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Background: Perioperative immunotherapy improves short-term outcomes in resectable non-small-cell lung cancer (NSCLC). We now report 5-year survival from the NADIM trial to assess its long-term benefit., Methods: NADIM was a multicentre, single-arm, phase 2 trial conducted across 18 hospitals in Spain. Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had histologically or cytologically confirmed, treatment-naive, resectable stage IIIA NSCLC (American Joint Committee on Cancer, 7th edition criteria). The neoadjuvant treatment consisted of three cycles of intravenous paclitaxel (200 mg/m 2 ) and carboplatin (area under the curve 6 mg/mL per min) with nivolumab (360 mg). After surgery, 1 year of adjuvant treatment with intravenous nivolumab monotherapy was administered (240 mg every 2 weeks for 4 months, followed by 480 mg every 4 weeks for 8 months). The primary endpoint was 24-month progression-free survival, with 5-year progression-free survival and overall survival as secondary endpoints, assessed in the intention-to-treat population (ie, all patients who received neoadjuvant treatment). Toxicity profile was also assessed as a secondary endpoint. This trial is registered at ClinicalTrials.gov (NCT03081689) and is complete; this is the final report of the trial., Findings: Between April 26, 2017, and Aug 25, 2018, 51 patients were assessed for eligibility, of whom 46 comprised the intention-to-treat population (34 [74%] male and 12 [26%] female, median age 63 years [IQR 58-70]). Follow-up was concluded at 60 months (data cutoff July 11, 2023; median follow-up 60·0 months [IQR 60·0-60·0]). 5-year progression-free survival in the intention-to-treat population was 65·0% (95% CI 49·4-76·9), and overall survival was 69·3% (53·7-80·6). Disease progression occurred in 11 (24%) patients; 14 (30%) patients died, including nine (20%) from disease relapse and five (11%) from non-tumour-related causes. Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 14 (30%) of 46 patients during neoadjuvant treatment and in seven (19%) of 37 during adjuvant treatment. The most common grade 3 or worse TRAEs were increased lipase and febrile neutropenia (three [7%] each) during neoadjuvant treatment, and elevated serum lipase (four [7%]) and elevated serum amylase (three [8%]) during adjuvant treatment. Serious TRAEs included elevated serum lipase and neutropenia (one [2%] each) during neoadjuvant treatment, and elevated serum lipase (one [3%]) during adjuvant treatment. No treatment-related surgery delays, deaths, or unexpected long-term toxicities were reported., Interpretation: Perioperative chemoimmunotherapy showed a promising long-term benefit with no concerning safety data, reinforcing its use in resectable stage IIIA NSCLC., Funding: Bristol-Myers Squibb, Spanish Ministry of Science, Instituto de Salud Carlos III, European Union., Competing Interests: Declaration of interests MP reports non-financial support (reagents for T-cell receptor sequencing) from ThermoFisher Scientific; grants, consulting fees, and non-financial support from Bristol Myers Squibb, Roche, and AstraZeneca; and consulting fees from MSD and Takeda; outside the submitted work. EN reports grants from Roche, Pfizer, Bristol Myers Squibb, Merck, and Nanostring; consulting fees from Roche, Bristol Myers Squibb, Merck Sharpe & Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre, Qiagen, and Bayer; payment of honoraria from Roche, Bristol Myers Squibb, Merck Sharpe & Dohme, Sanofi, Pfizer, Lilly, Amgen, Janssen, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, and Qiagen; support for attending meetings or travel from Takeda, MSD, Janssen, and Roche; and participation on advisory boards for Apollomics, Roche, and Pfizer. AI reports consulting fees from Pfizer, Amgen, and Astra Zeneca; payment for expert testimony from Bristol Myers Squibb, Roche, Pfizer, Astra Zeneca, and Takeda; support for attending meetings or travel from Roche, Takeda, and Pfizer; and participation on advisory boards for Roche and Bristol Myers Squibb. RG-C reports consulting fees from Bristol Myers Squibb, MSD, Roche, Pfizer, and AstraZeneca. MD reports consulting fees from AstraZeneca, Bristol Myers Squibb, MSD Oncology, Pfizer, Roche, and Takeda; and support for attending meetings or travel from AstraZeneca, MSD Oncology, Pfizer, and Takeda. BM reports consulting fees from Astra Zeneca and Amgen; payment or honoraria from Roche, Bristol Myers Squibb, and MSD; and support for attending meetings or travel from MSD and AstraZeneca. MM reports grants from Roche and Astra Zeneca; payment of honoraria from Roche, AstraZeneca, MSD, Pfizer, Helsinn, Cassen, Amgen, Janssen, Sanofi, Pierre Fabre, Bristol Myers Squibb, and Takeda; and support for attending meetings or travel from MSD, Roche, and AstraZeneca. DR-A reports honoraria for lectures from MSD, Roche, Bristol Myers Squibb, Novartis, Takeda, Lilly, and AstaZeneca; support for attending meetings or travel from Roche, MSD, Novartis, and Sanofi; and participation on advisory boards for Merck Sharpe & Dohme, Regeneron, Bristol Myers Squibb, GSK, and Lilly. AM-M reports consulting fees from AstraZeneca/MedImmune, Bristol Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, and Janssen; payment for expert testimony from AstraZeneca, MedImmune, Bristol Myers Squibb, and F. Hoffmann La Roche; support for attending meetings or travel from AstraZeneca, MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, Janssen, and Lilly; and participation on advisory boards for AstraZeneca, MedImmune, Merck Sharpe & Dohme, F. Hoffmann La Roche, and Bristol-Myers Squibb. JdC reports consulting fees from AstraZeneca, Bristol Myers Squibb, Roche, MSD, Boehringer, Janssen, Lilly, Sanofi, Takeda, Pfizer, and GSK; support for attending meeting or travel from AstraZeneca, MSD, and Roche; participation on advisory boards for AstraZeneca, Bristol Myers Squibb, Roche, MSD, Glaxo, Janssen, and Gilea; and speaker's bureau fees from AstraZeneca/MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche, Merck Sharpe & Dohme, MSD Oncology, Pfizer, and Janssen. DG reports payment or honoraria from Astra Zeneca and Bristol Myers Squibb. VC reports consulting fees from Roche, AstraZeneca, MSD, Bristol Myers Squibb, Takeda, Sanofi, and Amgen; payment or honoraria from Roche, AstraZeneca, MSD, Bristol Myers Squibb, Takeda, SanofiI, and Amgen; and support for attending meetings or travel from AstraZeneca, Roche, MSD, and Takeda. RP reports payment or honoraria from Guardant Health and Pfizer; and support for attending meetings or travel from Merck Sharpe & Dohme; participation on an advisory board for AstraZeneca. AR reports payment or honoraria from Illumina, Health in Code, and ThermoFisher Scientific; support for attending meetings or travel from ThermoFisher Scientific, Bristol Myers Squibb Foundation, and Takeda; and advisory board participation for Takeda. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction: EGFR tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma through circulating tumor DNA (ctDNA). Circulating tumor DNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection., Methods: This was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced NSCLC with EGFR mutations and on-study PD (RECIST [Response Evaluation Criteria in Solid Tumors]), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD and the first subsequent treatment (FLAURA only)., Results: Circulating tumor DNA PD preceded or co-occurred with RECIST-defined PD in 93 out of 146 patients (64%) in FLAURA and 82 out of 146 patients (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (mo) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, the median time from ctDNA PD to the first subsequent treatment (mo) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70)., Conclusions: Among patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD., Competing Interests: Disclosure Dr. Gray reports participation on the board of directors for IASLC; consulting or advisory fees from AbbVie, AstraZeneca, Blueprint Medicines, Daiichi-Sankyo, EMD Serono, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Novartis, OncoCyte, Spectrum ODAC, Takeda, and Triptych Health Partners; research grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co., Novartis, and Pfizer; employment with Moffitt Cancer Center; holding a leadership role as SWOG Lung Committee Chair and ASCO Education Committee Ex-Chair; and payments/honoraria from AbbVie, AstraZeneca, Blueprint Medicines, Daiichi-Sankyo, EMD Serono, Gilead Sciences, Inc., IDEOlogy Health, Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Novartis, OncoCyte, Spectrum ODAC, Takeda, and Triptych Health Partners. Dr. Markovets reports employment with AstraZeneca. Dr. Reungwetwattana reports honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, Takeda, Yuhan, and Zuellig; and research grants from AstraZeneca, Novartis, Roche, and Yuhan. Dr. Majem reports honoraria from Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Helsinn Therapeutics, Immedica, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, and Takeda; research grants from AstraZeneca, Bristol Myers Squibb, and Roche; and travel support from AstraZeneca, Eli Lilly, Merck Sharp & Dohme, Pfizer and Roche. Dr. Cho reports an advisory role for Bridge Biotherapeutics, Inc., Cyrus Therapeutics, Inc., Guardant Health, Joseah BIO, and KANAPH Therapeutic, Inc.; participation on boards of directors for Gencurix, Inc. and Interpark Bio Convergence Corp.; consulting fees from AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Medpacto, Merck Sharp & Dohme, Novartis, Ono Pharma Co., Ltd., Pfizer, Roche, Takeda, and Yuhan; employment with Yonsei University College of Medicine; being a founder of DAAN Biotherapeutics; grants or funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Champions Oncology, Dizal Pharmaceutical Co., Ltd., Dong-A ST, Eli Lilly, GI Innovation, Interpark Bio Convergence Corp., Janssen, Medpacto, Merck Sharp & Dohme, MOGAM Institute, Novartis, Ono Pharma Co., Ltd., and Yuhan; royalties from Champions Oncology; and stock or stock options with Bridge Biotherapeutics, Inc., Cyrus Therapeutics, Inc., Gencurix, Inc., KANAPH Therapeutic, Inc., Interpark Bio Convergence Corp., and TheraCanVac, Inc. Dr. Chewaskulyong reports honoraria and research grants from AstraZeneca. Dr. John reports consulting fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Gilead Sciences, Inc., Ignyta, Merck Sharp & Dohme, Merck KGaA, Novartis, Pfizer, PharmaMar, Roche/Genentech, and Specialised Therapeutics; honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche/Genentech; and travel support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche. Dr. Sebastian reports participation on an advisory board for Amgen; consulting fees from Amgen, AstraZeneca, Boehringer lngelheim, Bristol Myers Squibb, GSK, Johnson & Johnson, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Roche, and Takeda; grants or contracts from AstraZeneca; honoraria from Amgen, AstraZeneca, BioNTech, Boehringer lngelheim, Bristol Myers Squibb, CureVac, Daiichi-Sankyo, GSK, Johnson & Johnson, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, and Takeda; and travel support from Bristol Myers Squibb and Pfizer. Drs Todd, Rukazenkov, Barrett, and Chmielecki report employment and holding stock or stock options with AstraZeneca. Dr. Ramalingam reports personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, GSK, Merck, Takeda, and Tesaro and other non-financial support from AstraZeneca. Dr. Hartmaier reports being an inventor on patent US11066709B2, and employment and holding stock or stock options with AstraZeneca. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Non-small cell lung cancer (NSCLC) in early-stages (I-IIIA) with epidermal growth factor receptor (EGFR) mutation may have specific epidemiological, clinical characteristics and treatment implications. This review aims to summarise the available evidence on these particularities, especially focusing on patient characteristics, treatment outcomes and safety with EGFR-tyrosine-kinase inhibitor (TKI)., Methods: An exhaustive search of international bibliographic databases, as well as in abstracts of communications from major international congresses was performed for evidence related to EGFR-mutated NSCLC or early-stage NSCLC published in English before December 31st, 2023., Key Content and Findings: Early-stage NSCLC with EGFR mutation presents with a variable incidence depending on geographical aspects. The clinical, radiological and molecular features differ slightly from both early-stage NSCLC without EGFR mutation and advanced NSCLC with EGFR mutation. Adjuvant treatment with the third-generation EGFR-TKI osimertinib has led to improvements in disease-free survival and overall survival (OS) in these patients, representing a practice changing and a new standard of care in clinical practice. No new safety signals have been reported with EGFR-TKI in the adjuvant setting. Clinical trials are ongoing to explore new therapeutic options in the adjuvant and neoadjuvant setting as well as the optimal duration of adjuvant osimertinib., Conclusions: Detection of EGFR mutation in early-stage NSCLC is an important goal due to the different characteristics and additional therapeutic options that improve patient outcomes and follow-up.

Background: In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib's additional impact on quality of life (QOL)., Methods: In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m 2 intravenously every 3 weeks). Validated questionnaires captured patients' perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes., Results: Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients' symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs -8.4 at cycle 1 day 5 and 2.2 vs -5.8 at week 12)., Conclusions: Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC., Competing Interests: Declaration of competing interest David M. Waterhouse received consulting fees from Bristol Myers Squibb (BMS), Amgen, Janssen, Merck, Fresenius Kabi, and Novartis; received honoraria from BMS, AstraZeneca, Amgen, Janssen, EMD Serono, Fresenius Kabi, and Sanofi; received support to attend meetings and/or travel from BMS and Amgen; and participated on a data safety monitoring board or advisory board for BMS, AstraZeneca, AbbVie, Amgen, Janssen, Eisai, EMD Serono, Merck, Pfizer, Fresenius Kabi, Sanofi, Astellas, Gilead, Takeda, Daiichi, and Bayer. Sacha Rothschild received grants or research support from AstraZeneca, Merck Serono, Roche Pharma, and Amgen; received consulting fees from Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly, Janssen, Merck KG, MSD, Novartis, Otsuka, Pfizer, PharmaMar, Roche Pharma, Roche Diagnostics, Sanofi Aventis, and Takeda; received honoraria from Roche Pharma, BMS, AstraZeneca, Amgen, MSD Oncology, Novartis, Roche Diagnostics, and Takeda; received payment for expert testimony from Roche, AstraZeneca, and BMS; received support for attending meetings and/or travel from Roche Pharma, Eli Lilly, BMS, Amgen, AstraZeneca, and MSD; participated on a data safety monitoring board or advisory board for Roche Pharma; and is the vice president of the Swiss Group for Clinical Cancer Research (SAKK) and elected member of the Swiss Federal Drug Commission (Federal Health Office). Christophe Dooms has nothing to disclose. Bertrand Mennecier received honoraria from Amgen, Roche, AstraZeneca, Pharma Mar, Eli Lilly, BMS, MSD, Sanofi, Takeda, and Pfizer; and received support for attending meetings and/or travel from MSD, Roche, BMS, AstraZeneca, and Takeda. Farastuk Bozorgmehr received grant/research support from Roche and AstraZeneca; received honoraria from Novocure, Daiichi Sankyo, GSK, and AstraZeneca, received support for attending meetings and/or travel from Janssen; and participated in a data safety monitoring board or advisory board for Amgen, AstraZeneca, Daiichi Sankyo, and Janssen. Margarita Majem received consulting fees from AstraZeneca, Roche, MSD, Janssen, and Sanofi; received honoraria from MSD, Roche, AstraZeneca, Casen Recordati, Takeda, and Helsinn; received support for attending meetings and/or travel from MSD, Pfizer, Roche, and AstraZeneca, and is the vice president of ICAPEM and a board member of AEC Barcelona. Michel M. van den Heuvel participated on a data safety monitoring board or advisory board for Amgen. Helena Linardou received payment or honoraria for lectures and/or speakers bureaus from Roche, AstraZeneca, Pfizer, BMS, MSD, Novartis, Amgen, and GSK; received support for attending meetings and/or travel from Pfizer and Roche; participated on a data safety monitoring board or advisory board for Roche, AstraZeneca, MSD, BMS, Novartis, Pfizer, and Amgen; and held unpaid positions in non-profit organizations, including president of a scientific committee in the Hellenic Cooperative Oncology Group and board member for Hellenic Foundation of Cancer Research, FairLife Lung Cancer, and W4O-Hellas. Byoung Chul Cho received grant/research support from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GI Innovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Janssen, Lilly, MSD, Novartis, Nuvalent, Oncternal, Ono, Regeneron, Dong-A ST, Bridge Biotherapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph Therapeutics, Therapex, J INTS BIO, Hanmi, CHA Bundang Medical Center, and Vertical Bio AG. Rachel Roberts-Thomson received royalties from Champions Oncology, Crown Bioscience, Imagen, and PearlRiver Bio GmbH; received consulting fees from Abion, BeiGene, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, MedPacto, Blueprint Medicines, RaND Bio, and Hanmi; received honoraria from ASCO, AstraZeneca, Guardant, Roche, ESMO, IASLC, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, and Pfizer; participated on a scientific advisory board for Kanaph Therapeutics, Bridge Biotherapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, and Amgen; was a board member for J INTS BIO; owned stock in TheraCanVac Inc, Gencurix Inc, Bridge Biotherapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., and J INTS BIO; was employed by Yonsei University Health System and is a founder of DAAN Biotherapeutics. Kentaro Tanaka received consulting fees from Pfizer and received honoraria from Chugai Pharmaceutical, AstraZeneca, Eli Lilly, Takeda Pharmaceutical, Novartis, Ono Pharmaceutical, Daiichi Sankyo, Merck, MSD, and BMS. Normand Blais received consulting and speakership fees from Amgen. Gustavo Schvartsman received consulting fees from AstraZeneca, BMS, Merck, Sharp & Dome, and Daiichi Sankyo; received honoraria from Roche, Amgen, Adiu, and Pfizer; and received support for attending meetings and/or travel from Merck, Sharp & Dome and Daiichi Sankyo. Karin Holmskov Hansen participated in clinical trial safety meetings for MSD and Incyte (not paid) and was head of the Danish Oncology Group until February 2023 (not paid) and a member of the Expert Committee under the Danish Medicines Council (not paid). Izabela Chmielewska received consulting honoraria from Amgen; and received speakership fees from Amgen, BMS, Takeda, Roche, and MSD. Martin D. Forster received grant/research support from Cancer Research UK Early Detection Committee Program Grant, Bristol Myers Squibb Research Grant, NIHR RfPB Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, Merck Educational Grant, MSD Educational Grant, Cancer Research UK Science Committee Multidisciplinary Project Award, MRC BMC:DPFS Grant Award, and Boehringer Ingelheim Educational Grant and received consulting fees from Amgen and participated in an Advisory Board for Amgen. Christina Giannopoulou is an employee of Amgen Europe GmbH and holds stock in Amgen. Björn Stollenwerk is an employee of Amgen Europe GmbH and holds stock in Amgen. Cynthia C. Obiozor is an employee of and holds stock in Amgen. Yang Wang is an employee of and holds stock in Amgen.Silvia Novello received honoraria from AstraZeneca, Amgen, Thermo Fisher, MSD, Novartis, Sanofi, Roche, Pfizer, Takeda, and Janssen and participated on a data safety monitoring board or advisory board from Pfizer, AstraZeneca, Sanofi, Jannsen, and Daiichi., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: At the first interim analysis of the KEYNOTE-671 trial, adding perioperative pembrolizumab to neoadjuvant chemotherapy significantly improved event-free survival in participants with early-stage non-small-cell lung cancer (NSCLC). We report overall survival and health-related quality of life outcomes from the second interim analysis., Methods: KEYNOTE-671 was a global phase 3 trial done at 189 medical centres. Eligible participants (aged ≥18 years) with resectable stage II, IIIA, or IIIB (N2) NSCLC were randomly assigned (1:1) to four cycles of neoadjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant pembrolizumab (200 mg administered intravenously every 3 weeks) or to four cycles of neoadjuvant placebo (administered intravenously every 3 weeks) plus cisplatin-based chemotherapy followed by surgery and 13 cycles of adjuvant placebo (administered intravenously every 3 weeks). Randomisation was done centrally using an interactive response technology system and was stratified by disease stage, PD-L1 expression, histology, and geographical region in blocks of four. Participants, investigators, and sponsor personnel were masked to treatment assignments; local pharmacists were unmasked to support treatment preparation. The dual primary endpoints were overall survival and event-free survival evaluated in the intention-to-treat population. This study is registered at ClinicalTrials.gov, NCT03425643, and is ongoing but closed to enrolment., Findings: Between May 11, 2018, and Dec 15, 2021, 797 participants were randomly assigned to the pembrolizumab group (n=397) or the placebo group (n=400). Median study follow-up at the second interim analysis was 36·6 months (IQR 27·6-47·8). 36-month overall survival estimates were 71% (95% CI 66-76) in the pembrolizumab group and 64% (58-69) in the placebo group (hazard ratio 0·72 [95% CI 0·56-0·93]; one-sided p=0·0052; threshold, one-sided p=0·0054). Median event-free survival was 47·2 months (95% CI 32·9 to not reached) in the pembrolizumab group and 18·3 months (14·8-22·1) in the placebo group (hazard ratio 0·59 [95% CI 0·48-0·72]). In the as-treated population, grade 3-5 treatment-related adverse events occurred in 179 (45%) of 396 participants in the pembrolizumab group and in 151 (38%) of 399 participants in the placebo group. Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group and three (1%) participants in the placebo group., Interpretation: The significant overall survival benefit of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab compared with neoadjuvant chemotherapy alone coupled with a manageable safety profile support the use of perioperative pembrolizumab in patients with resectable, early-stage NSCLC., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA., Competing Interests: Declaration of interests JDS, MCG, HW, ML, TK, MT, S-HL, K-NC, CD, MM, EE, GLM, OB, DR-A, JEC, SN, and SG report funding to their institution from Merck Sharp & Dohme (MSD), a subsidiary of Merck & Co, Rahway, NJ, USA to support conduct of this study. JDS, MCG, HW, ML, TK, MT, S-HL, K-NC, CD, MM, EE, GLM, OB, DR-A, JEC, SN, JY, AA, SMK, AS, and SG received medical writing and editorial support for the preparation of this manuscript from MSD. JDS additionally reports receiving grants to the institution from AstraZeneca, MSD, Roche, BMS, CLS Therapeutics, Protalix Biotherapeutics, Pfizer, and Regeneron; receiving consulting fees from AstraZeneca, Merck, Roche, BMS, Novartis, Chemocentryx, Amgen, Protalix Biotherapeutics, Xenetic Biosciences, Regeneron, Eisai, and Pfizer; receiving payment for a speaking role from Peerview, OncLive, and Medscape; receiving support for attending meetings or travel from AstraZeneca, Merck, and BMS; participating on a clinical trial safety monitoring board for AstraZeneca; and receiving equipment, materials, drugs, gifts, or other services via grant to the institution from Roche, MSD, BMS, and AstraZeneca. MCG additionally reports receiving consulting fees from AstraZeneca, Abion, MSD International, Bayer, BMS, Boehringer Ingelheim Italia, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi-Sankyo, Regeneron, Merck & Co, Blueprint, Janssen, Sanofi, AbbVie, BeiGene, Oncohost, Medscape, Gilead, Io Biotech, and Revolution Medicines; receiving payment or honoraria for lectures, presentations, speakers' bureaus, or educational events from AstraZeneca, Merck & Co, Daiichi Sankyo, Gilead, Eli Lilly, and Regeneron; and receiving support for attending meetings or travel from AstraZeneca. HW additionally reports research funding to the institution from Bayer, AstraZeneca, BMS, Genentech/Roche, MSD, Helsinn, SeaGen, and Xcovery; serving as a compensated advisory board member for Mirati, IOBiotech, OncoC4, and BeiGene; serving as an uncompensated advisory board member for MSD, Genentech/Roche, BMS, and AstraZeneca; serving as a past president of the International Association for the Study of Lung Cancer (IASLC); and serving on the executive committee of ECOG-ACRIN. TK additionally reports research grants to the institution from AbbVie, Amgen, Arrivent, AstraZeneca, Bayer, BeiGene, BluePrint, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Gilead, GlaxoSmithKline, Haihe, Janssen, Merck KGaA, MSD, Novartis, Pfizer, Regeneron, and Takeda; receiving honoraria for lectures, presentations, speakers' bureaus, or educational events from Amgen, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Merck KGaA, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda; receiving honoraria for participation on a data safety monitoring board or advisory board from AstraZeneca, BeiGene, Chugai, Daiichi-Sankyo, Janssen, Merck KGaA, MSD, Novartis, and Pfizer; and having a spouse who is an employee of Eli Lilly. MT additionally reports research grants to the institution from MSD, AstraZeneca KK, Bristol-Myers Squibb KK, Ono Pharmaceutical Co, Eli Lilly Japan, Novartis, MiRXES, and Johnson & Johnson Japan; receiving honoraria for lectures from Amgen KK, Johnson & Johnson Japan, Medtronic Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co, Taiho Pharma, Bristol-Myers Squibb KK, Ono Pharmaceutical Co, Novartis, MSD, and Daiichi-Sankyo; serving as a participant on an advisory board for Bristol-Myers Squibb KK, AstraZeneca KK, MSD, Novartis, and MiRXES; and serving as a participant on a data safety monitoring board for Chugai Pharmaceutical Co. S-HL additionally reports research grants to the institution from MSD and receiving honoraria for a lecture from MSD. MM additionally reports receiving honoraria for lectures, presentations, speakers' bureaus, or educational events from MSD, Lilly, Pfizer, AstraZeneca, Roche, Sanofi, Regeneron, BeiGene, Immedica, Novartis, and BMS; and receiving support to attend meetings or travel from MSD, Pfizer, AstraZeneca, and Roche. EE additionally reports receiving payment for expert testimony from MSD. OB additionally reports support for attending meetings or travel from MSD for ASCO 2023 and from AstraZeneca for ESMO 2023 and ASCO 2024; and participating as a compensated advisory board member for BMS, Roche, Takeda, MSD, AstraZeneca, Janssen, and MSD. DR-A additionally reports receiving honoraria for lectures from MSD, Roche, BMS, Novartis, Takeda, Lilly, and AstraZeneca; receiving support for attending meetings or travel from Roche, MSD, Novartis, and Sanofi; and participation on an advisory board from MSD, Regeneron, BMS, GSK, and Lilly. JEC additionally reports receiving research grants to the institution from AstraZeneca, BMS, Novartis, Genentech, Merck & Co, and BeiGene; and receiving consulting fees from AstraZeneca, Boehringer Ingelheim, BMS, Lilly, Genentech, Merck & Co, Regeneron-Sanofi, Janssen, Guardant Health, Flame Biosciences, and Roche. SN additionally reports receiving honoraria for lectures, presentations, speakers' bureaus, or educational events from AstraZeneca, Amgen, BeiGene, Pfizer, MSD, Sanofi, Takeda, Thermo Fisher, Janssen, Novartis, and Roche; and participating on a data safety monitoring board or advisory board from AstraZeneca, Amgen, BeiGene, Pfizer, MSD, Sanofi, Takeda, Janssen, and Roche. JY additionally reports receiving salary for full-time employment from MSD. AA, SMK, and AS additionally report receiving salary for full-time employment from MSD and holding stock in Merck & Co, Rahway, NJ, USA., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Immunotherapy-based treatments have demonstrated high efficacy in patients with advanced and locally advanced non-small-cell lung cancer (NSCLC). BRAF mutations affect a small but significant fraction of NSCLC. The efficacy of these therapies in this subgroup of patients is unknown., Materials and Methods: Plasma and tissue samples from 116 resectable stage IIIA/B NSCLC patients, included in NADIM and NADIM II clinical trials (NADIM cohort), and from a prospective academic cohort with 84 stage IV NSCLC patients (BLI-O cohort), were analyzed by next-generation sequencing., Results: The p.G464E, p.G466R, p.G466V, p.G469V, p.L597Q, p.T599I, p.V600E (n = 2) BRAF mutations, were identified in four (3.45 %) samples from the NADIM cohort, all of which were cases treated with neoadjuvant chemoimmunotherapy (CH-IO), and four (4.76 %) samples from the BLI-O cohort, corresponding to cases treated with first-line immunotherapy (n = 2) or CH-IO (n = 2). All these patients were alive and had no evidence of disease at data cut-off. Conversely, patients with BRAF wild-type (wt) tumors in the BLI-O cohort had a median progression-free survival (PFS) of 5.49 months and a median overall survival (OS) of 12.00 months (P-LogRank = 0.013 and 0.046, respectively). Likewise, PFS and OS probabilities at 36 months were 60.5 % and 76.1 % for patients with BRAF-wt tumors in the NADIM cohort. The pathological complete response (pCR) rate after neoadjuvant CH-IO in patients with BRAF-positive tumors (n = 4) was 100 %, whereas the pCR rate in the BRAF-wt population was 44.3 % (RR: 2.26; 95 % CI: 1.78-2.85; P < 0.001)., Conclusion: BRAF mutations may be a good prognostic factor for advanced and locally advanced NSCLC patients undergoing immunotherapy-based treatments., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Provencio declares consulting fees, payment for lectures, presentations or speakers bureaus and support for attending meetings and/or travel from BRISTOL-MYERS SQUIBB, Astra Zeneca, MSD, Roche, Takeda. This author has also declared that he have a pending patent (n° EP 22 382 701.5). R. Serna-Blasco declares to be in possession of a pending patent (n° EP 22 382 701.5). E. Nadal declares Grants or contracts from Roche, Pfizer, Bristol-Myers Squibb and Merck Serono; consulting fees from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Janssen, AMGEN, Daiichi-Sankyo, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre, Qiagen, and Bayer; payment for lectures, presentations or speakers bureaus from Roche, Bristol Myers Squibb, Merck Sharp Dohme, Merck-Serono, Sanofi, Pfizer, Lilly, Janssen, Amgen, Boehringer-Ingelheim, AstraZeneca, Takeda, Sanofi, Pierre Fabre and Qiagen; support for attending meetings and/or travel from Roche, Takeda and Pfizer; and Participation on data safety Monitoring board or advisory board from Roche, Apollomics and MSD. M.P. Diz Taín declares Payment or honoraria for lectures, presentations or speakers bureaus from BRISTOL-MYERS SQUIBB, Astra-Zeneca, Roche, MSD, Takeda, Pfizer and Amgen; support for attending meetings and/or travel from BRISTOL-MYERS SQUIBB, Roche, MSD and Takeda; Participation on a Data Safety Monitoring Board or Advisory Board from BRISTOL-MYERS SQUIBB, Astra-Zeneca, and Boehringer Ingelheim; and other financial or non-financial interests from Astra-Zeneca, Roche, Mirati, and Pfizer. B. Massuti declares consulting fees and support for attending meetings and/or travel from Bristol-Myers Squibb, Takeda, Merck Sharpe and Dohme. J.L. González Larriba declares consulting fees from MSD, Janssen Cilag, Bristol Myers Squibb, Boehringer Ingelheim, and AMGEN; Payment or honoraria for lectures, presentations or speakers bureaus from MSD, Astra Zeneca, Roche, Pfizer, Janssen-Cilag, Novartis, Astella Pharma, and Bristol-Myers Squibb; Support for attending meetings and/or travel from MSD, Takeda, Bristol-Myers Squibb, Roche, Pfizer, and Janssen-Cilag. A. Insa declares Payment or honoraria for lectures, presentations or speakers bureaus from AMGEN, Bristol-Myers Squibb, Roche, and Takeda; Support for attending meetings and/or travel from Roche, Pfizer, and MSD; Participation on a Data Safety Monitoring Board or Advisory Board from Astra Zeneca, Sanofi, and Pfizer. A. Sánchez-Hernández declares Payment or honoraria for lectures, presentations or speakers bureaus from Roche, Lilly, MSD, Sanofi, Astra Zeneca, Janssen, Takeda, Merck, Novartis, Pfizer, and Bristol-Myers Squibb; Support for attending meetings and/or travel from Roche, Sanofi, MSD Takeda, Janssen, Pfizer, and Bristol-Myers Squibb. R. García-Campelo declares Grants or contracts from Bristol-Myers Squibb, Astra Zeneca, and MSC; consulting fees from Roche, Bristol-Myers Squibb, MSD, Sanofi, Takeda, Pfizer, Regeneron, AMGEN, and Astra Zeneca. J. Rogado declares Payment or honoraria for lectures, presentations or speakers bureaus from Roche, Astra Zeneca, MSD, MERCK, Ferrer, Persan Farma, Fresenius Kabi, and Sanofi; Support for attending meetings and/or travel from Roche, MSD, Bristol-Myers Squibb, Astra Zeneca, and Lilly; Participation on a Data Safety Monitoring Board or Advisory Board from Fresenius Kabi, MSD, Sanofi. A. Martínez-Martí declares consulting fees from AstraZeneca/MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche AG, MSD, and Pfizer; Payment or honoraria for lectures, presentations, speakers bureaus from AstraZeneca/MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche AG, MSD, MSD, and Pfizer; Payment for expert testimony from AstraZeneca/MedImmune; Support for attending meetings and/or travel from AstraZeneca/MedImmune, Bristol-Myers Squibb, F. Hoffmann La Roche AG, MSD, Pfizer, and Lilly; Participation on a Data Safety Monitoring Board or Advisory Board from AstraZeneca/MedImmune, MSD, F. Hoffmann La Roche, Bristol-Myers Squibb. J. Bosch-Barrera declares consulting fees from Sanofi and Roche; Payment or honoraria for lectures, presentations or speakers bureaus from Roche, Bristol-Myers Squibb, Astra Zeneca, and Pfizer; Support for attending meetings and/or travel from Takeda and MSD. R. Bernabé-Caro declares an investigational grant Roche; Payment or honoraria for lectures, presentations, speakers bureaus from Roche, Bristol-Myers Squibb, Pfizer, MSD, Amgen, Takeda, and Astra Zeneca; Participation on a Data Safety Monitoring Board or Advisory Board from Takeda, Roche, Bristol-Myers Squibb, and Astra Zeneca. J. de Castro Carpeño declares consulting from fees Astra Zeneca, Bristol Myers Squibb, Hoffmann- La Roche, MSD, Boehringer Ingelheim, Janssen, Lilly, Sanofi, Takeda, Pfizer, and Glaxo; Payment or honoraria for lectures, presentations, speakers bureaus from Astra Zeneca, Bristol Myers Squibb, Hoffmann- La Roche, MSD, Pfizer, Janssen, Takeda, and Sanofi; Support for attending meetings and/or travel from Astra Zaneca, MSD, and Hoffmann- La Roche; Participation on a Data Safety Monitoring Board or Advisory Board from Astra Zeneca, Bristol Myers Squibb, Hoffmann- La Roche, MSD, Glaxo, Janssen, Gilead, and Sanofi. N. Reguart declares Payment or honoraria for lectures, presentations or speakers bureaus from MSD, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Guardant Health, Bayer, Merck, Pfizer, Takeda, Novartis, Astra-Zeneca, Janssen Oncology, Sanofi, Eli Lilly, and Amgen; Support for attending meetings and/or travel from Roche, Takeda, and MSD. M. Dómine declares consulting fees and Payment or honoraria for lectures, presentations or speakers bureaus from Astra Zeneca, Bristol-Myers Squibb, MSD, Pfizer, Roche, and Takeda; Support for attending meetings and/or travel from Astra Zeneca, MSD, Pfizer, and Takeda. M. Majem declares Grants or contracts from Roche and Astra Zeneca; Payment or honoraria for lectures, presentations or speakers bureaus from Roche, Astra Zeneca, MSD, Pfizer, Helsinn, Cassen, AMGEN, Janssen, Sanofi, Pierre Fabre, Bristol-Myers Squibb, and Takeda; Support for attending meetings and/or travel from Astra Zeneca, MSD, and Roche. A. Estival declares Payment or honoraria for lectures, presentations or speakers bureaus from MSD, Pharmamar, Astra Zeneca, Takeda, Roche, and GSK; Support for attending meetings and/or travel from MSD, Boehringer Ingelheim, and Pharmamar; Participation on a Data Safety Monitoring Board or Advisory Board from Roche and MSD. A. López Martín declares Payment or honoraria for lectures, presentations, speakers bureaus from GSK, Bristol-Myers Squibb, and Astra Zeneca; Support for attending meetings and/or travel from Pfizer and Takeda. M. A. Sala González declares Payment or honoraria for lectures, presentations or speakers bureaus from Takeda and Roche; Support for attending meetings and/or travel from Roche and PharmaMar. M. Cobo declares consulting fees from Novartis, Roche, Astra Zeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, Lilly, Takeda, Pfizer, Kyowa, Sanofi, and Jansen. Payment or honoraria for lectures, presentations or speakers bureaus from Novartis, Astra Zeneca Boehringer-Ingelheim, Bristol-Myers Squibb, Roche, Lilly, MSD, Takeda, Kyowa, Pierre-Fabre, Novocure, Sanofi, and Jansen. I. Barneto declares Payment or honoraria for lectures, presentations or speakers bureaus from Bristol-Myers Squibb, Astra Zeneca, MSD, Takeda, AMGEN, and Novartis; Support for attending meetings and/or travel from MSD and Astra Zeneca; Participation on a Data Safety Monitoring Board or Advisory Board from Sanofi. V. Calvo declares consulting fees from Roche, Astra Zeneca, MSD, Bristol-Myers Squibb, Takeda, Sanofi, and AMGEN; Payment or honoraria for lectures, presentations or speakers bureaus from Roche, Astra Zeneca, MSD, Bristol-Myers Squibb, Takeda, Pfizer, and Janssen; Support for attending meetings and/or travel from Astra Zeneca, Roche, and Takeda. A. Collazo declares Payment or honoraria for lectures, presentations or speakers bureaus from Astra Zeneca and Janssen; Support for attending meetings and/or travel from MSD and Takeda. A. Romero declares consulting fees from Takeda; Payment or honoraria for lectures, presentations or speakers bureaus from Illumina, Health in code, and Thermofisher. Support for attending meetings and/or travel from Thermofisher Scientific. Bristol Myers Squibb Foundation, and Takeda; the author also declares a pending patent (n° EP 22 382 701.5). The rest of the authors declare no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC., Experimental Design: We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y)., Results: Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO&#95;DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy., Conclusions: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy., (©2024 American Association for Cancer Research.)

Introduction: Recent advances in the treatment of locally advanced NSCLC have led to changes in the standard of care for this disease. For the selection of the best approach strategy for each patient, it is necessary the homogenization of diagnostic and therapeutic interventions, as well as the promotion of the evaluation of patients by a multidisciplinary oncology team., Objective: Development of an expert consensus document with suggestions for the approach and treatment of locally advanced NSCLC leaded by Spanish Lung Cancer Group GECP., Methods: Between March and July 2023, a panel of 28 experts was formed. Using a mixed technique (Delphi/nominal group) under the guidance of a coordinating group, consensus was reached in 4 phases: 1. Literature review and definition of discussion topics 2. First round of voting 3. Communicating the results and second round of voting 4. Definition of conclusions in nominal group meeting. Responses were consolidated using medians and interquartile ranges. The threshold for agreement was defined as 85% of the votes., Results: New and controversial situations regarding the diagnosis and management of locally advanced NSCLC were analyzed and reconciled based on evidence and clinical experience. Discussion issues included: molecular diagnosis and biomarkers, radiologic and surgical diagnosis, mediastinal staging, role of the multidisciplinary thoracic committee, neoadjuvant treatment indications, evaluation of response to neoadjuvant treatment, postoperative evaluation, and follow-up., Conclusions: Consensus clinical suggestions were generated on the most relevant scenarios such as diagnosis, staging and treatment of locally advanced lung cancer, which will serve to support decision-making in daily practice., (© 2024. The Author(s).)

Introduction: The LIPI, based on pretreatment derived neutrophils/[leukocytes-neutrophils] ratio (dNLR) and LDH, is associated with immune checkpoint inhibitors (ICI) outcomes in advanced non-small-cell lung cancer (NSCLC). We aimed to assess baseline LIPI correlation with durvalumab consolidation outcomes in the locally advanced setting., Material and Methods: Multicentre retrospective study (330 patients) with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and December 2020; 65 patients treated with chemo-radiotherapy only. Baseline LIPI characterized 3 groups: good (dNLR≤3+LDH≤ULN), intermediate (dNLR>3/LDH>ULN) and poor (dNLR>3+LDH>ULN). Primary endpoint was overall survival (OS)., Results: In the durvalumab cohort, median age was 67 years, 95% smokers, 98% with a performance status of 0-1; 60% had nonsquamous histology and 16% a PD-L1 expression <1%. Radiotherapy was delivered concurrently in 81%. LIPI was evaluable in 216 patients: 66% good, 31% intermediate, 3% poor. LIPI significantly correlated with median OS (median follow-up: 19 months): 18.1 months vs. 47.0 months vs. not reached in poor, intermediate and good LIPI groups, respectively (P = .03). A trend between objective response rate and LIPI groups was observed: 0% vs. 41% vs. 45%, respectively (P = .05). The pooled intermediate/poor LIPI group was associated with shorter OS (HR 1.97; P = .03) and higher risk of progressive disease (OR 2.68; P = .047). Survivals and response were not influenced in the control cohort., Conclusion: Baseline LIPI correlated with outcomes in patients with locally advanced NSCLC treated with durvalumab consolidation, but not in those who only received chemo-radiotherapy, providing further evidence of its prognostic and potential predictive role of ICI benefit in NSCLC., Competing Interests: Disclosure VAA: Lectures and educational activities: Bristol-Myers Squibb, AstraZeneca, MSD; Travel, Accommodations, Expenses: Takeda, Sanofi, Janssen; RL: Personal fees: AstraZeneca, Bristol-Myers Squibb. Travel, Accommodations: Roche, Italfarmaco; RLC: Consulting, advisory role or lectures: Amgen, Bristol-Myers Squibb, Pierre-Fabre, Boehringer Ingelheim, Novartis, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pierre-Fabre, MSD, Novartis, Pfizer, Roche, Takeda. Clinical trials research: AstraZeneca, Roche. Travel, Accommodations, Expenses: Roche, Novartis, Takeda, Boehringer Ingelheim; JBB: Reports grants and personal fees from Roche and Pfizer, and personal fees from MSD, BMS, AstraZeneca, Boehringer-Ingelheim, Sanofi, and Novartis, outside the submitted work; SP: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Roche, Amgen, Takeda (outside the submitted manuscript); MT: Travel, accommodation, expenses: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly. Honoraria as medical writer: Novartis, Amgen, MSD. None related to the current manuscript; MS: Speaker, Advisory Role: Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi Avemtis, Siemens Healthineers, Takeda; Research support (institutional): Amgen, BMS, Dracen Pharmaceuticals, Janssen, Novartis, Pfizer, Siemens Healthiness; EN: has participated in lectures and advisory boards from Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Merck Serono, Pfizer, Lilly, Amgen, Boehringer Ingelheim, AstraZeneca, Takeda, Sanofi and Bayer. E. N. has received research funding support from Pfizer, Roche, Merck Serono, Bristol Myers Squibb and Nanostring; GL: Honorary from Boehringer Ingelheim, Blueprint Medicines, AstraZeneca, Merck, Janssen; Consulting and advisory role from Pfizer and AstraZeneca; Research funding from AstraZeneca, Lucence, Xilis, Merck Sharp and Dohme, EMD Serono, Blueprint Medicines, Tesaro, Vavarian Nordic, Novartis, G1 Therapeutics. AdaptImmune, BMS, GSK, Abbvie, Rgenix, Pfizer, Roche, Genentech, Lilly, Janssen; travel, accommodations and expenses from Boehringer Ingelheim, Pfizer, Squibb Sons, Janssen, Seattle Genetics, Celgene, Ibsen, Pharmacyclocs, Merck, AstraZeneca, Seagen; DS: Consulting, advisory role: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Sanofi. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Roche, Merck Sharp & Dohme. Principal Investigator in clinical trial sponsored by Bristol-Myers Squibb, Merck Sharp & Dohme, Eli Lilly. Travel, Accommodations: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer; RGC: Consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Takeda, Janseen, MSD, Roche, Pfizer, Eli Lilly, Amgen, Sanofi; honoraria (self) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Roche, MSD, Takeda, Eli Lilly, Novartis; clinical trials research from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis; VB: Consulting, advisory role: AstraZeneca, Bristol-Myers Squibb, MSD, Merck, Novartis, Pfizer, Roche. Clinical trials research: AstraZeneca, MSD, Roche; MC: Advisory or Consultancy role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, EUSA Pharma, Lilly, Roche. Honoraria, lectures: Abbot, AstraZeneca, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Merck, Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Roche, Takeda. Travel expenses: Ipsen, Lilly, Merck, Pfizer, Pierre Fabre. Institutional financial interests: Astra Zeneca, Merck, Pfizer, Roche; BB: Sponsored Research at Gustave Roussy Cancer Center, Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma; DP: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer; LM: Research grant/Funding (self): Bristol Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, Inivata; Advisory/Consultancy: Roche Diagnostics, Takeda; Honoraria (self): Bristol Myers Squibb, Tecnofarma, Roche; Travel/Accommodation/Expenses: Roche, Boehringer Ingelheim, Takeda, AstraZeneca. The remaining authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Osimertinib has been established as a standard of care for patients with common sensitizing EGFR -mutant advanced non-small-cell lung cancer (NSCLC) although the sequential approach (first-generation inhibitor gefitinib followed by osimertinib) has not been formally compared. The phase II APPLE trial (ClinicalTrials.gov identifier: NCT02856893) enrolled 156 treatment-naïve patients, and two treatment strategies were evaluated: osimertinib up front or the sequential treatment approach with gefitinib up front followed by osimertinib at the time of progression, either molecular progression (detection of plasma T790M resistance mutation) regardless of the radiologic status or just at the time of radiologic progression. Patients' characteristics were well balanced, except for the higher proportion of baseline brain metastases in the sequential approach (29% v 19%). Per protocol, 73% of patients switched to osimertinib in the sequential arm. Up-front treatment with osimertinib was associated with a lower risk of brain progression versus the sequential approach (hazard ratio [HR], 0.54 [90% CI, 0.34 to 0.86]), but a comparable overall survival was observed between both strategies (HR, 1.01 [90% CI, 0.61 to 1.68]), with the 18-month survival probability of 84% and 82.3%, respectively. The APPLE trial suggests that a sequential treatment approach is associated with more frequent progression in the brain but a similar survival in advanced EGFR -mutant NSCLC.

The incidence and mortality of lung cancer in women are rising, with both increasing by 124% between 2003 and 2019. The main risk factor for lung cancer is tobacco use, but indoor radon gas exposure is one of the leading causes in nonsmokers. The most recent evidence demonstrates that multiple factors can make women more susceptible to harm from these risk factors or carcinogens. For this consensus statement, the Association for Lung Cancer Research in Women (ICAPEM) invited a group of lung cancer experts to perform a detailed gender-based analysis of lung cancer. Clinically, female patients have different lung cancer profiles, and most actionable driver alterations are more prevalent in women, particularly in never-smokers. Additionally, the impact of certain therapies seems to be different. In the future, it will be necessary to carry out specific studies to improve the understanding of the role of certain biomarkers and gender in the prognosis and evolution of lung cancer., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Health-related quality of life (HRQoL) is an important consideration in cancer clinical research, which can be substantially influenced by cancer treatment procedures and medications. The treatment landscape for early-stage (stage I-III) non-small cell lung cancer (NSCLC) is rapidly evolving. In this light, it is important to evaluate the most suitable instruments for HRQoL assessment and timing. Given there is often a requirement for patients with early-stage disease to receive long-term treatment to reduce the risk of disease recurrence after surgery, maintenance or improvement in HRQoL is an important goal of both neoadjuvant and adjuvant treatments. Key challenges with assessing HRQoL relate to the suitability of existing instruments to measure relevant treatment-related adverse effects, consistency in HRQoL assessment approach between similar studies, gaps in data collection and reporting, and interpretation of longitudinal data. Frequent assessments during and after treatment are warranted to capture the true impact of treatment and disease progression on HRQoL, and changes in the relative importance of these factors over time. There is scope for improving existing HRQoL approaches, including ease of use and integration of digital tools to facilitate analysis and interpretation, to enhance the experience of both patients and healthcare professionals. In this narrative review, we discuss key considerations for HRQoL assessment and evaluate the tools currently available to measure HRQoL in NSCLC, many of which were designed with advanced disease in mind. We focus on the key challenges of measuring HRQoL for the specific needs of patients with early-stage disease, and consider future perspectives, to determine the most appropriate HRQoL instruments and analysis methods to use in early-stage NSCLC clinical trials. 1 ., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Margarita Majem reports consulting and advisory services for AstraZeneca, Roche, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim, Novartis, Helsinn Therapeutics, Takeda, Sanofi, Janssen Oncology and Pierre Fabre; received research funding to her institution from Bristol Myers Squibb, AstraZeneca and Roche; and received travel, accommodations, expenses from AstraZeneca, Merck Sharp & Dohme, Roche and Eli Lilly. Ethan Basch reports employment at University of North Carolina; board of directors for American Society of North Carolina; consulting fees from AstraZeneca, Sivan, Resilience, Navigating Cancer; and grants or funds from National Cancer Institute and the Patient-Centered Outcomes Research Institute (PCORI). David Cella reports employment at Northwestern University and is President of FACIT.org. Edward B. Garon reports consulting and advisory services for AbbVie, ABL-Bio, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Ipsen, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, Xilio and Zymeworks; and received grants or funds from ABL-Bio, AstraZeneca, Bristol Myers Squibb, Daiichi-Sankyo, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Gilead, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis. Roy S. Herbst has ownership of stocks and shares from Normunity, Checkpoint Therapeutics, Bolt Biotherapeutics, and Immunocore; reports consulting and advisory roles for AstraZeneca, Genentech/Roche, Merck, Pfizer, AbbVie, Bristol Myers Squibb, Lilly, EMD Serono, Junshi Pharmaceuticals, Loxo, NextCure, Novartis, Sanofi, Bolt Biotherapeutics, I-Mab, Mirati Therapeutics, Cybrexa Therapeutics, eFFECTOR Therapeutics, Candel Therapeutics, Oncternal Therapeutics, Xencor, Checkpoint Therapeutics, DynamiCure Biotechnology, Gilead/Forty-Seven, HiberCell, Immune-Onc Therapeutics, Johnson & Johnson, Ocean Biomedical, OncoCyte, Refactor Health, Ribon Therapeutics, Janssen, NextCure, Normunity, Regeneron, and Revelar; leadership roles for Junshi Pharmaceuticals, Immunocore, American Association for Cancer Research, IASLS, Society for Immunotherapy of Cancer, and SWOG; research funding from AstraZeneca, Merck, Lilly, and Genentech/Roche; and travel expenses from American Cancer Society, IASLC, and SWOG. Natasha B. Leighl has received honoraria from Bristol Myers Squibb and Merck Sharp & Dohme; consulting fees from EMD Serono; and grants or funds from AstraZeneca and Bristol Myers Squibb., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: We aimed to determine if advanced BRAF-mutant NSCLC has a higher thromboembolic events (TEE) rate than the expected., Methods: Between 2008 and 2021, 182 patients with BRAF-mutant advanced NSCLC (BRAF V600E, n = 70; BRAF non-V600E, n = 112) were retrospectively identified from 18 centers in Spain. Patients received chemotherapy (n = 147), immunotherapy (n = 69), targeted therapy (n = 42), and immunotherapy + chemotherapy (n = 26)., Results: Incidence rate of TEE was 26.4 % (95%CI: 19.9 %-32.9 %). A total of 72 TEE were documented among 48 patients, as 18 patients (37.5 %) developed more than one event. Median time to TEE onset was 2 months, 69 % of TEE occurred in the peridiagnostic period (+/- 90 days from cancer diagnosis), and in 16 pts. (33 %) TEE was the form of lung cancer presentation. Although most TEE were only venous (82 %; PE, n = 33; DVT, n = 16), arterial events were reported in 31 % and occurred earlier, or TEE presented in atypical locations (13.9 %). TEE were related to high hospitalization rate (59 %), recurrence (23 %), and mortality (10.4 %) despite appropriate anticoagulant/antiaggregant treatment. Median OS in patients without-TEE was 19.4 months (95%CI: 4.6-34.1), and significantly shorter in patients with arterial-TEE vs venous-TEE vs both of them: 9.9 months (95%CI: 0-23.5) vs 41.7 months (95%CI: 11.3-72.2 m) vs 2.7 months (95%CI: 2.1-3.3), p = 0.001. Neither clinical or molecular features (BRAF V600E/non-V600E), nor cancer treatment was associated to TEE occurrence. Khorana score underperformed to predict thrombosis at cancer diagnosis, as only 19.2 % of patients were classified as high-risk., Conclusions: Thrombotic events represent a new clinical feature of BRAF-mutant lung cancer. Patients with almost a 30 % incidence of TEE should be offered systematic anticoagulation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2023. Published by Elsevier Ltd.)

Background: Amivantamab has been approved for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) exon 20 insertions who have had disease progression during or after platinum-based chemotherapy. Phase 1 data showed the safety and antitumor activity of amivantamab plus carboplatin-pemetrexed (chemotherapy). Additional data on this combination therapy are needed., Methods: In this phase 3, international, randomized trial, we assigned in a 1:1 ratio patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy., Results: A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions., Conclusions: The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Funded by Janssen Research and Development; PAPILLON ClinicalTrials.gov number, NCT04538664.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Tarlatamab, a bispecific T-cell engager immunotherapy targeting delta-like ligand 3 and CD3, showed promising antitumor activity in a phase 1 trial in patients with previously treated small-cell lung cancer., Methods: In this phase 2 trial, we evaluated the antitumor activity and safety of tarlatamab, administered intravenously every 2 weeks at a dose of 10 mg or 100 mg, in patients with previously treated small-cell lung cancer. The primary end point was objective response (complete or partial response), as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1., Results: Overall, 220 patients received tarlatamab; patients had previously received a median of two lines of treatment. Among patients evaluated for antitumor activity and survival, the median follow-up was 10.6 months in the 10-mg group and 10.3 months in the 100-mg group. An objective response occurred in 40% (97.5% confidence interval [CI], 29 to 52) of the patients in the 10-mg group and in 32% (97.5% CI, 21 to 44) of those in the 100-mg group. Among patients with an objective response, the duration of response was at least 6 months in 59% (40 of 68 patients). Objective responses at the time of data cutoff were ongoing in 22 of 40 patients (55%) in the 10-mg group and in 16 of 28 patients (57%) in the 100-mg group. The median progression-free survival was 4.9 months (95% CI, 2.9 to 6.7) in the 10-mg group and 3.9 months (95% CI, 2.6 to 4.4) in the 100-mg group; the estimates of overall survival at 9 months were 68% and 66% of patients, respectively. The most common adverse events were cytokine-release syndrome (in 51% of the patients in the 10-mg group and in 61% of those in the 100-mg group), decreased appetite (in 29% and 44%, respectively), and pyrexia (in 35% and 33%). Cytokine-release syndrome occurred primarily during treatment cycle 1, and events in most of the patients were grade 1 or 2 in severity. Grade 3 cytokine-release syndrome occurred less frequently in the 10-mg group (in 1% of the patients) than in the 100-mg group (in 6%). A low percentage of patients (3%) discontinued tarlatamab because of treatment-related adverse events., Conclusions: Tarlatamab, administered as a 10-mg dose every 2 weeks, showed antitumor activity with durable objective responses and promising survival outcomes in patients with previously treated small-cell lung cancer. No new safety signals were identified. (Funded by Amgen; DeLLphi-301 ClinicalTrials.gov number, NCT05060016.)., (Copyright © 2023 Massachusetts Medical Society.)

Lung cancer (LC) is associated with ageing, with the average age of affected individuals being approximately 70 years. However, despite a higher incidence and prevalence among older people, the older adult population is underrepresented in clinical trials. For LC with Epidermal Growth Factor Receptor (EGFR) mutations, there is no clear association of this mutation with age. Geriatric assessments (GAs) and a multidisciplinary approach are essential for defining the optimal treatment. In this consensus, a group of experts selected from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (Sección de Oncogeriatría de la Sociedad Española de Oncología Médica-SEOM), the Spanish Lung Cancer Group (Grupo Español de Cáncer de Pulmón-GECP) and the Association for Research on Lung Cancer in Women (Asociación para la Investigación del Cáncer de Pulmón en Mujeres-ICAPEM) evaluate the scientific evidence currently available and propose a series of recommendations to optimize the management of older adult patients with advanced LC with EGFR mutations., (© 2023. The Author(s).)

Objective: Patients with lung cancer are at increased risk of SARS-CoV-2 infection and severe complications from COVID-19, but information on the efficacy of anti-SARS-CoV-2 vaccine in these patients is scarce. We aimed at evaluating the safety and immunogenicity of COVID-19 vaccines in this population., Patients and Methods: The prospective, nationwide SOLID substudy, enrolled adults with lung cancer who were fully vaccinated against COVID-19. Serum anti-SARS-CoV-2 IgG antibody levels were quantitatively assessed two weeks and six months after receipt of the last dose using a chemiluminescent microparticle immunoassay. Multivariate odds ratios for the association between demographic and clinical factors and seronegativity after vaccination were estimated., Results: 1973 lung cancer patients were enrolled. Most patients had stage IV disease (66%) and were receiving active cancer treatment (82.7%). No significant differences were found in the probability of being seronegative for anti-SARS-CoV-2 IgG antibodies after full vaccination between patients who were receiving active cancer treatment and those who were not (p = 0.396). The administration of immunotherapy or oral targeted therapy and immunization with mRNA-1273 COVID-19 vaccine were factors independently associated with increased odds of being seropositive after vaccination. From all patients, 1405 received the second dose of vaccine and high levels of antibody titers were observed in 93.6% of patients two weeks after second dose. At six months, multivariate logistic regression analysis showed that performance status ≥ 2 was independently associated with a higher probability of being seronegative after full vaccination with an OR 4.15. On the other hand, received chemotherapy or oral target therapy and vaccination with mRNA-1273 were a factor independently associated with lower odds of being seronegative after full vaccination with an OR 0.52, 0.37 and 0.34, respectively., Conclusions: Lung cancer patients can safely achieve a strong immune response against SARS-CoV-2 after full vaccination, regardless of the cancer treatment received., Trial Registration: NCT04407143., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: In ADAURA, adjuvant osimertinib significantly improved disease-free survival versus placebo in resected stage IB to IIIA EGFR-mutated NSCLC. We report in-depth analyses of three-year safety, tolerability, and health-related quality of life (HRQoL) from ADAURA., Methods: Patients were randomized 1:1 to osimertinib 80 mg or placebo once daily for up to 3 years. Safety assessments were performed at baseline, week 2, week 4, week 12, and every 12 weeks until treatment completion or discontinuation, and 28 days after treatment was stopped. The SF-36 survey measured HRQoL at baseline, week 12, week 24, and every 24 weeks until recurrence, treatment completion or discontinuation. Data cutoff: April 11, 2022., Results: Safety and HRQoL analysis sets: osimertinib, n = 337 and n = 339; placebo, n = 343 each. Median (range) total exposure duration was longer with osimertinib versus placebo: 35.8 (0-38) versus 25.1 (0-39) months. Most adverse events (AEs) were first reported within 12 months of starting treatment (osimertinib 97%, placebo 86%). AEs leading to dose reduction, interruption or discontinuation were reported in 12%, 27% and 13% respectively of patients with osimertinib; 1%, 13% and 3% with placebo. Stomatitis and diarrhea were the most common AEs leading to osimertinib dose reduction or interruption; interstitial lung disease was the most common leading to osimertinib discontinuation (per protocol). There were no differences in time to deterioration for SF-36 physical, mental component summaries between osimertinib and placebo., Conclusions: No new safety signals were reported and HRQoL was maintained with 3 years of adjuvant osimertinib treatment. Combined with significant efficacy benefit, these data further support adjuvant osimertinib in stage IB to IIIA EGFR-mutated NSCLC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone., Methods: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 weeks for up to 13 cycles. The dual primary end points were event-free survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death) and overall survival. Secondary end points included major pathological response, pathological complete response, and safety., Results: A total of 397 participants were assigned to the pembrolizumab group, and 400 to the placebo group. At the prespecified first interim analysis, the median follow-up was 25.2 months. Event-free survival at 24 months was 62.4% in the pembrolizumab group and 40.6% in the placebo group (hazard ratio for progression, recurrence, or death, 0.58; 95% confidence interval [CI], 0.46 to 0.72; P<0.001). The estimated 24-month overall survival was 80.9% in the pembrolizumab group and 77.6% in the placebo group (P = 0.02, which did not meet the significance criterion). A major pathological response occurred in 30.2% of the participants in the pembrolizumab group and in 11.0% of those in the placebo group (difference, 19.2 percentage points; 95% CI, 13.9 to 24.7; P<0.0001; threshold, P = 0.0001), and a pathological complete response occurred in 18.1% and 4.0%, respectively (difference, 14.2 percentage points; 95% CI, 10.1 to 18.7; P<0.0001; threshold, P = 0.0001). Across all treatment phases, 44.9% of the participants in the pembrolizumab group and 37.3% of those in the placebo group had treatment-related adverse events of grade 3 or higher, including 1.0% and 0.8%, respectively, who had grade 5 events., Conclusions: Among patients with resectable, early-stage NSCLC, neoadjuvant pembrolizumab plus chemotherapy followed by resection and adjuvant pembrolizumab significantly improved event-free survival, major pathological response, and pathological complete response as compared with neoadjuvant chemotherapy alone followed by surgery. Overall survival did not differ significantly between the groups in this analysis. (Funded by Merck Sharp and Dohme; KEYNOTE-671 ClinicalTrials.gov number, NCT03425643.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Among patients with resected, epidermal growth factor receptor ( EGFR )-mutated, stage IB to IIIA non-small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival., Methods: In this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety., Results: Of 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis., Conclusions: Adjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR -mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction: Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M resistance mutations, with demonstrated efficacy in EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC), including central nervous system (CNS) metastases. Here we present the rationale and study design for ADAURA2 (NCT05120349), which will evaluate adjuvant osimertinib vs. placebo in patients with stage IA2-IA3 EGFRm NSCLC, following complete tumor resection., Patients and Methods: ADAURA2 is a phase III, global, randomized, double-blind, placebo-controlled study. Patients will be adults aged ≥18 years with resected primary nonsquamous NSCLC stage IA2 or IA3 and central confirmation of an EGFR exon 19 deletion or L858R mutation. Patients will be stratified by pathologic risk of disease recurrence (high vs. low), EGFR mutation type (exon 19 deletion vs. L858R) and race (Chinese Asian vs. non-Chinese Asian vs. non-Asian), and randomized 1:1 to receive osimertinib 80 mg once daily (QD) or placebo QD until disease recurrence, treatment discontinuation, or a maximum treatment duration of 3 years. The primary endpoint of this study is disease-free survival (DFS) in the high-risk stratum. Secondary endpoints include DFS in the overall population, overall survival, CNS DFS, and safety. Health-related quality of life and pharmacokinetics will also be evaluated., Results: Study enrolment began in February 2022 and interim results of the primary endpoint are expected in August 2027., Competing Interests: Disclosure Y. Tsutani has undertaken an advisory role for AstraZeneca; received honoraria from AstraZeneca, Bristol-Myers Squibb, Carenet, Chugai Pharmaceutical Co, Ltd, Covidien Japan, Japan Blood Products Organization, Johnson & Johnson, Merck Sharp & Dohme, MiRTeL, Nihon Medi-Physics, Novartis, Ono Pharmaceutical Co, Ltd, Takeda, and Taiho Pharmaceutical Co, Ltd; and has received research support from Boehringer Ingelheim, Chugai Pharmaceutical Co, Ltd, Daiichi Sankyo, and Taiho Pharmaceutical Co, Ltd, J. W. Goldman has received honoraria from AstraZeneca, Bristol-Myers Squibb, Genentech, and Pfizer; has received research support from Advaxis, Array, AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, G1 Therapeutics, Genentech, Merck, and Pfizer; and has received travel fees from AstraZeneca. S. Dacic has undertaken advisory roles for AbbVie, AstraZeneca, Eli Lilly and Company, Genentech/Roche, Merck, and Takeda and has undertaken an officer role for Pulmonary Pathology Society. Y. Yatabe has undertaken advisory roles for Amgen Inc, ArcherCDx, AstraZeneca, Chugai Pharmaceutical Co, Ltd, Janssen, Merck Sharp & Dohme, Novartis, Takeda, and Thermo Fisher; has received research grants from ArcherDx, Konica Minolta, and ThermoFisher; and has undertaken speaker's bureau for AbbVie, Amgen, Inc, ArcherDx, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharmaceutical Co, Ltd, Eli Lilly and Company, Merck, Merck Sharpe & Dohme, Novartis, Ono Pharmaceutical Co, Ltd, Takeda, ThermoFisher, and Yansen. M. Majem has undertaken advisory roles for Amgen Inc, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche, and Sanofi; has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Kyowa Kyrin, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, and Takeda; and has received research support from AstraZeneca, Bristol-Myers Squibb, and Roche. X. Huang is employed by AstraZeneca and owns stocks and/or shares in AstraZeneca. A. Chen is employed by AstraZeneca. T. vd Gronde is employed by AstraZeneca and owns stock and/or shares in AstraZeneca. J. He has no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The phase III ADAURA (ClinicalTrials.gov identifier: NCT02511106) primary analysis demonstrated a clinically significant disease-free survival (DFS) benefit with adjuvant osimertinib versus placebo in EGFR-mutated stage IB-IIIA non-small-cell lung cancer (NSCLC) after complete tumor resection (DFS hazard ratio [HR], 0.20 [99.12% CI, 0.14 to 0.30]; P < .001). We report an updated exploratory analysis of final DFS data., Methods: Overall, 682 patients with stage IB-IIIA (American Joint Committee on Cancer/Union for International Cancer Control, seventh edition) EGFR-mutated (exon 19 deletion/L858R) NSCLC were randomly assigned 1:1 (stratified by stage, mutational status, and race) to receive osimertinib 80 mg once-daily or placebo for 3 years. The primary end point was DFS by investigator assessment in stage II-IIIA disease analyzed by stratified log-rank test; following early reporting of statistical significance in DFS, no further formal statistical testing was planned. Secondary end points included DFS in stage IB-IIIA, overall survival, and safety. Patterns of recurrence and CNS DFS were prespecified exploratory end points., Results: At data cutoff (April 11, 2022), in stage II-IIIA disease, median follow-up was 44.2 months (osimertinib) and 19.6 months (placebo); the DFS HR was 0.23 (95% CI, 0.18 to 0.30); 4-year DFS rate was 70% (osimertinib) and 29% (placebo). In the overall population, DFS HR was 0.27 (95% CI, 0.21 to 0.34); 4-year DFS rate was 73% (osimertinib) and 38% (placebo). Fewer patients treated with osimertinib had local/regional and distant recurrence versus placebo. CNS DFS HR in stage II-IIIA was 0.24 (95% CI, 0.14 to 0.42). The long-term safety profile of osimertinib was consistent with the primary analysis., Conclusion: These updated data demonstrate prolonged DFS benefit over placebo, reduced risk of local and distant recurrence, improved CNS DFS, and a consistent safety profile, supporting the efficacy of adjuvant osimertinib in resected EGFR-mutated NSCLC.

While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options., Competing Interests: Declaration of Competing Interest C.B. has been on an advisory council or committee for Blueprints Medicines; received consulting fee from Amgen; grants or funds from AstraZeneca, Novartis, Mirati, Spectrum, Roche, and Takeda. W.W. has received consulting fees from AstraZeneca. L.B. has ownership of stocks and shares from Roche and Novartis; been on an advisory council or committee for Amgen, AstraZeneca, Takeda, Boehringer Ingelheim, Bayer, Eli Lilly, and Merck Sharpe & Dohme; received honoraria from AstraZeneca, Bayer, Amgen, and Takeda; consulting fee from Johnson & Johnson; and grants and funds from Thermo Fisher and Systems Oncology. J.H. has no conflict of interest. M.M. has received honoraria from Merck Sharpe & Dohme, Boehringer Ingelheim, AstraZeneca, Roche AG, Kyowa Kyrin, Pierre Fabre, Takeda Pharmaceutical, Bayer AG, Amgen, Helsinn, Janssen, and Sanofi; consulting fees from Roche and AstraZeneca; and grants or funds from Bristol-Myers Squibb, Roche, and AstraZeneca. Y.S. has no conflict of interest. J.C. has received consulting fees from Merck, AstraZeneca, Genentech, Flame Biosciencea, Guardant Health, Janssen, Novartis, Arcus Biosciences, Bristol-Myers Squibb, and Regeneron-Sanofi; and grants or funds to institution from AstraZeneca, Bristol-Myers Squibb, Merck, Genetech, and Novartis., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted., (© 2023. The Author(s).)

Purpose: This Delphi panel study assessed the level of consensus between medical oncologists on the clinical management of patients with early-stage EGFR-mutated non-small cell lung cancer (NSCLC)., Methods: A modified two-round Delphi approach was used. A scientific committee comprised of medical oncologists developed an online questionnaire. Delphi panel experts rated their level of agreement with each questionnaire statement on a 9-point Likert scale. The questionnaire included 36 statements from 3 domains (clinical management of early-stage NSCLC: 15 statements; role of adjuvant therapy in early-stage NSCLC: 9 statements; and role of adjuvant therapy in early-stage NSCLC with sensitizing EGFR mutation: 12 statements)., Results: In round 1, consensus was reached for 24/36 statements (66.7%). Nine statements that did not achieve consensus after the first round were evaluated in round 2, and none of them reached consensus. Overall, 84.4% of the panelists agreed that EGFR mutation testing should be done after surgery. Consensus was not achieved on whether the implementation of EGFR mutation testing in resected early-stage NSCLC could limit the use of adjuvant osimertinib. The panelists recognized the rationale for the use of osimertinib in the adjuvant scenario (88%) and 72% agreed that it may change the treatment paradigm in stage IB-IIIA EGFR-mutated NSCLC. Consensus was not reached on the inconvenience of prolonged duration of osimertinib., Conclusions: This Delphi study provides valuable insights into relevant questions in the management of early-stage EGFR-mutated NSCLC. However, specific issues remain unresolved. The expert consensus emphasizes the role of adjuvant treatment with osimertinib in this scenario., (© 2022. The Author(s).)

Purpose: Durvalumab significantly improves overall survival for patients with unresectable stage III non-small-cell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that standard of care, COAST is a phase II study of durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting., Methods: Patients with unresectable stage III non-small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and no progression after cCRT were randomly assigned 1:1:1, ≤ 42 days post-cCRT, to durvalumab alone or combined with oleclumab or monalizumab for up to 12 months, stratified by histology. The primary end point was investigator-assessed confirmed objective response rate (ORR; RECIST v1.1)., Results: Between January 2019 and July 2020, 189 patients were randomly assigned. At this interim analysis (data cutoff, May 17, 2021), median follow-up was 11.5 months (range, 0.4-23.4 months; all patients). Confirmed ORR was numerically higher with durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2) and durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2). Progression-free survival (PFS) was prolonged with both combinations versus durvalumab (plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; and plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72), with higher 12-month PFS rates (plus oleclumab: 62.6% [95% CI, 48.1 to 74.2] and plus monalizumab: 72.7% [95% CI, 58.8 to 82.6] v durvalumab alone: 33.9% [95% CI, 21.2 to 47.1]). All-cause grade ≥ 3 treatment-emergent adverse events occurred in 40.7%, 27.9%, and 39.4% with durvalumab plus oleclumab, durvalumab plus monalizumab, and durvalumab, respectively., Conclusion: Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial.

Purpose: Neoadjuvant chemotherapy plus nivolumab has been shown to be effective in resectable non-small-cell lung cancer (NSCLC) in the NADIM trial (ClinicalTrials.gov identifier: NCT03081689). The 3-year overall survival (OS) and circulating tumor DNA (ctDNA) analysis have not been reported., Methods: This was an open-label, multicenter, single-arm, phase II trial in which patients with stage IIIA NSCLC, who were deemed to be surgically resectable, were treated with neoadjuvant paclitaxel (200 mg/m 2 once a day) and carboplatin (area under curve 6) plus nivolumab (360 mg) once on day 1 of each 21-day cycle, for three cycles, followed by adjuvant nivolumab monotherapy for 1 year (240 mg once every 2 weeks for 4 months, followed by 480 mg once every 4 weeks for 8 months). The 3-year OS and ctDNA analysis were secondary objectives of the trial., Results: OS at 36 months was 81.9% (95% CI, 66.8 to 90.6) in the intention-to-treat population, rising to 91.0% (95% CI, 74.2 to 97.0) in the per-protocol population. Neither tumor mutation burden nor programmed cell death ligand-1 staining was predictive of survival. Conversely, low pretreatment levels of ctDNA were significantly associated with improved progression-free survival and OS (hazard ratio [HR], 0.20; 95% CI, 0.06 to 0.63, and HR, 0.07; 95% CI, 0.01 to 0.39, respectively). Clinical responses according to RECIST v1.1 criteria did not predict survival outcomes. However, undetectable ctDNA levels after neoadjuvant treatment were significantly associated with progression-free survival and OS (HR, 0.26; 95% CI, 0.07 to 0.93, and HR, 0.04; 95% CI, 0.00 to 0.55, respectively). The C-index to predict OS for ctDNA levels after neoadjuvant treatment (0.82) was superior to that of RECIST criteria (0.72)., Conclusion: The efficacy of neoadjuvant chemotherapy plus nivolumab in resectable NSCLC is supported by 3-year OS. ctDNA levels were significantly associated with OS and outperformed radiologic assessments in the prediction of survival.

Background: Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery., Methods: Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes., Results: CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7 , and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B ; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples., Conclusions: Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC., Competing Interests: Competing interests: MP reports non-financial support (reagents for TCR sequencing) from ThermoFisher; grants, personal fees and non-financial support from BMS; grants, personal fees and non-financial support from ROCHE; grants, personal fees and non-financial support from ASTRAZENECA; personal fees from MSD; personal fees from TAKEDA; outside the submitted work. EN grants or contracts: Roche, Pfizer, Merck-Serono, BMS, and Nanostring. Consulting fees: Roche, BMS, MSD, Merck-Serono, Pfizer, Lilly, Amgen, Boehringer, AstraZeneca, Takeda, Bayer, and Sanofi. Payment honoraria: Roche, BMs, MSD, Merck-Serono, Pfizer, Lilly, Amgen, Boehringer, Astrazeneca, Takeda, Bayer, and Sanofi. Support For attending meetings and travel: MSD, Roche, and BMS. AI consulting fees: Pfizer, Amgen, and AstraZeneca. Payment for expert testimony: Bristol, Pfizer, Takeda, Roche, and AstraZeneca. Support for attending meetings or travels: Roche and Bristol. MRG-C reports personal fees from BMS, personal fees from MSD, personal fees from Roche, personal fees from Pfizer, personal fees from AstraZeneca, outside the submitted work; ML-Q: payment for honoraria: BMS, MSD, Ipsen, Astella, AstraZeneca, and Pfizer. Support for attendings meetings/travels: MSD, Takeda, Janssen, Pfizer, and BMS. MD reports personal fees from Astra-Zeneca, personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from MSD, personal fees from Pfizer, personal fees from Roche, outside the submitted work; MM reports grants and personal fees from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from Boehringer Ingelheim; personal fees, non-financial support, and other from AstraZeneca; personal fees, non-financial support, and other from Roche; personal fees from Kyowa Kyrin; personal fees from Pierre Fabre, outside the submitted work; DR-A: consulting fees: Roche, AstraZeneca, BMS, MSD, Lilly, Pfizer, and Novartis. Payment for honoraria: Roche, Astrazeneca, BMS, MSD, Lilly, Pfizer, and Novartis. Support for attending meetings/travels: Roche, MSD, and Novartis; AM-M: advisory board: AstraZeneca, BMS, Roche, MSD, and Pfizer. Speaker's bureau: AstraZeneca, BMS, Roche, MSD, and Pfizer. Support for attending meetings or travel: AstraZeneca, BMS, Roche, MSD, Pfizer, and Lilly. Payment for expert testimony: AstraZeneca. Steering committee member: AstraZeneca. JDCC reports personal fees from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Merck Sharp and Dohme, personal fees from Hoffmann-la Roche, personal fees from Bristol-Myers Squibb, personal fees from Takeda, personal fees from Pfizer, personal fees from Novartis, outside the submitted work; IBA reports consulting or advisory board for Bristol Myers, Takeda, Roche, AstraZeneca, and Behringer Inngelheim; BM reports grants and personal fees from Roche, personal fees and other from BMS, personal fees from Takeda, other from MSD, personal fees from Boehringer, other from Takeda, outside the submitted work; AR: consulting fees: AstraZeneca. Payment or honoraria: Vivo diagnóstico. Advisory board: Takeda. VC: payment or honoraria: Roche, BMS, MSD, AstraZeneca, and Boehringer., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Tumor PD-L1 expression is a predictive biomarker for patients with NSCLC receiving PD-(L)1 blockade agents. However, although increased tumor PD-L1 expression predicts responsiveness, clinical benefit has been observed regardless of tumor PD-L1 expression, suggesting the existence of other PD-L1 sources. The aim of our study was to analyze whether integrating systemic and tumor PD-L1 is more predictive of efficacy in patients with advanced NSCLC receiving PD-(L)1 blockade agents., Material and Methods: Twenty-nine healthy donors and 119 consecutive patients with advanced NSCLC treated with PD-(L)1 drug were prospectively included. Pretreatment blood samples were collected to evaluate PD-L1 levels on circulating immune cells, platelets (PLTs), platelet microparticles (PMPs), and the plasma soluble PD-L1 concentration (sPD-L1). Tumor PD-L1 status was assessed by immunohistochemistry. The percentages of circulating PD-L1 + leukocytes, sPD-L1 levels, and tumor PD-L1 were correlated with efficacy., Results: No differences in the percentages of circulating PD-L1 + leukocytes were observed according to tumor PD-L1 expression. Significantly longer progression-free survival was observed in patients with higher percentages of PD-L1 + CD14 + , PD-L1 + neutrophils, PD-L1 + PLTs, and PD-L1 + PMPs and significantly longer overall survival was observed in patients with higher percentages of PD-L1 + CD14 + and high tumor PD-L1 expression. Integrating the PD-L1 data of circulating and tumor PD-L1 results significantly stratified patients according to the efficacy of PD-(L1) blockade agents., Conclusions: Our results suggest that integrating circulating PD-L1 + leukocytes, PLT, PMPs, and sPD-L1 and tumor PD-L1 expression may be helpful to decide on the best treatment strategy in patients with advanced NSCLC who are candidates for PD-(L)1 blockade agents., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This retrospective observational study analyzed the clinical characteristics, treatment patterns and outcomes of 120 patients with advanced ALK-positive non-small-cell lung cancer (ALK+ NSCLC) according to data collected between November 2019 and October 2020 in 38 Spanish hospitals. Patients had progressed after 1-5 prior treatment lines (which included crizotinib in any prior line) and received subsequent therapy with alectinib in a local expanded access program. Median age was 58.7 years, 50% of patients were female, 64.1% had ECOG PS of 0-1, 85% presented stage IV, 95% had adenocarcinoma histology and 20.8% had brain metastases. After a median 9.6 months of alectinib treatment, objective response rate (ORR) was 54.5%, disease control rate (DCR) was 80%, median progression-free survival (PFS) was 9.4 months and median overall survival (OS) was 24.1 months. Patients with brain metastases achieved an intracranial DCR of 71.4%. Adverse events (AEs) were reported in 35.8% of patients (14.2% of AEs were grade ≥3). Over 40% of patients received some treatment after alectinib, most frequently lorlatinib (65.2%) and brigatinib (32.6%). This study provides information on real-world treatment patterns and confirms the tolerability and prolonged PFS and OS observed with alectinib in clinical trials, in unselected pretreated patients with advanced ALK+ NSCLC., Competing Interests: CONFLICTS OF INTEREST R. B.-C. reports advisory honoraria from Roche, Bristol-Myers Squibb, and AstraZeneca; speaker honoraria from Roche, Bristol-Myers Squibb, and Amgen; and grants from Roche. P. G. reports consultancy fees from Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck-Sharp-Dome, Medscape, Novartis, Pfizer, Roche, Takeda and Sanofi, and speaker honoraria from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck-Sharp-Dome, Novartis, Pfizer, Roche, and Takeda. R. G.-C. reports consultancy fees and speaker honoraria from Merck-Sharp-Dome, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Bayer and Janssen. R. P. reports speaker honoraria from Guardant Health, Pfizer, Roche, Boehringer-Ingelheim, Eli-Lilly, Bristol-Myers Squibb, AstraZeneca, and Merck-Sharp-Dome; travel/meeting attendance expenses from Merck-Sharp-Dome and Roche, and membership of data safety monitoring from Boehringer-Ingelheim and Roche. A. A. reports consultancy fees from Roche, Takeda, AstraZeneca, and Bristol-Myers Squibb. C. B. reports consultancy fees from Boehringer-Ingelheim and AstraZeneca; speaker honoraria from Pfizer, Merk, Roche, Bristol-Myers Squibb, Takeda, Merck-Sharp-Dome, and Amgen; meeting and courses attendance expenses from Merck-Sharp-Dome, Roche, Merk, AstraZeneca and Boehringer-Ingelheim. D. R.-A. reports honoraria for lectures and consultancy fees from Bristol-Myers Squibb, MSD and Hoffmann-La Roche. M. L.-B. reports travel grants from Bristol-Myers Squibb, Roche, Pfizer, and Merck-Sharp-Dome; speaker honoraria, consulting fees and continuing medical education expenses from Roche, Bristol-Myers Squibb, Merck-Sharp-Dome, Pfizer, AstraZeneca, and Takeda. A. P. declares no conflicts of interests. D. V. reports speaker honoraria from Merck-Sharp-Dome, Pfizer, and AstraZeneca; and travel/accommodation expenses from Merck-Sharp-Dome, Pfizer, and AstraZeneca. J. M. S.-T. reports consultancy fees from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer, Roche, and Takeda; and travel/accommodation expenses from Boehringer-Ingelheim, Merck-Sharp-Dome, and Roche. M. M. reports grants from Bristol-Myers Squibb, Roche, and AstraZeneca; personal fees from Bristol-Myers Squibb, AstraZeneca, Roche, Merck-Sharp-Dome, Boehringer-Ingelheim, Takeda, Sanofi-Aventis, Novartis, Vifor and Bayer. P. D. reports speaker honoraria and consultancy fees from Bristol-Myers Squibb, AstraZeneca, Boehringer-Ingelheim, Roche, Merck-Sharp-Dome, and Takeda; speaker honoraria from Pfizer and Amgen; institutional research grants from AstraZeneca and Mirati, and personal and institutional research grants from AstraZeneca and Roche. R. G. and M. G. are Roche Farma employees. J. d. C. reports educational fees from Astra Zeneca, Bristol-Myers Squibb, Merck-Sharp-Dome, and Roche; consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen-Cilag, Lilly, Merck-Sharp-Dome, Novartis, Pfizer, Roche, and Takeda. All potential conflicts of interests were outside of the submitted work., (Copyright: © 2022 Bernabé-Caro et al.)

Purpose: Central nervous system metastases are a prominent cause of morbidity and mortality in patients with ALK-positive (ALK+) non-small cell lung cancer (NSCLC). The phase II ASCEND-7 (NCT02336451) study was specifically designed to assess the efficacy and safety of the ALK inhibitor (ALKi) ceritinib in patients with ALK+ NSCLC metastatic to the brain and/or leptomeninges., Patients and Methods: Patients with active brain metastases were allocated to study arms 1 to 4 based on prior exposure to an ALKi and/or prior brain radiation (arm 1: prior radiotherapy/ALKi-pretreated; arm 2: no radiotherapy/ALKi-pretreated; arm 3: prior radiotherapy/ALKi-naïve; arm 4: no radiotherapy/ALKi-naïve). Arm 5 included patients with leptomeningeal carcinomatosis. Patients received ceritinib 750 mg once daily (fasted condition). Primary endpoint was investigator-assessed whole-body overall response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR) and intracranial/extracranial responses., Results: Per investigator assessment, in arms 1 (n = 42), 2 (n = 40), 3 (n = 12), and 4 (n = 44), respectively: whole-body ORRs [95% confidence interval (CI)] were 35.7% (21.6-52.0), 30.0% (16.6-46.5), 50.0% (21.1-78.9), and 59.1% (43.2-73.7); whole-body DCR (95% CI): 66.7% (50.5-80.4), 82.5% (67.2-92.7), 66.7% (34.9-90.1), and 70.5% (54.8-83.2); intracranial ORRs (95% CI): 39.3% (21.5-59.4), 27.6% (12.7-47.2), 28.6% (3.7-71.0), and 51.5% (33.5-69.2). In arm 5 (n = 18), whole-body ORR was 16.7% (95% CI, 3.6-41.4) and DCR was 66.7% (95% CI, 41.0-86.7). Paired cerebrospinal fluid and plasma sampling revealed that ceritinib penetrated the human blood-brain barrier., Conclusions: Ceritinib showed antitumor activity in patients with ALK+ NSCLC with active brain metastases and/or leptomeningeal disease, and could be considered in the management of intracranial disease. See related commentary by Murciano-Goroff et al., p. 2477., (©2022 American Association for Cancer Research.)

Purpose: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB-IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA., Patients and Methods: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB-IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual., Results: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46-47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), -1.18 (-2.02 to -0.34) and -1.34 (-2.40 to -0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82-1.67) and HR, 0.98 (95% CI, 0.70-1.39), respectively., Conclusions: HRQoL was maintained with adjuvant osimertinib in patients with stage IB-IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204., (©2022 The Authors; Published by the American Association for Cancer Research.)

Introduction: Durvalumab is the standard-of-care as consolidation therapy after chemo-radiotherapy in stage III unresectable non-small cell lung cancer (NSCLC); however, its activity across patients with NSCLC harbouring driver genomic alterations (dGA) is poorly characterised., Material and Methods: Multicentre retrospective study including patients with stage III unresectable NSCLC treated with durvalumab after chemo-radiotherapy between April 2015 and October 2020 at 26 centres in Europe and America. Clinical and biological data were collected; dGA included: EGFR/BRAF/KRAS mutations (m) and ALK/ROS1 rearrangements (r). We evaluated progression-free survival (PFS) and overall survival (OS) based on dGA., Results: Out of 323 patients included, 43 patients had one dGA: KRASm (n = 26; 8 G12C), EGFRm (n = 8; 6 del19/ex21), BRAFm (n = 5; 4 V600E) and ALKr (n = 4). The median age was 66 years [39-84], gender ratio 1:1, with 98% performance status (PS) 0-1 and 19% non-smokers; 88% had adenocarcinoma. PD-L1 was positive in 85% (n = 4 missing). In the whole cohort, the median PFS was 17.5 months (mo.) (95% CI, 13.2-24.9) and median OS 47 mo (95%CI, 47-not reached [NR]). No statistically significant differences in terms of the median PFS were observed between patients with dGA vs. non-dGA: 14.9 mo (95% CI, 8.1-NR) vs. 18 mo. (95% CI, 13.4-28.3) (P = 1.0); however, when analysed separately: the median PFS was NR (11.3-NR) in the KRASm G12C vs. 8.1 mo (5.8-NR) in the EGFRm del19/ex21 vs. 7.8 mo (7.7-NR) in the BRAFm V600E/ALKr (P = 0.02)., Conclusions: We observed limited activity of durvalumab consolidation in patients with stage III unresectable NSCLC with EGFR/BRAFm and ALKr but not for those harbouring KRASm. Larger prospective studies are needed to confirm these findings., Competing Interests: Conflict of interest statement MMj: advisory and consultancy honoraria from Roche, Merck, BristolMyers Squibb, AstraZeneca, Amgen, Boehringer, Sanofi and Takeda; speaker honoraria from Roche, Merck, Bristol-Myers Squibb, AstraZeneca, Bayer, Amgen, Pfizer and Boehringer; grants from AstraZeneca and BristolMyers Squib, and travel/accommodation expenses from Roche, Merck and Lilly. RLC: honoraria from Kyowa Kirin, Pierre-Fabre, Takeda, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Roche, Merck Serono, Pfizer; consulting or advisory role from Roche, Astra-Zeneca, Boehringer Ingelheim, Aristo, Novartis; research funding from Roche, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, AstraZeneca. JBB: grants and personal fees from Roche-Genentech, Pfizer, MSD, BMS, Astrazeneca, Novartis, Boehringer-Ingelheim, Vifor, Sanofi, LEO Pharma, outside the submitted work. SP: Consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Roche, Amgen. MT: travel grants from Roche, Bristol-Myers Squibb, AstraZeneca, Takeda; honoraria as medical writer from Novartis, Amgen. GZ: research grants from Roche-France, Bristol-Myers Squibb, and Takeda outside of the submitted work; perceived fees from Bristol-Myers Squibb, AstraZeneca, Pfizer, and Boehringer Ingelheim outside the submitted work; and reimbursement for international meetings assistance from AbbVie, Merck Sharp & Dohme, AstraZeneca, Bristol-Myers Squibb, and Roche-France. XM-R: Research grant funding from Brystol-Myers Squibb; consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim; honoraria (self) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Roche, MSD; clinical trials research from Boehringer Ingelheim, Pfizer, Roche, Abbvie; travel, accommodations and expenses from Roche, Pfizer, Brysto-Myers Squibb. JB: educational grants by AMGEN. MSch: speaker and advisory role honoraria, travel accommodations from AMGEN, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Novartis, Pfizer, Roche, Takeda; personal research support from AMGEN, Dracen Pharmaceuticals, Siemens Healthineers; institutional research support from Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche. EN: research support from Roche, Merck Serono, Bristol Myers Squibb and Pfizer and participated in advisory boards or lectures from Bristol Myers Squibb, Merck Serono, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Bayer, Boehringer Ingelheim, Amgen and AstraZeneca. DS: Consulting, advisory role, honoraria from AstraZeneca, Merck Sharp & Dohme, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi, Eli Lilly; travel grants from Roche. RGC: Consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Takeda, Janseen, MSD, Roche, Pfizer, Eli Lilly, Amgen, Sanofi; honoraria (self) from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Pfizer, Roche, MSD, Takeda, Eli Lilly, Novartis; clinical trials research from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis. JMe: Advisory Boards/Honoraria/Speakers’ fee/Consultant for Astra-Zeneca, Boeringher Ingelheim, BMS, Roche, MSD; travel grants from Astra-Zeneca, Boeringher Ingelheim, BMS, Ipsen, Roche, MSD. VB: Clinical trial research from AstraZeneca, Roche, MSD; advisory role/consulting/speaker from Pfizer, MSD, AstraZeneca, Roche, Bristol, Merck, Takeda. MC: Advisory or Consultancy role from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, EUSA Pharma, Lilly, Roche; honoraria, lectures from Abbot, Bristol-Myers Squibb, EUSA Pharma, Ipsen, Novartis, Pfizer, Pierre Fabre, Roche; travel, expenses from Ipsen, Lilly, Merck, Pfizer, Pierre Fabre; institutional financial interests from Astra Zeneca, Merck, Roche, Pfizer. GR: consulting, advisory role or lectures from AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Merck Sharp & Dome, Pfizer, Roche, Takeda; sponsored Research Amgen and Janssen. BB: sponsored research at Gustave Roussy Cancer Centre Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. DP: consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche; clinical trials research from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo; travel, accommodations, expenses from AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. LM: research grant/Funding (self) from Bristol Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, Inivata; advisory/consultancy from Roche, Takeda; honoraria (self) from Bristol Myers Squibb, Roche, Takeda, AstraZeneca; travel/Accommodation/Expenses from Roche, Bristol Myers Squibb, Takeda, AstraZeneca; non-remunerated activity/ies from AstraZeneca. MR, EA, MMo, ND, EE, RL, JMo, FA, SP, AD, MSp, EM, RR, JCB, LL, BD, AdG, CAV and GL declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Adjuvant chemotherapy is recommended in patients with resected stages II to IIIA (and select IB) NSCLC; however, recurrence rates are high. In the phase 3 ADAURA study (NCT02511106), osimertinib was found to have a clinically meaningful improvement in disease-free survival (DFS) in patients with resected stages IB to IIIA EGFR-mutated (EGFRm) NSCLC. Here, we report prespecified and exploratory analyses of adjuvant chemotherapy use and outcomes from ADAURA., Methods: Patients with resected stages IB to IIIA EGFRm NSCLC were randomized 1:1 to receive osimertinib or placebo for 3 years. Adjuvant chemotherapy before randomization was not mandatory, per physician and patient choice. DFS in the overall population (IB-IIIA), with and without adjuvant chemotherapy, was a prespecified analysis. Exploratory analyses included the following: adjuvant chemotherapy use by patient age, disease stage, and geographic location; DFS by adjuvant chemotherapy use and disease stage., Results: Overall, 410 of 682 patients (60%) received adjuvant chemotherapy (osimertinib, n = 203; placebo, n = 207) for a median duration of 4.0 cycles. Adjuvant chemotherapy use was more frequent in patients: aged less than 70 years (338 of 509; 66%) versus more than or equal to 70 years (72 of 173; 42%); with stages II to IIIA (352 of 466; 76%) versus stage IB (57 of 216; 26%); and enrolled in Asia (268 of 414; 65%) versus outside of Asia (142 of 268; 53%). A DFS benefit favoring osimertinib versus placebo was observed in patients with (DFS hazard ratio = 0.16, 95% confidence interval: 0.10-0.26) and without adjuvant chemotherapy (hazard ratio = 0.23, 95% confidence interval: 0.13-0.40), regardless of disease stage., Conclusions: These findings support adjuvant osimertinib as an effective treatment for patients with stages IB to IIIA EGFRm NSCLC after resection, with or without previous adjuvant chemotherapy., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: It has been recognized that increasing body mass index (BMI) is associated with improved outcome from immune checkpoint inhibitors (ICIs) in patients with various malignancies including non-small cell lung cancer (NSCLC). However, it is unclear whether baseline BMI may influence outcomes from first-line chemoimmunotherapy combinations., Methods: In this international multicenter study, we evaluated the association between baseline BMI, progression-free survival (PFS) and overall survival (OS) in a cohort of patients with stage IV NSCLC consecutively treated with first-line chemoimmunotherapy combinations. BMI was categorized according to WHO criteria., Results: Among the 853 included patients, 5.3% were underweight; 46.4% were of normal weight; 33.8% were overweight; and 14.5% were obese. Overweight and obese patients were more likely aged ≥70 years (p=0.00085), never smokers (p<0.0001), with better baseline Eastern Cooperative Oncology Group-Performance Status (p=0.0127), and had lower prevalence of central nervous system (p=0.0002) and liver metastases (p=0.0395). Univariable analyses showed a significant difference in the median OS across underweight (15.5 months), normal weight (14.6 months), overweight (20.9 months), and obese (16.8 months) patients (log-rank: p=0.045, log rank test for trend: p=0.131), while no difference was found with respect to the median PFS (log-rank for trend: p=0.510). Neither OS nor PFS was significantly associated with baseline BMI on multivariable analysis., Conclusions: In contrast to what was observed in the context of chemotherapy-free ICI-based regimens, baseline BMI does not affect clinical outcomes from chemoimmunotherapy combinations in patients with advanced NSCLC., Competing Interests: Competing interests: AC received speaker fees and grant consultancies from AstraZeneca, MSD, BMS, Roche, Novartis, and EISAI. GLB received grant consultancies from AstraZeneca and Astellas Pharma. LM reports receiving research grant/funding (self) from Bristol-Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, and Inivata; serving in advisory/consultancy for Roche and Takeda; receiving honoraria (self) from Bristol-Myers Squibb, Takeda, and Roche; receiving travel/accommodation/expenses from Roche, Bristol-Myers Squibb, Takeda, and AstraZeneca; and having non-remunerated activities from AstraZeneca. AA received consulting fees from BMS, AstraZeneca, Boehringer-Ingelheim, Roche, MSD, Pfizer, Eli Lilly, and Astellas; speakers fees from Eli Lilly and AstraZeneca. MT received speaker and consultant fees from AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche, MSD, Boehringer Ingelheim, Otsuka, Takeda, Pierre Fabre, Amgen, and Merck. MT received institutional research grants from AstraZeneca, and Boehringer Ingelheim. CC received honorarium/educational grants from Lilly, Pfizer, and Boehringer-Inghelheim. DJP received lecture fees from ViiV Healthcare and Bayer Healthcare and travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, AstraZeneca, DaVolterra, and BMS; and received research funding (to institution) from MSD and BMS. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Here, we summarize the initial results from the ADAURA clinical study looking at treatment with osimertinib in patients with a specific type of non-small cell lung cancer (also called NSCLC). Osimertinib (TAGRISSO®) is a medication used to treat a type of NSCLC with a change (mutation) in the EGFR gene, known as EGFR-mutated NSCLC. EGFR stands for 'epidermal growth factor receptor'. It is a protein present on the surface of both healthy and cancer cells that can regulate how cells grow and divide. Sometimes, certain mutations in EGFR can result in the EGFR protein malfunctioning, which can lead to the formation of cancer, like EGFR-mutated NSCLC. Based on previous clinical studies, osimertinib is already approved for use in patients with EGFR-mutated NSCLC that has spread beyond the lung (metastatic disease). This medication works to stop, prevent, or slow the growth of EGFR-mutated NSCLC tumors, by specifically blocking the activity of EGFR. In the ADAURA clinical study, participants had resectable EGFR-mutated NSCLC, which means they had tumors that can be removed by surgery. Participants took either osimertinib or a placebo (a dummy drug with no active ingredient) after having their tumors removed by surgery. Post-surgery chemotherapy was allowed, but not compulsory (this was decided by the participant and their doctor). To date, the study has shown that osimertinib could be beneficial for patients with resectable EGFR-mutated NSCLC. Participants who took osimertinib have stayed cancer-free for longer than those who took the placebo, regardless of whether or not they received chemotherapy after surgery. Osimertinib treatment also reduced the risk of tumors spreading to the brain and spinal cord, otherwise known as the central nervous system (also called CNS). The side effects experienced by the participants taking osimertinib have been consistent with what we already know. Based on the results from ADAURA, osimertinib has been approved for the treatment of resectable EGFR-mutated NSCLC after tumor removal. The ADAURA study is still ongoing and more results are expected to be released in the future. ClinicalTrials.gov NCT number: NCT02511106.

Aim of the Study: The AZENT (NCT02841579) study aimed to assess the efficacy and safety of first-line osimertinib in patients with epidermal growth factor receptor(EGFR)mutation-positive advanced non-small-cell lung cancer (NSCLC) and with a coexisting low allelic fraction of Thr790Met., Methods: In this multicentre, single-arm, open-label, phase IIa study, patients with locally advanced or metastatic NSCLC harbouring centrally confirmedEGFR Thr790Met mutation received 80 mg osimertinib daily. The primary end-point was objective response rate (ORR). The secondary end-points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Efficacy was assessed as per Response Evaluation Criteria in Solid Tumours, version 1.1. Blood samples collected at baseline, end of week 2 and disease progression were analysed using next-generation sequencing. As osimertinib was approved as a first-line therapy during the trial, this led to early termination of phase II; thus, analysis is considered exploratory., Results: Twenty-two patients were enrolled and received osimertinib. All 22 patients were included in the efficacy and safety analysis. At the data cutoff, 10 (50%) patients remained on treatment. The median duration of follow-up was 24.4 months (interquartile range 12.9 to 26.0). The ORR was 77.3% (17/22 [95% confidence interval {CI} 54.6 to 89.3]). The DCR was 86.4% (19/22, [95% CI 65.1 to 97.1]). The median PFS was 23.1 months (95% CI 14.1 to NE). The median OS was 28·4 months (95% CI 25.6 to NE)., Conclusion: Despite early study termination, osimertinib first-line therapy yields an overall PFS of 23.1 months in EGFR-mutant patients harbouring a coexisting low allelic fraction of EGFR Thr790Met mutation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations., Methods: We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan-Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS)., Results: Median age was 58.9 years (range 42.8-81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2-3 previous treatment lines. Docetaxel was administered at 75 mg/m 2 /3 weeks to 16 patients, at 60 mg/m 2 to 2 patients and at 45 mg/m 2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1-38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9-7.3] and the median OS 10.1 months (95% CI 5.9-14.3). The objective response rate (ORR) was 44.4% (23.7-66.8%) and the disease control rate (DCR) 72.2% (49.4-88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1-10.5) versus (vs.) 4.8 (95% CI 3.5-6.1) and a median OS of 12.3 months (95% CI 8.6-16.0) vs. 6.7 months (95% CI 3.9-9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0-6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported., Conclusions: Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC., (© 2021. Federación de Sociedades Españolas de Oncología (FESEO).)

Purpose: Treatment guidelines for advanced non-small-cell lung cancer (aNSCLC) recommend broad molecular profiling for targeted therapy selection. This study prospectively assessed comprehensive next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) compared with standard-of-care (SOC) tissue-based testing to identify guideline-recommended alterations in aNSCLC., Patients and Methods: Patients with treatment-naïve aNSCLC were tested using a well-validated NGS cfDNA panel, and results were compared with SOC tissue testing. The primary objective was noninferiority of cfDNA vs. tissue analysis for the detection of two guideline-recommended biomarkers ( EGFR and ALK ) and an additional six actionable biomarkers. Secondary analyses included tissue versus cfDNA biomarker discovery, overall response rate (ORR), progression-free survival (PFS) to targeted therapy, and positive predictive value (PPV) of cfDNA., Results: The primary objective was met with cfDNA identifying actionable mutations in 46 patients versus 48 by tissue ( P < .05). In total, 0/186 patients were genotyped for all eight biomarkers with tissue, compared with 90.8% using cfDNA. Targetable alterations or KRAS were identified in 80.7% when cfDNA was used first versus 57.1% when tissue was used first. PPV for cfDNA-detected EGFR was 100.0% (25/25). ORR and PFS in patients receiving targeted therapy based on tissue or cfDNA were similar to those previously reported., Conclusion: This prospective study confirms a previous report that comprehensive cfDNA testing is noninferior to SOC tissue testing in detecting aNSCLC-recommended biomarkers. Furthermore, cfDNA-based first-line therapy produced outcomes similar to tissue-based testing, demonstrating the clinical utility of comprehensive cfDNA genotyping as the initial genotyping modality in patients with treatment-naïve aNSCLC when tissue is insufficient or when all actionable biomarkers cannot be rapidly assessed.

Purpose: Characterization of the T-cell receptor (TCR) repertoire may be a promising source for predictive biomarkers of pathologic response to immunotherapy in locally advanced non-small cell lung cancer (NSCLC)., Experimental Design: In this study, next-generation TCR sequencing was performed in peripheral blood and tissue samples of 40 patients with NSCLC, before and after neoadjuvant chemoimmunotherapy (NADIM clinical trial, NCT03081689), considering their complete pathologic response (CPR) or non-CPR. Beyond TCR metrics, tissue clones were ranked by their frequency and spatiotemporal evolution of top 1% clones was determined., Results: We have found a positive association between an uneven TCR repertoire in tissue samples at diagnosis and CPR at surgery. Moreover, TCR most frequently ranked clones (top 1%) present in diagnostic biopsies occupied greater frequency in the total clonal space of CPR patients, achieving an AUC ROC to identify CPR patients of 0.967 (95% confidence interval, 0.897-1.000; P = 0.001), and improving the results of PD-L1 tumor proportion score (TPS; AUC = 0.767; P = 0.026) or tumor mutational burden (TMB; AUC = 0.550; P = 0.687). Furthermore, tumors with high pretreatment top 1% clonal space showed similar immune cell populations but a higher immune reactive gene expression profile. Finally, the selective expansion of pretreatment tissue top 1% clones in peripheral blood of CPR patients suggests also a peripheral immunosurveillance, which could explain the high survival rate of these patients., Conclusions: We have identified two parameters derived from TCR repertoire analysis that could outperform PD-L1 TPS and TMB as predictive biomarkers of CPR after neoadjuvant chemoimmunotherapy, and unraveled possible mechanisms of CPR involving enhanced tumor immunogenicity and peripheral immunosurveillance., (©2021 The Authors; Published by the American Association for Cancer Research.)

Introduction: In the KEYNOTE-010 study, pembrolizumab improved overall survival (OS) versus docetaxel in patients with previously treated, advanced NSCLC with programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% and ≥1%. We report 5-year efficacy and safety follow-up for the KEYNOTE-010 study., Methods: Patients were randomized to pembrolizumab 2 mg/kg or 10 mg/kg once every 3 weeks or docetaxel 75 mg/m 2 once every 3 weeks for up to 35 cycles (2 y). Patients who completed pembrolizumab treatment and subsequently had recurrence could receive second-course pembrolizumab for up to 17 cycles (1 y). Pembrolizumab doses were pooled in this analysis., Results: A total of 1034 patients were randomized (pembrolizumab, n = 691; docetaxel, n = 343). Median study follow-up was 67.4 months (range: 60.0‒77.9). The hazard ratio (95% confidence interval) for OS was 0.55 (0.44‒0.69) for patients with PD-L1 TPS ≥50% and 0.70 (0.61‒0.80) with PD-L1 TPS ≥1%. The 5-year OS rates for pembrolizumab versus docetaxel were 25.0% versus 8.2% in patients with PD-L1 TPS ≥50% and 15.6% versus 6.5% with PD-L1 TPS ≥1%. Among 79 patients who completed 35 cycles/2 years of pembrolizumab, the OS rate 3 years after completion (∼5 y from randomization) was 83.0%. A total of 21 patients received second-course pembrolizumab; 11 (52.4%) had an objective response after starting the second course and 15 (71.4%) were alive at data cutoff. Exploratory biomarker analysis revealed that higher tissue tumor mutational burden (≥175 mutations per exome) was associated with improved outcomes with pembrolizumab., Conclusions: Pembrolizumab continued to provide long-term benefit than docetaxel in patients with previously treated advanced NSCLC with PD-L1 TPS ≥50% and ≥1%. Our findings confirm pembrolizumab as a standard-of-care treatment in the second-line or later setting., (Copyright © 2021. Published by Elsevier Inc.)

Objectives: The aim of LungBEAM was to determine the value of a novel epidermal growth factor receptor (EGFR) mutation test in blood based on BEAMing technology to predict disease progression in advanced non-small cell lung cancer (NSCLC) patients treated with first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Another goal was to monitor the dynamics of EGFR mutations, as well as to track EGFR exon 20 p.T790M (p.T790M) resistance during treatment, as critical indicators of therapeutic efficacy and patient survival., Methods: Stage IV NSCLC patients with locally confirmed EGFR-TKI sensitizing mutations (ex19del and/or L858R) in biopsy tissue who were candidates to receive first- or second-generation EGFR-TKI as first-line therapy were included. Plasma samples were obtained at baseline and every 4 weeks during treatment until a progression-free survival (PFS) event or until study completion (72-week follow-up). The mutant allele fraction (MAF) was determined for each identified mutation using BEAMing., Results: A total of 68 of the 110 (61.8%) patients experienced a PFS event. Twenty-six patients (23.6%) presented with an emergent p.T790M mutation in plasma at some point during follow-up, preceding radiologic progression with a median of 76 (interquartile ratio: 54-111) days. Disease progression correlated with the appearance of p.T790M in plasma with a hazard ratio (HR) of 1.94 (95% confidence interval [CI], 1.48-2.54; p < 0.001). The HR for progression in patients showing increasing plasma sensitizing mutation levels (positive MAF slope) versus patients showing either decreasing or unchanged plasma mutation levels (negative or null MAF slopes) was 3.85 (95% CI, 2.01-7.36; p < 0.001)., Conclusion: Detection and quantification of EGFR mutations in circulating tumor DNA using the highly sensitive BEAMing method should greatly assist in optimizing treatment decisions for advanced NSCLC patients., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated., Methods: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m 2 ) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS)., Results: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports., Conclusions: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Pneumonitis (Pn) is one of the main immune-related adverse effects, having a special importance in lung cancer, since they share affected tissue. Despite its clinical relevance, Pn development remains an unpredictable treatment adverse effect, whose mechanisms are mainly unknown, being even more obscure when it is associated to chemoimmunotherapy., Methods: In order to identify parameters associated to treatment related Pn, we analyzed clinical variables and molecular parameters from 46 patients with potentially resectable stage IIIA non-small-cell lung cancer treated with neoadjuvant chemoimmunotherapy included in the NADIM clinical trial (NCT03081689). Pn was defined as clinical or radiographic evidence of lung inflammation without alternative diagnoses, from treatment initiation to 180 days., Results: Among 46 patients, 12 developed Pn (26.1%). Sex, age, smoking status, packs-year, histological subtype, clinical or pathological response, progression-free survival, overall survival and number of nivolumab cycles, were not associated to Pn development. Regarding molecular parameters at diagnosis, Pn development was not associated to programmed death ligand 1, TPS, T cell receptor repertoire parameters, or tumor mutational burden. However, patients who developed Pn had statistically significant lower blood median levels of platelet to monocyte ratio (p=0.012) and teratocarcinoma-derived growth factor 1 (p=0.013; area under the curve (AUC) 0.801), but higher median percentages of natural killers (NKs) (p=0.019; AUC 0.786), monocytes (p=0.017; AUC 0.791), MSP (p=0.006; AUC 0.838), PARN (p=0.017; AUC 0.790), and E-Cadherin (p=0.022; AUC 0.788). In addition, the immune scenario of Pn after neoadjuvant treatment involves: high levels of neutrophils and NK cells, but low levels of B and T cells in peripheral blood; increased clonality of intratumoral T cells; and elevated plasma levels of several growth factors (EGF, HGF, VEGF, ANG-1, PDGF, NGF, and NT4) and inflammatory cytokines (MIF, CCL16, neutrophil gelatinase-associated lipocalin, BMP-4, and u-PAR)., Conclusions: Although statistically underpowered, our results shed light on the possible mechanisms behind Pn development, involving innate and adaptative immunity, and open the possibility to predict patients at high risk. If confirmed, this may allow the personalization of both, the surveillance strategy and the therapeutic approaches to manage Pn in patients receiving chemoimmunotherapy., Competing Interests: Competing interests: EN reports personal fees from Bristol Myers Squibb, personal fees from Merck Sharpe & Dohme, personal fees from AstraZeneca, grants and personal fees from Roche, grants and personal fees from Pfizer, personal fees from Lilly, personal fees from Amgen, personal fees from Boehringer Ingelheim, outside the submitted work; AI reports personal fees from Bristol, personal fees from BOERINGHER, personal fees from MSD, personal fees from PFIZER, personal fees from Roche, personal fees from ASTRA ZENECA, outside the submitted work; MD reports personal fees from Astra-Zeneca, personal fees from BMS, personal fees from Boehringer Ingelheim, personal fees from MSD, personal fees from Pfizer, personal fees from Roche, outside the submitted work; MM reports grants and personal fees from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from BOEHRINGER INGELHEIM, personal fees, non-financial support and other from ASTRA ZENENCA, personal fees, non-financial support and other from ROCHE, personal fees from KYOWA KYRIN, personal fees from PIERRE FABRE, outside the submitted work; DRA reports grants and personal fees from Bristol-Myers-Squibb, personal fees from GENENTECH/ROCHE, personal fees from MSD, personal fees from ASTRA ZENECA, personal fees from BOEHRINGER INGELHEIM, personal fees from Novartis, personal fees from Lilly, outside the submitted work; AM-M reports personal fees and non-financial support from Bristol-Myers Squibb, personal fees and non-financial support from F. Hoffmann La Roche AG, personal fees and non-financial support from Merck Sharp & Dohme, personal fees and non-financial support from Pfizer, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from MSD Oncology, personal fees, non-financial support and other from AstraZeneca, outside the submitted work; JDCC reports personal fees from Astra Zeneca, personal fees from Boehringer Ingelheim, personal fees from Merck Sharp and Dohme, personal fees from Hoffmann-la Roche, personal fees from Bristol-Myers Squibb, personal fees from Takeda, personal fees from Pfizer, personal fees from Novartis, outside the submitted work; EDB reports non-financial support from ROCHE, BMS, PFIZER, ASTRA-ZENECA, MERCK, during the conduct of the study; IBA reports consulting or advisory board for Bristol Myers, Takeda, Roche, Astra Zeneca, Behringer Inngelheim; SV reports personal fees and non-financial support from BMS, personal fees and non-financial support from ROCHE, personal fees from MSD, personal fees from ABBVIE, non-financial support from OSE IMMUNOTHERAPEUTICS, non-financial support from MERCK SERONO, outside the submitted work; BM reports grants and personal fees from Roche, personal fees and other from BMS, personal fees from Takeda, other from MSD, personal fees from Boehringer, other from Takeda, outside the submitted work; AT.R. reports personal fees from Boehringer Ingelheim, outside the submitted work;MP reports grants, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from ROCHE, grants, personal fees and non-financial support from ASTRAZENECA, personal fees from MSD, personal fees from TAKEDA, outside the submitted work; BS-R, AC-B, YG, JM, JC-R, MCo, GLV, RB, NV, RL-B, MC, AG-G and FF declare no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: dNLR at the baseline (B), defined by neutrophils/[leucocytes-neutrophils], correlates with immune-checkpoint inhibitor (ICI) outcomes in advanced non-small-cell lung cancer (aNSCLC). However, dNLR is dynamic under therapy and its longitudinal assessment may provide data predicting efficacy. We sought to examine the impact of dNLR dynamics on ICI efficacy and understand its biological significance., Patients and Methods: aNSCLC patients receiving ICI at 17 EU/US centres were included [Feb/13-Jun/18]. As chemotherapy-only group was evaluated (NCT02105168). dNLR was determined at (B) and at cycle2 (C2) [dNLR≤3 = low]. B+C2 dNLR were combined in one score: good = low (B+C2), poor = high (B+C2), intermediate = other situations. In 57 patients, we prospectively explored the immunophenotype of circulating neutrophils, particularly the CD15+CD244-CD16 low cells (immature) by flow cytometry., Results: About 1485 patients treatment with ICI were analysed. In ICI-treated patients, high dNLR (B) (~1/3rd) associated with worse progression-free (PFS)/overall survival (OS) (HR 1.56/HR 2.02, P < 0.0001) but not with chemotherapy alone (N = 173). High dNLR at C2 was associated with worse PFS/OS (HR 1.64/HR 2.15, P < 0.0001). When dNLR at both time points were considered together, those with persistently high dNLR (23%) had poor survival (mOS = 5 months (mo)), compared with high dNLR at one time point (22%; mOS = 9.2mo) and persistently low dNLR (55%; mOS = 18.6mo) (P < 0.0001). The dNLR impact remained significant after PD-L1 adjustment. By cytometry, high rate of immature neutrophils (B) (30/57) correlated with poor PFS/OS (P = 0.04; P = 0.0007), with a 12-week death rate of 49%., Conclusion: The dNLR (B) and its dynamics (C2) under ICI associate with ICI outcomes in aNSCLC. Persistently high dNLR (B+C2) correlated with early ICI failure. Immature neutrophils may be a key subpopulation on ICI resistance., Competing Interests: Conflict of interest statement LM: Sponsored Research: Amgen, Bristol-Myers Squibb, Boehringer Ingelheim. Consulting, advisory role: Roche Diagnostics, Takeda, Roche. Lectures and educational activities: Bristol-Myers Squibb, Tecnofarma, Roche. Travel, Accommodations, Expenses: Bristol-Myers Squibb, Roche. Mentorship program with key opinion leaders: funded by AstraZeneca. IP has served as a consultant for AstraZeneca, Pfizer and BluePrint Medicines. EA: Travel expenses: Mundipharma. Lectures and educational activities: Sanofi Genzymes. DS, HR, JR, SP, SC, FB, FT, MLR, PS, JG, AJP, MC, MN, CR, APM, LC and WPhad nothing to disclose. LH: none related to the current article, outside of the current article: research funding Roche Genentech, Boehringer Ingelheim, AstraZeneca (all institution), advisory board: Boehringer, BMS, Eli Lilly, Roche Genentech, Pfizer, Takeda, MSD, Boehringer Ingelheim, Amgen (all institution), speaker: MSD, travel/conference reimbursement: Roche Genentech (self); mentorship program with key opinion leaders: funded by AstraZeneca; fees for educational webinars: Quadia (self), interview sessions funded by Roche Genentech (institution), local PI of clinical trials: AstraZeneca, Novartis, BMS, MSD/Merck, GSK, Takeda, Blueprint Medicines, Roche Genentech, Janssen Cilag. EN: none related to the current article, outside of the current article: research support from Roche and Pfizer; advisory boards from Bristol Myers Squibb, Merck Sharpe & Dohme, Lilly, Roche, Pfizer, Takeda, Boehringer Ingelheim, Amgen and AstraZeneca. PM: Principal/subinvestigator of Clinical Trials for Abbvie, Adaptimmune, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co, Clovis Oncology, Cullinan-Apollo, Daiichi Sankyo, Debiopharm, Eisai, Eisai Limited, Eli Lilly, Exelixis, Forma Tharapeutics, Gamamabs, Genentech, Glaxosmithkline, H3 Biomedicine, Hoffmann La Roche Ag, Imcheck Therapeutics, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kyowa Kirin Pharm. Dev, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Molecular Partners Ag, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncopeptides, Orion Pharma, Ose Pharma, Pfizer, Pharma Mar, Pierre Fabre, Medicament, Roche, Sanofi Aventis, Sotio A.S, Syros Pharmaceuticals, Taiho Pharma, Tesaro, Xencor Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche. CAV: Personal fees from Roche, AbbVie, MSD, Bristol-Myers Squibb, Novartis, Astra Zeneca, Takeda and Ipsen. PB: Speaker bureau: AstraZeneca, BMS, Roche, MSD. Honoraria: Beigene. SN: Speaker Bureau/Advisor: Amgen, AstraZeneca, Boehringer, Beigene, MSD, Roche, Takeda, Pfizer. MDH receives research support from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles and Arcus; received travel support/honoraria from AstraZeneca, Eli Lilly and Bristol-Myers Squibb; has options from Shattuck Labs, Immunai and Arcus; has a patent filed by his institution related to the use of tumour mutation burden to predict response to immunotherapy (PCT/US2015/062,208), which has received licensing fees from PGDx. GZ: Grants and personal fees from BMS, non-financial support from MSD, personal fees from Borhinger, non-financial support from Roche, personal fees from Astra-Zeneca, non-financial support from Abbvie, outside the submitted work. MM: Grants and personal fees from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from BOEHRINGER INGELHEIM, personal fees, non-financial support and other from ASTRA ZENENCA, personal fees, non-financial support and other from ROCHE, personal fees from KYOWA KYRIN, personal fees from PIERRE FABRE, outside the submitted work. LPA: Honoraria (self): Adacap, Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Incyte, Ipsen, Merck, Merck Sharp and Dohme, Novartis, Pfizer, Pharmamar, Roche, Sanofi, Servier, Sysmex, Takeda; Leadership role: Altum sequencing; Research grant/Funding (self): AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer; Officer/Board of Directors Genómica. AMD: Consulting, advisory role or lectures: Roche, Eli Lilly, Boehringer Ingelheim, Astra Zeneca, Pfizer, BMS, Amgen, Novartis, MSD, Takeda, Pharmamar. Research support: Amgen, Abbvie, BMS. DP: Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer; Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer. CME, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene. Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmune, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer. NC: Sponsored Research at Gustave Roussy Cancer Center BMS fondation, GSK, Sanofi, advisory role and lectures: AstraZeneca. These are outside the scope of this work. GL: Research support Merck serono, BMS, Pfizer, AstraZeneca, Blueprint medicines. KA: Consultant for Astrazeneca and Iovance Biotherapeutics. Her institution has received non-monetary research support from Takeda and Novartis on her behalf. BB: Sponsored Research at Gustave Roussy Cancer Center Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Immunotherapy is being tested in early-stage non-small cell lung cancer (NSCLC), and achieving higher rates of complete pathological responses (CPR) as compared to standard of care. Early identification of CPR patients has vital clinical implications. In this study, we focused on basal peripheral immune cells and their treatment-related changes to find biomarkers associated to CPR., Methods: Blood from 29 stage IIIA NSCLC patients participating in the NADIM trial (NCT03081689) was collected at diagnosis and post neoadjuvant treatment. More than 400 parameters of peripheral blood mononuclear cells (PBMCs) phenotype and plasma soluble factors were analyzed., Results: Neoadjuvant chemoimmunotherapy altered more than 150 immune parameters. At diagnosis, 11 biomarkers associated to CPR were described, with an area under the ROC curve >0.70 and p-value <.05. CPR patients had significantly higher levels of CD4 + PD-1 + cells, NKG2D, and CD56 expression on T CD56 cells, intensity of CD25 expression on CD4 + CD25hi + cells and CD69 expression on intermediate monocytes; but lower levels of CD3 + CD56 - CTLA-4 + cells, CD14 ++ CD16 + CTLA-4 + cells, CTLA-4 expression on T CD56 cells and lower levels of b-NGF, NT-3, and VEGF-D in plasma compared to non-CPR. Post treatment, CPR patients had significantly higher levels of CD19 expression on B cells, BCMA, 4-1BB, MCSF, and PARC and lower levels of MPIF-1 and Flt-3L in plasma compared to non-CPR., Conclusions: Patients achieving CPR seem to have a distinctive peripheral blood immune status at diagnosis, even showing different immune response to treatment. These results reinforce the different biology behind CPR and non-CPR responses., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Purpose: In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)-mutated metastatic non-small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors., Methods: This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety., Findings: Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median T max for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29-1.69), with an increase in exposure (AUC tau and C max ) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%)., Implications: Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104., Competing Interests: DISCLOSURES Dr. Moreno has received personal fees (advisory board honoraria) from Bristol Myers Squibb, Bayer, Pieris, Janssen, Roche and Basilea, outside of the current work. Dr. Greil has received personal fees from AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, AbbVie, Gilead, Daiichi Sankyo, and Janssen, outside of the current work. Dr. Arkenau is employed by the Sarah Cannon Research Institute, UK (part of HCA Healthcare UK); and has received personal fees (advisory board honoraria) from Pierre Fabre, Servier, BeiGene, Bicycle, BioNTech, iOnctura, Roche, Guardant and Taiho, outside of the current work. Dr. Majem has received grant support and personal fees from Bristol Myers Squibb; personal fees and non-financial support from Merck Sharp & Dohme and Boehringer Ingelheim; personal fees, non-financial support, and other support from AstraZeneca and Roche; and personal fees from Kyowa Kirin and Pierre Fabre, all of which are outside of the current work. Dr. Wermke has received grant support (research funding) and personal fees (honoraria) from Novartis, outside of the current work. Dr. Basque, Kapoor, and Giovannini and Mr. Nidamarthy are full-time employees of Novartis. Dr. Cui is a full-time employee and shareholder of Novartis. The authors have indicated that they have no other conflicts of interest regarding the content of this article. Data were collected and analyzed by the sponsor (Novartis Pharmaceuticals Corporation) in conjunction with the authors., (Copyright © 2021. Published by Elsevier Inc.)