fees and other from Lunit, Inc., personal fees from MD Health (Brazil), personal fees from Medscape/WebMD, grants, personal fees and other from Merck Serono, grants, personal fees and other from Merck Sharp & Dohme, personal fees and other from Mirati Therapeutics Inc., personal fees from MoreHealth, grants, personal fees and other from Novartis, personal fees and other from OrigiMed, personal fees from PeerVoice, personal fees from Physicians' Education Resource, personal fees from P. Permanyer SL, grants, personal fees and other from Pfizer, Inc, personal fees from prIME Oncology, personal fees and other from Puma Technology Inc, personal fees from Research to Practice, grants, personal fees and other from Roche, personal fees and other from Sanofi-Aventis R&D, personal fees and other from Takeda, personal fees from Touch Medical Media, other from Virtus Medical Group, personal fees and other from Yuhan Corporation, other from AstraZeneca PLC, other from Hutchison Chi-Med, other from Sanomics Ltd., grants from Clovis Oncology, grants from SFJ Pharmaceuticals, grants from XCovery, outside the submitted work. MP reports grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from AstraZeneca, personal fees from ELI LILLY, personal fees and non-financial support from Pfizer, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from B Bristol Myers Squibb, personal fees and non-financial support from Merck Sharp & Dohme, personal fees from Novartis, grants and personal fees from Takeda, personal fees and non-financial support from Chugai, personal fees from Amgen, personal fees from Illumina, personal fees from Gritstone, outside the submitted work. MR reports personal fees from Amgen, personal fees from AstraZeneca, personal fees from BMS, personal fees from Boehringer-Ingelheim, personal fees from Lilly, personal fees from Merck, personal fees from MSD, personal fees from Mirati, personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from Samsung, outside the submitted work. BS reports personal fees from Roche/Genentech, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Amgen, personal fees from Eli Lilly, personal fees from Loxo Oncology, personal fees from Merck, personal fees from Bristol Myers Squibb, personal fees from PharmaMar, personal fees from Pfizer, outside the submitted work. J-CS reports other from AstraZeneca, other from AstraZeneca, during the conduct of the study; other from Gritstone Oncology, other from Daiichi Sankyo, other from Relay Therapeutics, outside the submitted work. DSWT reports grants and personal fees from Novartis, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Celgene, grants and personal fees from Astra Zeneca, personal fees from Eli Lilly, personal fees from LOXO, personal fees from Merck, grants and personal fees from Pfizer, personal fees from Roche, personal fees from Takeda, grants from GlaxoSmithKline, personal fees from Merrimack, outside the submitted work. SP reports personal fees from AbbVie, personal fees from Amgen, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Biocartis, personal fees from Boehringer-Ingelheim, personal fees from Bistrol-Myers Squibb, personal fees from Clovis, personal fees from Daiichi Sankyo, personal fees from Debiopharm, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Foundation Medicine, personal fees from Illumina, personal fees from Janssen, personal fees from Merck Sharp and Dohme, personal fees from Merck Serono, personal fees from Merrimack, personal fees from Novartis, personal fees from Pharma Mar, personal fees from Pfizer, personal fees from Regeneron, personal fees from Sanofi, personal fees from Seattle Genetics and Takeda, personal fees from AstraZeneca, personal fees from Boehringer-Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Eli Lilly, personal fees from F. Hoffmann-La Roche, personal fees from Merck Sharp and Dohme, personal fees from Novartis, personal fees from Pfizer, personal fees from Takeda, non-financial support from Sponsored by Amgen, non-financial support from AstraZeneca, non-financial support from Boehringer-Ingelheim, non-financial support from Bristol-Meyers Squibb, non-financial support from Clovis, non-financial support from F. Hoffmann-La Roche, non-financial support from Illumina, non-financial support from Merck Sharp and Dohme, non-financial support from Merck Serono, non-financial support from Novartis, non-financial support from Pfizer, non-financial support from Sanofi, personal fees from Bioinvent, outside the submitted work. All fees to institution. MDH reports personal fees from Merck, personal fees from Genentech/Roche, grants, personal fees and non-financial support from BMS, personal fees and non-financial support from AstraZeneca, personal fees from Mirati, personal fees from Syndax, personal fees and other from Shattuck Labs, personal fees from Nektar, personal fees and other from Immunai, personal fees and other from Arcus, from Eli Lilly, during the conduct of the study; In addition, Dr. Hellmann has a patent A patent filed by Memorial Sloan Kettering related to the use of tumor mutational burden to predict response to immunotherapy (PCT/US2015/062208) licensed to PGDx., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Cisplatin-based chemotherapy administered concurrently to thoracic radiation therapy is the recommended treatment for fit patients with unresectable stage III NSCLC. The aim of this study was to describe patient profiles and clinical outcomes for the different treatment strategies in a real-word setting., Methods: The epidemio-strategy and medical economics (ESME) database for advanced and metastatic lung cancer is a French, national, multicenter, observational cohort. Out of 8514 Patients, 822 patients with unresectable locally advanced NSCLC in 2015-016 were selected (mean age, 65.3 years; male gender, 69%; performance status 0-1, 77%; smokers or former smokers, 89%)., Results: Treatment was initiated for 736 (90%) of patients (concurrent chemoradiotherapy, n = 283; sequential chemoradiotherapy, n = 121; chemotherapy alone, n = 194; radiotherapy alone, n = 121; targeted therapy alone, n = 8; other, n = 9). Compared to the other treatment strategy groups, patients with radiotherapy alone appeared the most fragile (e.g. higher age, lower body weight or higher frequency of chronic obstructive pulmonary disease). OS rates at 12 and 24 months were 79.5% (95% CI, 73.4-84.3) and 55.3% (95% CI, 44.9-64.5) for concurrent chemoradiotherapy, and 64.3% (95% CI, 52.8-73.8) and 53.2 (95% CI, 33.2-69.6) for sequential chemoradiotherapy., Conclusions: Real-world evidence shows that concurrent chemoradiotherapy is administered to the most fit patients with non resectable locally-advanced NSCLC. Clinical outcomes are actually higher than those reported in landmark clinical trials, which suggests that an optimized and individualized selection of patients allows for prolonged survival. Long-term outcomes are similar after sequential or concurrent chemoradiotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The limited knowledge on the molecular profile of patients with BRAF -mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF -mutant NSCLC., Experimental Design: This was a prospective study of 78 patients with advanced BRAF -mutant NSCLC, enrolled in 27 centers across France. Blood samples ( n = 208) were collected from BRAF-TT-naïve patients ( n = 47), patients nonprogressive under treatment ( n = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA., Results: BRAF V600E ctDNA was detected in 74% of BRAF-TT-naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF -mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1 , and CTNNB1 ., Conclusions: ctDNA sequencing is clinically relevant for the detection of BRAF -activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF -mutant NSCLC., (©2020 American Association for Cancer Research.)

Aim: To estimate the cost-effectiveness of atezolizumab compared with docetaxel and nivolumab for the treatment of advanced non-small cell lung cancer (NSCLC), as a second-line treatment, in a French setting. Materials and methods: A three-state partitioned-survival model was developed (progression-free survival, post-progression survival, death) based on the phase IIIOAK trial on a 10-year time horizon. The comparison between nivolumab and atezolizumab came from a network meta-analysis. Utilities were estimated from the OAK trial EQ-5D applying the French utility tariffs. Overall survival (OS), progression-free survival (PFS), and treatment duration were estimated using parametric models selected using Akaike and Bayesian information criterion. Extrapolation beyond the trial duration followed NICE DSU TSD 14. Economic perspective was the one of all payers, discount rate fixed at 4% on benefits and costs. This analysis was aligned with French Haute Autorité de Santé recommendations. Results were expressed in total cost (2019) and €/QALY (Quality Adjusted Life Year). Model robustness was checked through sensitivity analyses, and a probabilistic sensitivity analysis was conducted. Results: In comparison to docetaxel, atezolizumab costs 49,429€ more and increased life expectancy by 8 months, generating 0.47 QALY. Incremental cost-effectiveness ratio was estimated at 104,835€/QALY. When comparing nivolumab to atezolizumab, a cost minimization analysis was conducted since no clear evidence supporting a difference in terms of survival benefit was reported. Using list price, and the Market Access Authorization regimens, atezolizumab saved approximately 6,000€, 9.5% of its total costs. Sensitivity analyses confirmed the robustness of our findings. Conclusion: Atezolizumab is more efficient and more costly than docetaxel in the second-line treatment of NSCLC of stage IIIB or IV, in France, with results consistent to previous French authorities' evaluation of immunotherapies in similar indication. Lastly, atezolizumab is a cost saving alternative to nivolumab, based on list price.

Objectives: Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib., Materials and Methods: This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS)., Results: 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors (mainly crizotinib then ceritinib). At brigatinib initiation, 59.1% had performance status 0-1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (95% CI, 0.06-20.7) months. Median PFS was 6.6 (4.8-9.9) months for the entire population. For patients who received 2, 3-4 and >4 lines of treatment before brigatinib, PFS was 4.3 (2.5-8.9), 10.4 (5.9-13.9) and 3.8 (0.8-7.4) months, respectively. In the 91 evaluable patients, disease control rate was 78.2%. From brigatinib start, median overall survival was 17.2 (11.0-not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Median OS from the diagnosis of NSCLC was 75.3 (38.2-174.6) months., Conclusion: These real-world results confirm the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC)., Methods: We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types., Results: In prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures., Conclusion: CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.

Non-small-cell lung cancer (NSCLC) patients inevitably progress to first-line therapy and further active treatments are warranted. In the past few years, new second-line therapies, beyond chemotherapy agents, have become available in clinical practice. To date, several options for the second-line treatment of non-oncogene-addicted NSCLC patients ranging from chemotherapy in combination with antivascular endothelial growth factor receptor to immunotherapeutics are available. In oncogene-driven tumors, the better knowledge of mechanisms of acquired resistance to earlier tyrosine kinase inhibitors is leading to novel active inhibitors now available/in development. The second-line algorithm treatment of NSCLC becomes very intricate and the selection of proper patients with one of the new available therapeutic options is of paramount importance to personalize and optimize the treatment. In this review we discuss the second-line treatment opportunities of addicted as well as not-addicted NSCLC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib were compared in the multicenter, international, randomized, head-to-head phase 2b LUX-Lung 7 trial for first-line treatment of advanced EGFR mutation-positive NSCLCs. Afatinib and gefitinib costs and patients' outcomes in France were assessed., Methods: A partitioned survival model was designed to assess the cost-effectiveness of afatinib versus gefitinib for EGFR mutation-positive NSCLCs. Outcomes and safety were taken primarily from the LUX-Lung 7 trial. Resource use and utilities were derived from that trial, an expert-panel questionnaire, and published literature, limiting expenditures to direct costs. Incremental cost-effectiveness ratios (ICERs) were calculated over a 10-year time horizon for the entire population, and EGFR exon 19 deletion or exon 21 L858R mutation (L858R) subgroups. Deterministic and probabilistic sensitivity analyses were conducted., Results: For all EGFR mutation-positive NSCLCs, the afatinib-versus-gefitinib ICER of was €45,211 per quality-adjusted life-year (QALY) (0.170 QALY gain for an incremental cost of €7697). ICERs for EGFR exon 19 deletion and L858R populations were €38,970 and €52,518, respectively. Afatinib had 100% probability to be cost-effective at a willingness-to-pay threshold of €70,000/QALY for patients with common EGFR mutations., Conclusion: First-line afatinib appears cost-effective compared with gefitinib for patients with EGFR mutation-positive NSCLCs., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: In approximately 60% of patients with NSCLC who are receiving EGFR tyrosine kinase inhibitors, resistance develops through the acquisition of EGFR T790M mutation. We aimed to demonstrate that a highly sensitive and quantitative next-generation sequencing analysis of EGFR mutations from urine and plasma specimens is feasible., Methods: Short footprint mutation enrichment next-generation sequencing assays were used to interrogate EGFR activating mutations and the T790M resistance mutation in urine or plasma specimens from patients enrolled in TIGER-X (NCT01526928), a phase 1/2 clinical study of rociletinib in previously treated patients with EGFR mutant-positive advanced NSCLC., Results: Of 63 patients, 60 had evaluable tissue specimens. When the tissue result was used as a reference, the sensitivity of EGFR mutation detection in urine was 72% (34 of 47 specimens) for T790M, 75% (12 of 16) for L858R, and 67% (28 of 42) for exon 19 deletions. With specimens that met a recommended volume of 90 to 100 mL, the sensitivity was 93% (13 of 14 specimens) for T790M, 80% (four of five) for L858R, and 83% (10 of 12) for exon 19 deletions. A comparable sensitivity of EGFR mutation detection was observed in plasma: 93% (38 of 41 specimens) for T790M, 100% (17 of 17) for L858R, and 87% (34 of 39) for exon 19 deletions. Together, urine and plasma testing identified 12 additional T790M-positive cases that were either undetectable or inadequate by tissue test. In nine patients monitored while receiving treatment with rociletinib, a rapid decrease in urine T790M levels was observed by day 21., Conclusions: DNA derived from NSCLC tumors can be detected with high sensitivity in urine and plasma, enabling diagnostic detection and monitoring of therapeutic response from these noninvasive "liquid biopsy" samples., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Angiogenesis, one of the hallmarks of cancer, occurs when new blood vessels feed malignant cells, providing oxygen and nutrients, promoting tumor growth, and allowing tumor cells to escape into the circulation, thus leading to metastases. To date, a series of antiangiogenic drugs (either monoclonal antibodies or small molecules) have been approved by regulatory agencies for the treatment of advanced non-small cell lung cancer, and they are currently available for both first- and second-line therapy. The overall benefit of these drugs seems modest (although clearly significant), especially when administered as a single agent, and there is no clear consensus with regard to which patients should be candidates to receive these drugs across the different disease settings. From the biological perspective, angiogenesis represents a difficult and complex process to explore, given the interference with other key pathways and the dynamic evolution during the disease's history. Indeed, this process is complicated by the presence of multiple targets to hit, polymorphisms, hypoxia-dependent modifications, and epigenetics. These difficulties do not allow capture of which specific key pathways can be identified as biomarkers of efficacy so as to maximize to overall benefit of such drugs. An International Experts Panel Meeting was inspired by the absence of clear recommendations to address which patients should receive antiangiogenic drugs in the context of advanced non-small cell lung cancer so as to support decisions for clinical practice on a daily basis and determine priorities for future research. After a literature review and panelists consensus, a series of recommendations were defined to support decisions for the daily clinical practice and to indicate a potential road map for translational research., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Retrospective studies suggested a benefit of first-line tyrosine kinase inhibitor (TKI) treatment continuation after response evaluation in solid tumors (RECIST) progression in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. The aim of this multicenter observational retrospective study was to assess the frequency of this practice and its impact on overall survival (OS). The analysis included advanced EGFR-mutated NSCLC patients treated with first-line TKI who experienced RECIST progression between June 2010 and July 2012. Among the 123 patients included (67 ± 12.7 years, women: 69 %, non smokers: 68 %, PS 0-1: 87 %), 40.6 % continued TKI therapy after RECIST progression. There was no difference between the patients who did and did not continue TKI therapy with respect to progression-free survival (PFS1: 10.5 versus 9.5 months, p = 0.4). Overall survival (OS) showed a non-significant trend in favor of continuing TKI therapy (33.0 vs. 21.2 months, p = 0.054). Progressions were significantly less symptomatic in the TKI continuation group than in the discontinuation group (18 % vs. 37 %, p < 0.01). Univariate analysis showed a higher risk of death among patients with PS >1 (HR 4.33, 95 %CI: 2.21-8.47, p = 0.001), >1 one metastatic site (HR 1.96, 95 %CI: 1.06-3.61, p = 0.02), brain metastasis (HR 1.75, 95 %CI: 1.08-2.84, p = 0.02) at diagnosis, and a trend towards a higher risk of death in cases of TKI discontinuation after progression (HR 1.62, 95 %CI: 0.98-2.67, p = 0.056 ). In multivariate analysis only PS >1 (HR 6.27, 95 %CI: 2.97-13.25, p = 0.00001) and >1 metastatic site (HR 2.54, 95 %CI: 1.24-5.21, p = 0.02) at diagnosis remained significant. This study suggests that under certain circumstances, first-line TKI treatment continuation after RECIST progression is an acceptable option in EGFR-mutated NSCLC patients., Clinical Trial Information: NCT02293733.

Background: Response Evaluation Criteria in Solid Tumors (RECIST) are widely used to assess the effect of chemotherapy in patients with cancer. We hypothesised that the change in unidimensional tumour size handled as a continuous variable was more reliable than RECIST in predicting overall survival (OS)., Methods: The prospective Pharmacogenoscan study enrolled consecutive patients with non-small-cell lung cancer (NSCLC) at any stage seen between 2005 and 2010 at six hospitals in France, given chemotherapy. After exclusion of patients without RECIST or continuous-scale tumour size data and of those with early death, 464 patients were left for the survival analyses. Cox models were built to assess relationships between RECIST 1.1 categories or change in continuous-scale tumour size and OS. The best model was defined as the model minimising the Akaike Information Criterion (AIC)., Results: OS was 14.2 months (IQR, 7.3-28.9 months). According to RECIST 1.1, 146 (31%) patients had a partial or complete response, 245 (53%) stable disease, and 73 (16%) disease progression. RECIST 1.1 predicted better OS than continuous-scale tumour in early (<6 months) predicted survival analyses (p = 0.03) but the accuracy of the two response evaluation methods was similar in late (≥6 months) predicted survival analyses (p = 0.15)., Conclusion: In this large observational study, change in continuous-scale tumour size did not perform better than RECIST 1.1 in predicting survival of patients given chemotherapy to treat NSCLC., Trial Registration: NCT00222404.

Objectives: Platinum-based chemotherapy regimens are the standard treatment of non-small cell lung cancer (NSCLC). In this study, our objective was to identify tumor tissue protein biomarkers that might predict a benefit from these treatments., Materials and Methods: The Pharmacogenoscan study prospectively included consecutive chemotherapy-naive NSCLC patients at any stage between 2005 and 2010 at six hospitals in the Rhône-Alpes-Auvergne region of France. Of the 537 patients in the full analysis set, 460 had a complete histological diagnosis. We used the tumor tissue samples for an immunohistochemical evaluation of eight biomarkers: ERCC1, BRCA1, p53, p27kip1, class III β-tubulin (TUBB3), Bax, Fas, and FasL. We looked for associations between these biomarkers and the disease control rate (DCR) after 2/3 cycles of platinum-based chemotherapy, progression-free survival (PFS), and overall survival (OS)., Results: A tissue sample adequate for testing at least one biomarker was available for 289 patients. We found no significant association between biomarker expression levels and clinical or pathological variables; TUBB3 showed a trend toward higher expression in adenocarcinomas (P=0.005). For none of the biomarkers were significant associations found between expression level and DCR, PFS, or OS. TUBB3-negative and FasL-negative tumors showed associations of borderline significance with higher DCR., Conclusion: In a large cohort of patients with predominantly advanced or metastatic NSCLC, none of eight tested immunohistochemical biomarkers predicted the chemotherapy response or survival. Our data indicate limited usefulness of protein biomarkers in metastatic NSCLC and a need for further research based on molecular signatures of greater complexity., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

This article describes the treatment rationale and study-related procedures for the A Randomized, Double-Blind, Phase 3 Study of Docetaxel and Ramucirumab Versus Docetaxel and Placebo in the Treatment of Stage IV Non-Small-Cell Lung Cancer Following Disease Progression after One Prior Platinum-Based Therapy (REVEL) study (I4T-MC-JVBA; ClinicalTrials.govNCT01168973). This international, randomized, placebo-controlled, double-blinded phase III trial examines the efficacy and safety of ramucirumab treatment administered in combination with docetaxel, as compared with docetaxel administered with placebo, in patients with stage IV non-small-cell lung cancer (NSCLC) whose disease progressed during or after first-line platinum-based chemotherapy with or without maintenance treatment. The primary end point is overall survival; secondary end points include progression-free survival, objective response rate, disease control rate, patient-reported outcomes, and assessment of safety and tolerability of ramucirumab. Eligible patients (enrollment N = 1242) are randomized at a 1:1 ratio to receive either docetaxel (75 mg/m(2)) plus ramucirumab (10 mg/kg) (Arm A) or docetaxel (75 mg/m(2)) plus placebo (Arm B). Both drugs are administered via intravenous infusion once every 3 weeks until evidence of disease progression, unacceptable toxicity, noncompliance, or patient's consent withdrawal. Efficacy and safety will be compared between the study arms and in patient subgroups including patients with nonsquamous versus squamous tumor histology and patients who received prior bevacizumab treatment. Multiple blood and tumor tissue biomarker samples are collected during the study. The goal of the REVEL study is to demonstrate that ramucirumab in combination with docetaxel improves overall survival of patients with NSCLC with progressive disease after first-line therapy, and to advance our knowledge of the role of angiogenesis blockade in patients with NSCLC by identifying patients who are likely to experience maximum benefit based on extensive clinical biomarker correlative analysis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: The aim of this study was to describe the characteristics and epidermal growth factor receptor (EGFR) mutational status of patients with non-small cell lung cancer (NSCLC) with osteoblastic reactions diagnosed before or during treatment with EGFR tyrosine kinase inhibitors (TKIs)., Methods: Retrospective study including patients with 36 NSCLC with at least one site of osteoblastic reaction at the time of diagnosis or during treatment with EGFR-TKI., Results: The rate of patients with mutated EGFR tumors with osteoblastic reactions before or after EGFR-TKI treatment was similar. Median progression-free survival (PFS) for the entire group was more than 9 months and median survival was more than 12 months. There was no statistically significant difference in survival between patients with osteoblastic reactions before initiation of TKI and those diagnosed during TKI treatment. Patients with extraosseous metastases when treated with TKI had the lowest survival (P < 0.0001)., Conclusions: In patients with NSCLC treated with TKI, initial or development of an osteoblastic reaction seems to be related to a more favorable outcome. In patients with osteoblastic reactions, tumors present with clinical and biologic characteristics of better survival and response to TKI. The occurrence of osteoblastic reactions during treatment with TKI, while primary tumor and metastases are stable or in response, should not be considered as disease progression.

Background: The Lung Cancer Cetuximab Study is an open-label, randomized phase II pilot study of cisplatin and vinorelbine combined with the epidermal growth factor receptor (EGFR)-targeted monoclonal antibody cetuximab versus cisplatin and vinorelbine alone, in patients with advanced EGFR-expressing, non-small-cell lung cancer (NSCLC). End points of the study are activity, safety and pharmacokinetics., Patients and Methods: Following randomization, for a maximum of eight cycles, patients received three-weekly cycles of cisplatin (80 mg/m(2), day 1) and vinorelbine (25 mg/m(2) on days 1 and 8) alone or following cetuximab treatment (initial dose 400 mg/m(2), followed by 250 mg/m(2) weekly thereafter)., Results: Eighty-six patients were randomly allocated to the study (43 per arm). Confirmed response rates were 28% in the cisplatin/vinorelbine arm (A) and 35% in the cetuximab plus cisplatin/vinorelbine arm (B). Median progression-free survival (PFS) was 4.6 months in arm A and 5.0 months in arm B, with PFS rates at 12 months of 0% and 15%, respectively. Median survival was 7.3 months in arm A and 8.3 months in arm B. The 24-month survival rates were 0% and 16%, respectively. The cetuximab combination was well tolerated., Conclusion: In the first-line treatment of advanced NSCLC, the combination of cetuximab plus cisplatin/vinorelbine demonstrated an acceptable safety profile and the potential to improve activity over cisplatin/vinorelbine alone.

Unlabelled: The aim of this study was to determine the impact of patient selection based on age, comorbidity and performance status on the efficacy of platinum-free combination therapy on non-small-cell lung cancer after 65 years of age. We analyzed the overall response rate, the median survival time, the 1-year survival rate, toxicity and quality of life after one to three 6-week cycles of docetaxel 30mg/m(2) weekly and gemcitabine 900mg/m(2) at weeks 1, 2, 4 and 5. Fifty patients (median age 73.7 years) were eligible. The mean number of comorbid conditions per patient was 0.8 [Balducci L. Lung cancer and aging. ASCO 2005. Educational book. p. 587-91; Piquet J, Blanchon F, Grivaux M, et al. Primary bronchial carcinoma in elderly subjects in France. Rev Mal Respir 2003;20:691-9; Jatoi A, Hillman S, Stella P, et al. Should elderly non-small-cell lung cancer patients be offered elderly-specific trials? Results of a pooled analysis from the North Central Cancer Treatment Group. J Clin Oncol 2005;23:9113-9; Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist 2000;5:224-37]. Forty-five patients were assessable: 17 (34%) had an objective response, 18 (36%) had stable disease and 10 progressed (20%). The median survival time was 7 months and the 1-year survival rate 23.5%. The main grade III-IV adverse event was neutropenia (32% of patients)., Conclusion: Platinum-free dual-agent chemotherapy gives similar results in patients over 65, selected on the basis of their precise age and comorbidity, to that reported in younger subjects.

Unlabelled: Few data are available on the economics of target therapy or refractory non-small-cell lung cancer (NSCLC)., Objective: To determine the mean global management costs (MC) per patient treated with gefitinib for NSCLC, and the costs of the different management phases., Method: A Markov approach was used to model treatment costs in a cohort of 106 patients treated with gefitinib as part of a compassionate-use program (third-line treatment) in six public-sector teaching hospitals. The economic analysis adopted the health care payer's perspective, and only direct costs were taken into account., Results: The mean duration of gefitinib treatment was 4.6 +/- 5.8 months (1-29 months); median survival was 4 months, 1-year and 2-year survival rates were 12.3% and 4.7%, respectively. The mean total management cost was 39,979 euros +/- 20,279. The model showed that first- and second-line treatments accounted for respectively 29.5% and 44.1% of this cost, while gefitinib periods represented 10.7%, periods of remission 1.25%, and terminal care 14.5%. A sensitivity analysis showed that the price of gefitinib had little influence on the total cost., Conclusion: The cost of third-line gefitinib therapy for NSCLC appears acceptable from the healthcare payer's perspective, but this needs to be confirmed in dedicated cost-effectiveness studies.

Background: Brain metastases (BM) considerably worsen the prognosis of non-small-cell lung cancer (NSCLC) patients. The usefulness and choice of chemotherapy remain uncertain in this indication since these patients are excluded from most clinical trials. We conducted a phase II study to determine the efficacy and tolerability of up-front chemotherapy with association of temozolomide and cisplatin in NSCLC patients with BM., Patients and Methods: Fifty NSCLC patients with BM received temozolomide (200 mg/m(2)/day for 5 days every 28 days) and cisplatin (75 mg/m(2) at day 1 of each cycle), up to six cycles, followed by whole brain radiotherapy (WBRT). An evaluation was carried out every two cycles and after WBRT. WBRT was performed earlier in case of progressive disease at any time or stable disease after cycle 4., Results: Eight objective responses were achieved (16%). Overall median survival was 5 months. Median time to progression was 2.3 months. Ten patients (20%) presented a grade 3/4 neutropenia and 11 patients (22%) presented a grade 3/4 thrombopenia., Conclusion: This study demonstrates a lack of efficacy of up-front chemotherapy with association of temozolomide and cisplatin in these patients. Nevertheless, it supports the feasibility of chemotherapy before brain radiotherapy in NSCLC patients with BM.

Background: We conducted an economic analysis of a phase III clinical trial comparing sequential radiochemotherapy (RT-CT) with concurrent RT-CT in patients with locally advanced non-small-cell lung cancer., Patients and Methods: The trial was a randomized multicenter study comparing three cycles of chemotherapy (arm A) followed by radiotherapy against an RT-CT combination (two cycles of platinum etoposide) followed by two cycles of platinum-vinorelbine (arm B). The economic analysis adopted the payer's perspective and only included direct costs. Costs (euro, 1996-2003) were recorded until the cut-off date. A cost minimization analysis and a sensitivity analysis were carried out., Results: Data from 173 patients were used in the economic study. Protocol costs tended to be higher in arm B, while relapse costs were significantly higher in arm A. The total number of hospital days was higher in arm B. The average total cost per patient was euro16,074 in arm A and euro15,245 in arm B (P=0.15). The cost minimization analysis favored arm B. This advantage persisted in the sensitivity analysis., Conclusions: Concurrent RT-CT was not the more costly strategy in this phase III trial, despite lengthier hospitalization for toxicity. Other studies of similar design are needed to confirm these results in future randomized trials.

Purpose: To evaluate the efficacy and safety of gemcitabine and carboplatin in the treatment of previously untreated patients with advanced non-small cell lung cancer (NSCLC)., Methods: A randomized phase II study was conducted by the Groupe Français de Pneumo-Cancérologie (GFPC) in 15 centers. The patients were randomized in either arm A (GC): gemcitabine 1250 mg/m2 on days 1 and 8+carboplatin AUC 6 mg/(mLmin) on day 1; or in arm B (VP): vinorelbine 30 mg/m2 weekly+cisplatin 80 mg/m2 on day 1. Treatment cycles were repeated every 3 weeks., Results: A total of 100 patients were randomized with stage IV or stage III NSCLC with malignant pleural effusion: 51 patients in arm A and 49 patients in arm B. A total of 190 cycles were administered in the GC arm and 172 cycles in the VP arm, with a median of four cycles per patient in each arm. The dose intensity was 84.9% for gemcitabine, 99.8% for carboplatin, 97.7% for cisplatin and 67.7% for vinorelbine. The objective response rates were 19.6% (95% CI, 9.8-33.1) for GC and 29.2% (95% CI, 17.0-44.1) for VP in an ITT analysis. The response duration was 169 days in arm A and 226 days in arm B. The TTP was similar with 140 days (GC) and 148 days (VP), respectively. Overall survival rates were 334 days in the GC combination and 304 days in the VP combination. Overall, the treatment was safe and toxicities observed were different in each arm: neutropenia was the most common toxicity in the VP treatment, whereas thrombocytopenia was more frequent in the GC combination. Anemia was similar in both arms. Non-haematologic toxicity was mild. One toxic death in arm A and three toxic deaths in arm B were observed., Conclusion: In terms of response rate, the gemcitabine-carboplatin combination was not efficient enough to allow further phase III study. Survival data are in the same range as the standard arm. This chemotherapy is feasible and may represent an alternative to a standard cisplatin-based regimen, allowing treatment in an outpatient setting.

Purpose: To investigate variations of circulating serum levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNFalpha), and interleukin-10 (IL-10) during three-dimensional conformal radiation therapy (3D-CRT) in patients with non-small-cell lung cancer and correlate these variations with the occurrence of radiation pneumonitis., Patients and Methods: Ninety-six patients receiving 3D-CRT for stage I to III disease were evaluated prospectively. Circulating cytokine levels were determined before, every 2 weeks during, and at the end of treatment. Radiation pneumonitis was evaluated prospectively between 6 and 8 weeks after 3D-CRT. The predictive value of clinical, dosimetric, and biologic (cytokine levels) factors was evaluated both in univariate and multivariate analyses., Results: Forty patients (44%) experienced score 1 or more radiation pneumonitis. No association was found between baseline cytokine levels and the risk of radiation pneumonitis. In the whole population, mean levels of TNFalpha, IL-6, and IL-10 remained stable during radiotherapy. IL-6 levels were significantly higher (P = .047) during 3D-CRT in patients with radiation pneumonitis. In the multivariate analysis, covariations of IL-6 and IL-10 levels during the first 2 weeks of 3D-CRT were evidenced as independently predictive of radiation pneumonitis in this series (P = .011)., Conclusion: Early variations of circulating IL-6 and IL-10 levels during 3D-CRT are significantly associated with the risk of radiation pneumonitis. Variations of circulating IL-6 and IL-10 levels during 3D-CRT may serve as independent predictive factors for this complication.

Background: Approximately 30% of lung cancer cases are diagnosed in patients > 70 years of age. Standard chemotherapy regimens are generally considered too toxic for elderly patients. We conducted a multicenter phase II trial to determine the efficacy and safety of carboplatin combined with vinorelbine every 4 weeks as first-line treatment for advanced non-small-cell lung cancer (NSCLC) in elderly patients., Patients and Methods: Patients were eligible if they were aged >OR= 70 years, had stage IIIB (with pleural effusion) or stage IV NSCLC, had a performance status of 0/1, had not previously received chemotherapy, and had normal organ function. Forty patients (31 men and 9 women) were enrolled and received 3-5 courses of treatment. Median age was 72 years (range, 70-82 years). Eighty percent of patients had stage IV NSCLC, with squamous cell (n=21), adenocarcinoma (n=12), and undifferentiated (n=7) histologies., Results: Forty patients were assessable for toxicity and 32 for treatment response. Among these 32 patients, 8 had a partial response (intent-to-treat response rate, 20%), and 10 (25%) had stable disease. The median survival was 7.8 months (range, 4-11.6 months). The 1- and 2-year survival rates were 25% and 7%, respectively; median time to progression was 4.3 months (range, 0.2-13.8 months). Grade 3/4 neutropenia was seen in 27 patients (68%), and grade 3/4 anemia was seen in 5 patients (13%). One patient died of febrile neutropenia during treatment. The main nonhematologic adverse effect was fatigue (grade 3/4 in 18% of patients)., Conclusion: Carboplatin/vinorelbine is well tolerated by elderly patients with extensive-stage NSCLC. Efficacy is low but similar to that of other treatments used in this setting.

This study determined the prevalence and the prognostic value of the expression of microtubule components in tumors of 19 patients with non small cell lung cancer receiving taxane-based regimens. Patient samples were stained with antibodies directed against total beta tubulin, classes I, II and III beta tubulin isotypes, delta2 alpha tubulin, tau protein, and the P-gp protein involved in the classical multidrug resistance phenotype. All tumors were stained with pan-beta tubulin antibody and class I tubulin isotype. A majority of the tumor samples expressed class II and class III, although the percentage of positive cells varied significantly between tumors. delta2 alpha tubulin, tau protein and Pgp protein were found in only one tumor sample each. Progression-free survival was shorter (41 days) in patients whose tumors expressed high levels of class III tubulin isotype in comparison to patients with low levels (288 days, p = 0.02). There were 2 responses to chemotherapy among 9 patients (22%) with high levels of class III tubulin vs. 6 among 10 patients (60%) with low levels of expression (Fisher exact test: p = 0.11). These data suggest that high expression of class III tubulin by tumor cells is associated with poor prognosis in patients with NSCLC receiving a taxane-based regimen.

Purpose: Radiation pneumonitis is the restricting complication following lung cancer irradiation. The correlation between dose-volume histograms (DVHs) and pneumonitis, with a clinical, radiological, and respiratory function evaluation was assessed. Special endpoint was the evaluation of respiratory function after three-dimensional conformal radiotherapy (3D-CRT)., Methods and Materials: Fifty-four patients with non metastatic non-small-cell lung cancer (NSCLC) were treated with a curative intent with 3D-CRT (66 Gy). Thirty-one patients were treated postoperatively (pneumonectomy in 9 patients) for residual tumor or massive nodal involvement (N2 or N3); 23 patients were treated with exclusive radiotherapy. Clinical evaluation, CT scan, and pulmonary functional tests were performed before and 6 weeks after irradiation. The DVHs were calculated applying lung density heterogeneity., Results: Twenty patients had radiation pneumonitis. Irradiation significantly decreased total lung capacity. Volume of the PTV2 (more than 200 cm(3)) was a significant prognostic factor for lung complication., Conclusion: DVHs combined with initial pulmonary functional tests can predict pulmonary toxicity and could allow us to adjust volume that received total highest dose with acceptable toxicity.

Study Objectives: compare the costs of two regimens of chemotherapy. Apply weighted costs to an economic model in a hospital perspective., Design: prospective randomized study of two groups of patients receiving: branch B, mitomycin-navelbine-cisplatin (MNP); branch A, mitomycin-vindesine-cisplatin (MVP)., Setting: pneumologic units of University and non-University hospitals., Methods: clinical evaluation during chemotherapy incorporated events enabling construction of an event tree. Direct hospital costs included those of: cytostatic agents, materials used and nursing time; costs of side-effects (medical and paramedical time, diagnostic and therapeutic examinations). Effectiveness was measured in terms of response rates., Patients: 209 patients were included, 100 in arm B, 109 in arm A., Results: the response rates were 25% in branch B, 17% in branch A. In the hypothesis of equivalence of the two strategies, we compared only overall mean cost per patient. Despite the fact arm B needed more hospital injections, the difference was low (+4.6%). For a difference in effectiveness, the opposite was observed for the average cost-effectiveness ratio: arm B was less costly (-12 339.40 FF for a responder)., Conclusion: incorporation of economic parameters was found to have a bearing on the choice of chemotherapeutic regimen for the treatment of non-small cell lung cancer. Economic analyses of this kind can provide useful extra information for rational therapeutic decisions.

Collaborative phase I and II studies of the combination of gemcitabine and cisplatin in patients with advanced non-small cell lung cancer are ongoing at five centres in the UK and France. In the initial completed phase I study, 16 patients (15 evaluable) have been entered using a fixed dose of gemcitabine 1000 mg/m2 given as a 30 min intravenous infusion weekly for 3 weeks. On the third week the gemcitabine was immediately followed by cisplatin with pre- and post-hydration. This regimen required only 1 night of hospitalization every 4 weeks. The study design was for sequential groups of patients to receive 3 dose levels of cisplatin (60 mg/m2, 75 mg/m2 and 100 mg/m2) but these doses would be modified and the number of patients at any dose level could be increased if significant toxicity was observed. Three patients were to be entered at the first two dose levels and 10 patients were to confirm the maximum tolerated dose (if reached) or expand the database on toxicity at the final predetermined dose level. The major haematological toxicities were neutropenia (grade 4 in 3 patients) and thrombocytopenia (grade 3 or 4 in 5 patients) but both were of short duration and uncomplicated. Grade 3 nausea and vomiting occurred in 12 patients but was no worse than would be expected from cisplatin alone. Alopecia was not a problem (no hair loss in 10 patients and grade 1 or 2 in 6 patients) and no significant renal or neurotoxicity was seen. A phase II study using cisplatin 100 mg/m2 in combination with gemcitabine 1000 mg/m2 has been opened and to date 19 patients are evaluable for response. Eight (42%) have achieved partial remissions. The study is ongoing and will recruit 50 evaluable patients.

The efficacy of the association of cisplatinum-mitomycine and vindesine on inoperable non-small cell bronchial cancer has been assessed in a prospective study. Cisplatinum 120 mg/m2 and mitomycine 8 mg/m2 on day 1, day 28 and day 70, and vindesine 3 mg/m2 once per week for the first cycle, once every 15 days for the second and third cycles. 98 patients were included in the study between February 1989 and June 1990: there were 89 men and 9 women with a mean age of 60. There were 57 epidermoid cancers, 22 adenocarcinomas, 1 neuroendocrine carcinoma and 18 large cell cancers. There was an objective response (RO) in 25% (of whom 5% had a complete response) without any significant difference between the 56 cancers at stage III (32% RO) and 42 cancers in stage IV (17% RO). The median survival of the responders was 14 months again 5 months for the non-responders. The initial loss of weight seemed to be a prognostic factor because the number of objective responders was significantly greater in the patients with only a small weight loss: 37% of RO if the weight loss was less than 5%, against 11% for a weight loss of greater than 5%. The myelotoxicity of this association was important because 85% of those patients presented with a leucopenia at least grade II OMS. Peripheral neuropathies occurred in 27% of cases: 4 cases of cardiotoxicity were reported.