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For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB 1,2 . Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial 3 . Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8 + cytotoxic T cells, but relative sparing of CD4 + effector subsets. Dual ICB potently engaged CD4 + effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4 + and CD8 + T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations., Competing Interests: Competing interests F.S. reports consulting for AstraZeneca, Amgen, Revolution Medicines, Novartis, BridgeBio, Beigene, BergenBio, Guardant Health, Calithera Biosciences, Tango Therapeutics, Hookipa Pharma, Novocure, Merck Sharp & Dohme, Roche; grant or research support from Amgen, Mirati Therapeutics, Revolution Medicines, Pfizer, Novartis, Merck & Co; stockholder in BioNTech, Moderna; and honoraria from ESMO, Japanese Lung Cancer Society, Medscape, Intellisphere, VSPO McGill Universite de Montreal, RV Mais Promocao Eventos, MJH Life Sciences, IDEOlogy Health, MI&T, PER, CURIO, DAVA Oncology, the American Association for Cancer Research and the International Association for the Study of Lung Cancer. M.M. reports stockholder in Roche Holdings. N.J. reports shareholder and former employee of Pionyr Immunotherapeutics. J.M.J. reports stock of D2G Oncology. C.M., Y.Y., X.P. and A.H. report employee of Tango Therapeutics. K.C.A. reports personal fees from Sanofi Genzyme and other support from Revolution Medicines, Genentech, and Mirati outside the submitted work. N.V. receives consulting fees from Sanofi Genzyme, Oncocyte, Eli Lilly, Regeneron, and research funding to the institution from Mirati, Oncocyte, and Circulogene, outside the submitted work. P.D.P. reports advisory fees from AstraZeneca and Jazz Pharmaceuticals. M.E.M. reports research funding from Eli Lilly (Inst), AstraZeneca (Inst), Merck (Inst), Genentech (Inst); consulting role with AstraZeneca, Novocure, Boehringer Ingelheim, Janssen, Takeda, Blueprint Pharmaceuticals, Bayer, Bristol Myers Squibb, Ikena; honorarium from Thermo Fisher Scientific; and stock in Merck, Johnson & Johnson. M.M.A. reports grants and personal fees from Genentech, Bristol Myers Squibb and AstraZeneca; grants from Lilly; and personal fees from Maverick, Blueprint Medicine, Syndax, Nektar, Gritstone, ArcherDX, Mirati, NextCure, Novartis, EMD Serono and Panvaxal/NovaRX, outside of the submitted work. J.C.M. reports consulting or honoraria: MJH Life Sciences, Johnson & Johnson and Doximity; and research funding (to institution): Merck via the Conquer Cancer Foundation. J.F.G. reports served as a compensated consultant or received honoraria from Bristol Myers Squibb, Genentech (Roche), Takeda, Loxo (Lilly), Blueprint Medicine, Gilead, Moderna, AstraZeneca, Mariana Therapeutics, Mirati, Jounce, Merus Pharmacueticals, Nuvalent, Pfizer, Novocure, AI Proteins, Novartis, Merck, iTeos, Karyopharm and Silverback Therapeutics; research support from Novartis, Genentech (Roche) and Takeda; institutional research support from Bristol Myers Squibb, Palleon, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis and Alexo; has equity in AI Proteins; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. A.D. reports honoraria: Intellisphere, Roche (Genentech); ad board: TP Therapeutics, Guardant Health, AnHeart Therapeutics, ChromaCode; clinical trial support: Syntrix Pharmaceuticals, Novartis, Merck, AnHeart Therapeutics, Sorrento Therapeutics, Guardant Health and Philogen. C. M. Bestvina reports consulting or advisory role: AstraZeneca, Genentech, AbbVie, Curio Science, OncLive Clinical Congress Consultants, Seagen, Creative Educational Concepts, Takeda, Janssen, CVS, Bristol Myers Squibb (Celgene), Jazz Pharmaceuticals, Novartis, Sanofi–Regeneron and Novocure; speakers’ bureau: Merck; research funding: Bristol Myers Squibb and AstraZeneca. C.A.S. reports advisory boards to AstraZeneca, Gilead, Janssen, Genentech, Mirati, Takeda and Arcus Biosciences. J.W.R. reports honoraria or consulting (self): Boehringer Ingelheim, BMS, Turning Point Roche (Genentech), Biodesix, EMD Serono, Daiichi Sankyo, Blueprint, Novartis, Regeneron, Sanofi, Janssen, Jazz Pharmaceuticals, Bayer, Beigene, Merus and Seagen; research support (to institution): ArriVent, Merck, Novartis, AstraZeneca, Spectrum, Revolution Medicines, IO Biotech and Kinnate. C. M. Blakely reports research funding: AstraZeneca, Novartis, Mirati, Spectrum, Takeda, Puma and Pfizer; and consulting: Janssen and Bayer. C.V.P. reports a founder and equity and intellectual property in EnFuego Therapeutics. F.T. reports speaker bureau or honoraria: Roche, AstraZeneca, Novartis and Takeda. M.S. reports institutional support: Dracen Pharmaceuticals; advisory board: Amgen, AstraZeneca, Boehringer Ingelheim, Janssen Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Aventis, Siemens Healthineers, Takeda Pharmaceuticals and Bristol Myers Squibb; leadership or fiduciary role: ESMO and EORTC. S.D. reports independent image analysis for hospital-contracted clinical research trials programs for Merck, Pfizer, Bristol Myers Squibb, Novartis, Roche, Polaris, Cascadian, Abbvie, Gradalis, Bayer, Zai laboratories, Biengen, Resonance and Analise; research grants from Lunit, GE, Qure AI; and an honorarium from Siemens. M.J.M. reports AstraZeneca, Bristol Myers Squibb and Istari Oncology & Regeneron. A.G.S. reports AstraZeneca, Genentech (Roche) and Bristol Myers Squibb. A.N.S. reports serving as a consultant and/or advisory board member for Eli Lilly, Daiichi Sankyo and Zymeworks; and research funding from Eli Lilly, Novartis, Daiichi Sankyo, Genentech, AstraZeneca, Memgen, Mersana, Turning Point Therapeutics, BioAtla and Genmab to his institution. J.R. reports consulting fees or honoraria from AstraZeneca, Takeda, Sanofi Genzyme, Genentech, Guardant Health, Summit, G1 Therapeutics, BioAtla, Jazz, Amgen, and Janssen; contracted for research (institutional) with AstraZeneca, BioAtla, Blueprint Medicines, EpimAb Biotherapeutics, LOXO Oncology, Enliven, Redcloud and ORIC. T.S. reports advisory board or consulting fees for Seagen, Astellas and AstraZeneca; and research grant GRAIL. S.B.G. reports research funding from AstraZeneca, Boehringer Ingelheim and Mirati; and consulting or advisory board member for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech, Amgen, Blueprint Medicine, Sanofi Genzyme, Daiichi Sankyo, Takeda, Janssen, Summit Therapeutics, Merck and Regeneron. J.K. reports for Arterys. K.S. reports consultant, advisor or speaker for Clinica Alemana Santiago, Shattuck Labs, AstraZeneca, EMD Serono, Takeda, Torque/Repertoire Therapeutics, CSRlife, Agenus, Genmab, OnCusp, Parthenon Therapeutics, Bristol Myers Squibb, Roche, Molecular Templates, Abbvie, Sanofi, Merck, PeerView, PER and Forefront Collaborative; research funding from Navigate BP, Tesaro/GSK, Moderna, Takeda, Surface Oncology, Pierre-Fabre, Merck, Bristol Myers Squibb, AstraZeneca, Ribon Therapeutics, Eli Lilly, Boehringer Ingelheim, Genentech (Roche) and Akoya Biosciences. K.D.D. reports consulting fees or other remuneration from Rain Therapeutics. V.A. reports research funding to Johns Hopkins University from AstraZeneca and Personal Genome Diagnostics, has received research funding to Johns Hopkins University from Bristol Myers Squibb and Delfi Diagnostics in the past five years and is an advisory board member for Neogenomics and AstraZeneca. V.A. is an inventor on patent applications (63/276,525, 17/779,936, 16/312,152, 16/341,862, 17/047,006 and 17/598,690) submitted by Johns Hopkins University related to cancer genomic analyses, ctDNA therapeutic response monitoring and immunogenomic features of response to immunotherapy that have been licensed to one or more entities. Under the terms of these license agreements, the University and inventors are entitled to fees and royalty distributions. K.A.M. reports consulting or advisory fees from AstraZeneca, Amgen, Janssen, Mirati Therapeutics, Daiichi Sankyo (Lilly) and Puma Biotechnology, as well as honoraria from AstraZeneca. K.A.M. receives research funding to Johns Hopkins University from Bristol Myers Squibb and Mirati Therapeutics. P.M.F. reports consulting fee (for example, advisory board): Ascendis, AstraZeneca, BMS, Curevac, Novartis, Regeneron, G1, Genelux, Genentech, Gritstone, Merck, Janssen, F-Star, Sanofi, Amgen, Fosun, Teva, Synthekine, Flame, Iteos, Tavotek and Teva; contracted research: AstraZeneca, BMS, Novartis, Regeneron and BioNTech. B.R. reports advisory board or consultant: Regeneron, AstraZeneca, Amgen; honoraria: Targeted Oncology. E.M.V.A reports advisory or consulting: Tango Therapeutics, Genome Medical, Genomic Life, Enara Bio, Manifold Bio, Monte Rosa, Novartis Institute for Biomedical Research, Riva Therapeutics and Serinus Bio; research support: Novartis, BMS and Sanofi; equity: Tango Therapeutics, Genome Medical, Genomic Life, Syapse, Enara Bio, Manifold Bio, Microsoft, Monte Rosa, Riva Therapeutics and Serinus Bio; patents: institutional patents filed on chromatin mutations and immunotherapy response, and methods for clinical interpretation; intermittent legal consulting on patents for Foaley & Hoag; editorial boards: JCO Precision Oncology and Science Advances. A.L.C. reports consulting for AstraZeneca, Merus and Tempus; research funds from AstraZeneca, Genentech (Roche), Merck and Novartis. J.W.G. reports research grants: AstraZeneca, BMS, Eli Lilly, Genentech, Merck and Pfizer; consulting fees: AstraZeneca, BMS, Genentech, Gilead, Gritstone, Eli Lilly, Pfizer and Regeneron. C.A. reports consulting or advisory role: Genentech, Lilly, Celgene, Merck, AstraZeneca, Blueprint Genetics, Shionogi, Daiichi Sankyo–AstraZeneca, Sanofi/Regeneron, Eisai, BeiGene, Turning Point Therapeutics, Pfizer, Janssen, Boehringer Ingelheim; research funding: Genentech/Roche (Inst), Incyte (Inst), Macrogenics (Inst), Merck Sharp & Dohme (Inst) and AstraZeneca–MedImmune (Inst). L.R. reports honoraria: Merck, AstraZeneca, Genzyme, EMD Serono and Astellas Pharmas; consulting or advisory role: Amgen. J.W.N. reports honoraria: CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, HMP education consulting or advisory role: AstraZeneca, Genentech (Roche), Exelixis, Takeda Pharmaceuticals, Eli Lilly, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, Abbive, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, Anheart Therapeutics Research Funding: Genentech (Roche), Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektart Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GlaxoSmithKline, Janssen Pharmaceuticals, Abbvie Pharmaceuticals and Novocure. Y.Y.E. reports honoraria: CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, HMP education consulting or advisory role: AstraZeneca, Genentech (Roche), Exelixis, Takeda Pharmaceuticals, Eli Lilly, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, Abbive, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, Anheart Therapeutics Reserach Funding: Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektart Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GlaxoSmithKline, Janssen Pharmaceuticals, Abbvie Pharmaceuticals and Novocure. M.V.N. reports research funding to institution: Mirati, Novartis, Checkmate (ended), Alaunos, AstraZeneca, Pfizer, Genentech, Navire; consultant or advisory board: Mirati, Merck/MSD, Novartis and Genentech. X.L. reports receiving consulting or advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen, Blueprint Medicines, Regeneron, Sensei Biotherapeutics, Abion and Abbvie, and research funding from Eli Lilly, EMD Serono, Janssen, ArriVent, Teligene, BlackDiamond, Regeneron and Boehringer Ingelheim. V.K.L. reports consultant or advisory role for Takeda, Seattle Genetics, BMS, AstraZeneca, Guardant Health and AnHeart Therapeutics and has received research funding from GSK, BMS, AstraZeneca, Merck and Seattle Genetics. W.E.L. reports advisory boards: Eisai and Takeda, Grand Rounds and BMS for repotrectinib. J.A.R. reports consultancy, stock, Genprex; patents issued and pending. T.C. reports speaker fees or honoraria from the Society for Immunotherapy of Cancer (SITC), Mark Foundation for Cancer Research, Bristol Myers Squibb, Roche, Medscape, IDEOlogy Health, Physicians’ Education Resource (PER), OncLive and PeerView; travel and/or food/beverage expenses from SITC, International Association for the Study of Lung Cancer, Parker Institute for Cancer Immunotherapy, PER, Dava Oncology, IDEOlogy Health, AstraZeneca and Bristol Myers Squibb; advisory role or consulting fees from MedImmune–AstraZeneca, Bristol Myers Squibb, Merck, Genentech, Arrowhead Pharmaceuticals, Pfizer and Regeneron; and institutional research funding from MedImmune–AstraZeneca, Bristol Myers Squibb and EMD Serono. J.Z. reports grants from Merck, grants and personal fees from Johnson & Johnson and Novartis, personal fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent and Hengrui outside the submitted work. G.R.B. reports grant or contract for clinical trial from MacroGenics; grants from Amgen, Bayer, Adaptimmune, Exelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, MacroGenics, Torque, AstraZeneca, Bristol Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Sanofi, Xcovery, Tmunity Therapeutics, Regeneron, BeiGene, Repertoire Immune Medicines, Verastem, CytomX Therapeutics and Duality Biologics; consulting fees from AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Genzyme, Gilead, Eli Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Sanofi, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics, BeiGene, Regeneron, Cytomx Therapeutics, Intervenn Biosciences and Onconova Therapeutics; participation in advisory boards at Virogin Biotech and Maverick Therapeutics; stock in Virogin Biotech; and employment of family member at Johnson & Johnson/Janssen. C.G. reports member of the advisory board at Jazz Pharmaceuticals, AstraZeneca and Bristol Myers Squibb and served as speaker for AstraZeneca and BeiGene. L.A.B. reports consulting fees and research funding from AstraZeneca, GenMab and Sierra Oncology and research funding from Tolero Pharmaceuticals and served as advisor or consultant for PharmaMar, AbbVie, Bristol Myers Squibb, Alethia, Merck, Pfizer, Jazz Pharmaceuticals, Genentech and Debiopharm Group. D.L.G. reports AstraZeneca, Eli Lilly, Menarini Richerche, 4D Pharma, Onconova Therapeutics and Sanofi. A.T. reports Ariad, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Seattle Genetics, Gilead Sciences and Summit Therapeutics. T.G.B. reports Chan-Zuckerberg Biohub. D.R.C. reports CoI Company sponsored trials at institution (PI roles): AZ, Roche (Genentech) advisory role: ad hoc advisory boards or consultations 2023: Abbvie (steering committee), Anheart, Beigene (IDMC), Eli Lilly (IDMC), Imagene, Immunocore, Janssen, Mirati (IDMC), Prelude, Seattle Genetics, Valencee; 2022: Abbvie, Anheart, Appolomics (SRC), AstraZeneca–Daiichi (ILD adjudication committee), Beigene (DSMB) Dizal, EMD Serono, Elevation, Hengrui, (DSMB), Hummingbird, Janssen, Medtronic, Mersana (ILD adjudication committee), Mirati, Nalo Therapeutics, Onkure, Regeneron, Roche, Sanofi, Takeda, Theseus, Xcovery; 2021: Abbvie, Amgen, Anheart, Apollomics (SRC), AstraZeneca (SRC/SC), Beigene (DSMC), Bio-Thera (DSMB), Blueprint, Daiichi Sankyo (ILD adjudication committee), Elevation (SRC), Eli Lilly (DSMB and NCCN), EMD Serono, Helsinn (DSMB), Hengrui (DSMC), Janssen, Kestrel (SAB, Shares), Mersana, Nuvalent (SAB), Puma (NCCN), Ribon, Roche (Genentech), Sanofi, Seattle Genetics, Takeda and Turning Point. J.E.G. reports honoraria: Jazz Pharmaceuticals, Merck and OncoCyte; consulting or advisory role: AstraZeneca, Blueprint Medicines, Bristol Myers Squibb, EMD Serono, Lilly, Sanofi, Merck Sharp & Dohme, Loxo, Jazz Pharmaceuticals, Novartis, AstraZeneca–MedImmune, Janssen Scientific Affairs, National Comprehensive Cancer Network, AbbVie and Regeneron; research funding: Merck (Inst), AstraZeneca (Inst), Bristol Myers Squibb (Inst), Boehringer Ingelheim (Inst), Genentech (Roche) (Inst), G1 Therapeutics (Inst), Novartis (Inst), Pfizer (Inst), Ludwig Institute for Cancer Research (Inst), SWOG (Inst), Array BioPharma (Inst) and ECOG-ACRIN (Inst). N.L. reports CME and research funding: AstraZeneca. B.L. reports Genentech (Roche), Eli Lilly, Merck, Pfizer, Janssen, Daiichi Sankyo, Takeda, Mirati, Novartis and Guardant 360. J.R.B. reports grant funding: AstraZeneca; advisory board: AstraZeneca, Amgen, Novartis, Incyte, Bristol Myers Squibb, Genentech, Janssen, Sanofi, Regeneron, Merck, GlaxoSmithKline; DSMB: Sanofi, Janssen and GlaxoSmithKline. M.C.G. reports AstraZeneca, Abion, MSD International, Bayer, BMS, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Incyte, Novartis, Pfizer, Roche, Takeda, Seattle Genetics, Mirati, Daiichi Sankyo, Regeneron, Merck, Blueprint, Janssen, Sanofi, AbbVie, BeiGenius, Oncohost and Medscape. D.R.G. reports institutional research grants from Amgen, AstraZeneca, Genentech and Merck; consultant or advisory board for Adagene, AstraZeneca, Roche (Genentech), Guardant, IO Biotech, Oncocyte, OncoHost, Lilly, Merck and Novartis. E.B.G. reports consulting or advisory role: Novartis, GlaxoSmithKline, Merck, Boehringer Ingelheim, Shionogi, Eisai, Bristol Myers Squibb, ABL Bio, Xilio Therapeutics, Natera, Sanofi–Regeneron, Lilly, Personalis, Gilead Sciences, AstraZeneca, AbbVie–Abbott, Arcus Biosciences, Seagan and Summit Therapeutics; research funding: Merck (Inst), Genentech (Inst), AstraZeneca (Inst), Novartis (Inst), Lilly (Inst), Bristol Myers Squibb (Inst), Mirati Therapeutics (Inst), Dynavax Technologies (Inst), Iovance Biotherapeutics (Inst), Neon Therapeutics (Inst), EMD Serono (Inst), ABL Bio (Inst) and Daiichi Sankyo–UCB Japan (Inst); patents, royalties, other intellectual property: diagnosistic and therapeutic use of ‘Motif Neoepitopes’ as defined by Cummings et al.76. N.A.R. reports an employee at Synthekine and holds equity at Synthekine and Gritstone. G.V.S. reports honoraria, research funding and personal fees from AstraZeneca, Bayer, BeiGene Switzerland, F. Hoffman–La Roche, Merck Sharpe & Dohme, Eli Lilly, Johnson & Johnson, Pfizer, Takeda Oncology, Tesaro and Verastem outside the submitted work. J.W. reports advisory boards and lecture fees: Amgen, AstraZeneca, Bayer, Blueprint, BMS, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Ignyta, Janssen, Lilly, Loxo, Merck, Mirati, MSD (Merck Sharp & Dohme), Novartis, Nuvalent, Pfizer, Roche, Seattle Genetics, Takeda and Turning Point; research support (to institution): BMS, Janssen, Novartis, Pfizer and AstraZeneca. B.B. reports receiving grants from AbbVie, Amgen, AstraZeneca, Chugai, Daiichi Sankyo, Ellipse, EISAI, Genmab, Genzyme Corporation, Hedera Dx, Inivata, IPSEN, Janssen, MSD, PharmaMar, Roche (Genentech), Sanofi, Socar Research, Tahio Oncology and Turning Point Therapeutics. R.S.H. reports consulting roles with AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Biodesix, Bolt Biotherapeutics, Bristol Myers Squibb, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Genentech (Roche), Genmab, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Merck, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Oncternal Therapeutics, Pfizer, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen and WindMIL Therapeutics; advisory board roles with AstraZeneca, Bolt Biotherapeutics, Cybrexa Therapeutics, EMD Serono, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Neon Therapeutics, Novartis and STCube Pharmaceuticals; research support from AstraZeneca, Eli Lilly, Genentech (Roche) and Merck; and non-executive board membership for Junshi Pharmaceuticals and Immunocore. H.A.W. reports grants or contracts from any entity: Bayer, Arrys Therapeutics, AstraZeneca–Medimmune, BMS, Clovis Oncology, Genentech (Roche), Merck, Novartis, Seagen, Xcovery and Helsinn; advisory board: Mirati, Merck and Genentech (Roche); leadership: International Association for the Study of Lung Cancer (IASLC), President; ECOG-ACRIN, executive committee. N.A.P. reports an employee at Synthekine and holds equity at Synthekine and Gritstone. A.T.S. is currently an employee of Novartis. P.A.J. reports stock and other ownership interests: Gatekeeper Pharmaceuticals and Loxo; consulting or advisory role: Pfizer, Boehringer Ingelheim, AstraZeneca, Merrimack, Chugai, Roche (Genentech), Loxo, Mirati Therapeutics, Araxes Pharma, Ignyta, Lilly, Takeda, Novartis, Biocartis, Voronoi Health Analytics, SFJ Pharmaceuticals Group, Sanofi, Daiichi Sankyo, Silicon Therapeutics, Nuvalent, Eisai, Bayer, Syndax, AbbVie, Allorion Therapeutics, Accutar Biotech, Transcenta, Monte Rosa Therapeutics, Scorpion Therapeutics, Merus, Frontier Medicines, Hongyun Biotech and Duality Biologics; research funding: AstraZeneca (Inst), Astellas Pharma (Inst), Daiichi Sankyo (Inst), Lilly (Inst), Boehringer Ingelheim (Inst), Puma Biotechnology (Inst), Takeda (Inst) and Revolution Medicines (Inst); patents, royalties, other intellectual property: I am a co-inventor on a DFCI owned patent on EGFR mutations licensed to Lab Corp. I receive post-marketing royalties from this invention. D.P.C. reports advisory boards or consulting: Abbvie, Arcus Biosciences, AstraZeneca, BMS Israel, G1 Therapeutics, Genentech, GlaxoSmithKline, InThought, Iovance Biotherapeutics, Janssen, Jazz, JNJ, Merck–EMD Serono, Merck KGaA, Mirati, MSD, Novartis, Novocure, OncoHost, Pfizer Egypt, Regeneron, Roche and Sanofi; KOL/presentation/education/forum: AstraZeneca, Curio Science, Intellisphere, Merck US, OncLive, Pfizer, PPD Development and Roche Taiwan. M.D.H. is an employee of and stockholder in AstraZeneca. C.M.R. reports consulted regarding oncology drug development with AbbVie, Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech (Roche), Ipsen, Jazz, Kowa, Lilly, Merck and Syros. He serves on the scientific advisory boards of Auron, Bridge Medicines, DISCO, Earli and Harpoon Therapeutics. L.A. is an employee of Foundation Medicine and a stockholder of Roche Holding AG. H.M. reports full-time employee of AstraZeneca and stock/shares. Z.Z. reports employee of AstraZeneca as well as stockholder of AstraZeneca and Pfizer. Z.L. reports full-time employee and stock owner of AstraZeneca. R.S. reports other support from AstraZeneca during the conduct of the study, as well as other support from Pfizer outside the submitted work. S.P. reports consultation or advisory role: AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Nykode Therapeutics, Novartis, Novocure, PharmaMar, Promontory Therapeutics, Pfizer, Regeneron, Roche (Genentech), Sanofi, Seattle Genetics and Takeda; Board of Directors position: Galenica; talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Roche (Genentech), Sanofi and Takeda; receipt of grants or research support: principal investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, Arcus, AstraZeneca, Beigene, Bristol Myers Squibb, GSK, iTeos, Merck Sharp and Dohme, Mirati, PharmaMar, Promontory Therapeutics, Roche (Genentech) and Seattle Genetics. J.M.J. and M.J.R. are employees and shareholders of D2G Oncology. I.P.W. is a co-founder, employee and shareholder of D2G Oncology. M.M.W. is a co-founder, shareholder, member of the board of directors and compensated scientific advisor of D2G Oncology. I.P.W. and M.M.W. are co-inventors of patents relating to technologies for an autochthonous mouse model of human cancer, which D2G Oncology has exclusively licensed from Stanford University. V.A.P. reports Pfizer employee and stockholder. K.K.W. is a founder and equity holder of G1 Therapeutics and has sponsored research agreements with Takeda, TargImmune, Bristol Myers Squibb, Mirati, Merus and Alkermes, and consulting and sponsored research agreements with AstraZeneca, Janssen, Pfizer, Novartis, Merck, Zentalis, BridgeBio and Blueprint. P.J. reports employee and stock or stock options of AstraZeneca. I.I.W. reports honoraria from Genentech (Roche), Bayer, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, Guardant Health, Flame, Novartis, Sanofi, Daiichi Sankyo, Amgen, Janssen, Merus, G1 Therapeutics, Abbvie, Catalyst Therapeutics, Regeneron, Oncocyte, Medscape, Platform Health and Physicians’ Education Resources; research support from Genentech, Merck, Bristol Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis and Akoya. A.G.P. reports Pfizer. J.V.H. reports Advisory Committees: Genentech, Mirati Therapeutics, Eli Lilly, Janssen, Boehringer Ingelheim, Regeneron, Takeda, BerGenBio, Jazz, Curio Science, Novartis, AstraZeneca, BioAlta, Sanofi, Spectrum, GlaxoSmithKline, EMD Serono, BluePrint Medicine and Chugai; research support: AstraZeneca, Boehringer Ingelheim, Spectrum, Mirati, Bristol Myers Squibb and Takeda; licensing or royalties: Spectrum. H.A.A., M.T.D., A.G.C., Y.Q., R.P., D.M., D.H.O., R.M., J.A.H., L.M., S.C.M.L., R.P.J., C.L., Z.W., M.G.W., D.V., H.S., M.K., S.K., Y.N., J.T.A., J.S., L.L., H.N.K., B.C., S.S., R.L., T.Z., J.J.L., D.P., M.L.J. T.T., A.P., Y.K. and J.L.: no disclosures were reported by these authors., (© 2024. The Author(s).)

Introduction: Small cell lung cancer (SCLC) is known to express high levels of the proangiogenic factor vascular endothelial growth factor (VEGF). We assessed the safety and tolerability of cediranib, an oral inhibitor of VEGF receptor tyrosine kinases, in combination with etoposide and cisplatin as first-line therapy for extensive-stage (ES) SCLC or metastatic lung neuroendocrine cancer (NEC)., Methods: Patients received up to six 21-day cycles of etoposide (100 mg/m 2 , days 1-3) and cisplatin (80 mg/m 2 , day 1) with once-daily cediranib until disease progression or unacceptable toxicity. Cediranib dosing started at 30 mg with de-escalation cohorts planned based on cycle 1 dose-limiting toxicities (DLTs). An expansion cohort of 12 patients was enrolled at the recommended phase II dose., Results: Twenty-two patients (18 with ES SCLC, 4 with NEC) received treatment. Only 4 patients were enrolled at the 30 mg cediranib dose before other studies established 20 mg/day as the recommended dose with chemotherapy. Among the 18 patients enrolled at the 20-mg dose, common adverse events included nausea/vomiting, neutropenia, and diarrhea; 8 patients (44%) had grade 1 or 2 hypertension, and 2 (11%) had grade 3 hemoptysis. For all 18 patients, the objective response rate and median progression-free survival duration were 67% and 7.9 months. Plasma levels of VEGF were significantly higher, and those of soluble VEGFR2 were significantly lower, on day 22 than at baseline but were not correlated with tumor shrinkage., Conclusions: Cediranib (20 mg) plus etoposide and cisplatin is well tolerated and has promising clinical activity., Competing Interests: Disclosure Kyle F. Concannon, MD: None. Bonnie S. Glisson, MD: None – Retired. Robert C. Doebele, MD, PhD: Licensing Fees for Biologic Materials: Roche, Foundation Medicine, ThermoFisher, Voronoi, Loxo, Takeda, Casma Therapeutics, Black Diamond, Histocyte. Payment or Honoraria: Clinical Cancer Research Journal (AACR), Guardant. Licensing Fees for Patent: Rain Oncology. Shareholder: Rain Oncology. Chao Huang, MD: None. Marcelo Marotti, MD, PhD: Employee: Summit Therapeutics. Shareholder: AstraZeneca, Summit Therapeutics. D. Ross Camidge, MD, PhD: Consulting Fees: Abbvie,Anheart, Apollomics, AstraZeneca/Daiichi, Beigene, BMS, Eli Lilly, Genesis, Sutro, Takeda. John V. Heymach, MD, PhD: Consulting Fees: AbbVie, AnHeart Therapeutics, ArriVent Biopharma, AstraZeneca, BioCurity Pharmaceuticals, BioNTech AG, Blueprint Medicines, BI, BMS, Chugai Pharmaceutical, Curio Science, DAVA Oncology, Eli Lily & Co, EMD Serono, Genentech, GlaxoSmithKline, IDEOlogy Health, Immunocore, InterVenn Biosciences, Janssen Biotech, Janssen Pharmaceuticals, Mirati Therapeutics, Moffitt Cancer Center, ModeX, Nexus Health Systems, Novartis Pharmaceuticals, OncoCyte, RefleXion, Regeneron Pharmaceuticals, Roche, Sandoz Pharmaceutical, Sanofi, Spectrum Pharmaceuticals, Takeda, uniQure. Honoraria or Speaker Fees: MJH Events, Dr. Neil Love. Support for Attending Meetings: AACR., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be spread by individuals unaware they are infected. Such dissemination has heightened ramifications in cancer patients, who may need to visit healthcare facilities frequently, be exposed to immune-compromising therapies, and face greater morbidity from coronavirus disease 2019 (COVID-19). We determined characteristics of (1) asymptomatic, clinically diagnosed, and (2) serologically documented but clinically undiagnosed SARS-CoV-2 infection among individuals with lung cancer., Patients and Methods: In a multicenter registry, individuals with lung cancer (regardless of prior SARS-CoV-2 vaccination or documented infection) underwent collection of clinical data and serial blood samples, which were tested for antinucleocapsid protein antibody (anti-N Ab) or IgG (N) levels. We used multivariable logistic regression models to investigate clinical characteristics associated with the presence or absence of symptoms and the presence or absence of a clinical diagnosis among patients with their first SARS-CoV-2 infection., Results: Among patients with serologic evidence or clinically documented SARS-CoV-2 infection, 80/142 (56%) had no reported symptoms at their first infection, and 61/149 (40%) were never diagnosed. Asymptomatic infection was more common among older individuals and earlier-stage lung cancer. In multivariable analysis, non-white individuals with SARS-CoV-2 serologic positivity were 70% less likely ever to be clinically diagnosed (P = .002)., Conclusions: In a multicenter lung cancer population, a substantial proportion of SARS-CoV-2 infections had no associated symptoms or were never clinically diagnosed. Because such cases appear to occur more frequently in populations that may face greater COVID-19-associated morbidity, measures to limit disease spread and severity remain critical., Competing Interests: Disclosure The authors report no conflicts directly relevant to the submitted work. Beyond this submission, the authors report the following disclosures: P.C.M. reports participation in advisory boards for Guardant Health, consulting for Vivace Therapeutics, and honoraria from Amgen. A.C.M. reports advisory board participation with Bayer, BMS, Exact Sciences, Gilead, and Novartis and board of directors of NTRKers. A.M.’s spouse, Dr. Martin Moore, is CSO and co-founder of Meissa Vaccines. J.C.K. reports consulting and advisory board participation for the following companies, all paid to GO2 for Lung Cancer: Amgen, Bristol Myers Squibb, Boehringer Ingelheim, and EQRX. C.R. reports speaker honoraria from AstraZeneca, Roche, and MSD; advisory board honoraria from Inivata, Archer, Boston Pharmaceuticals, MD Serono and Novartis, Bayer, Invitae, Regeneron, and Bostongene; scientific advisory board member for Imagene; institutional research funding from LCRF-Pfizer and NCRF; non-re-numerated research support from Guardant Health and Foundation Medicine; nonrenumerated leadership roles at the International Society of Liquid Biopsy (ISLB), the International Association for Study of Lung Cancer (IASLC), the European School of Oncology (ESO), and Oncology Latin American Association (OLA). J.D.M. reports licensing fees from the NIH and UTSW for distribution of human tumor cell lines. S.B. reports serving in consulting/advisory roles for Takeda, Mirati, and Merus. F.K. reports filed patents through The Icahn School of Medicine at Mount Sinai relating to SARS-CoV-2 serological assays, NDV-based SARS-CoV-2 vaccines, influenza virus vaccines, and influenza virus therapeutics, which list F.K. as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS- CoV-2, and another company, Castlevax, to develop SARS-CoV-2 vaccines. F.K. is co-founder and scientific advisory board member of Castle-vax. F.K. has consulted for Merck, Curevac, Seqirus, and Pfizer and is currently consulting for third Rock Ventures, GSK, Gritstone, and Avimex. He is also collaborating with Dynavax on influenza vaccine development. A.G.-S. has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avi-mex, Johnson & Johnson, Dynavax, 7Hills Pharma,Pharmamar, ImmunityBio, Accurius, Nanocompo-6, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories, and Merck, outside of the reported work; consulting agreements for the following companies involving cash and/or stock: Castlevax, Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Syn-airgen, Paratus, Pfizer, and Prosetta, outside of the reported work; has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astrazeneca; and is an inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer, owned by the Icahn School of Medicine at Mount Sinai, New York, outside of the reported work. K.L.R. has served on advisory boards for Amgen, AstraZeneca, Bluprint, Daiichi Sankyo, EMD Serono, Genentech, GlaxoSmithKline, Janssen, Lilly, Novocure, and Mirati A.A.M. holds a consultant or advisory role at Novartis, Amgen and MorphoSys and has research funding from Amgen and Pfizer. S.S.R. reports research funding (institutional) from AstraZeneca, Amgen, Merck, Bristol Myers Squibb, and Pfizer. F.R.H. reports advisory board participation with Amgen, AstraZeneca, Genentech, Merck, Novo-cure, NextCure, Regeneron, Sanofi, Daiichi, G1 Therapeutics, Novartis, Merus Therapeutics, and ITeos Therapeutics. F.R.H. also reports a patent through University of Colorado on ‘‘EGFR Protein and Gene Copy Number as Predictive Biomarker for EGFR-directed Therapy. D.E.G. reports consulting fees from Catalyst Pharmaceuticals; U.S. patent 11,747,345; pending patents 17/045,482, 63/386,387, 63/382,972, and 63/382,257; participating in advisory boards for Astra-Zeneca, Daiichi-Sankyo, Elevation Oncology, Janssen Scientific Affairs, Jazz Pharmaceuticals, Regeneron Pharmaceuticals, and Sanofi; stock shares in Gilead; and serving as co-founder and Chief Scientific Officer of OncoSeer Diagnostics, Inc. M.S., C.-Y.H., Y.H., J.E.G., A.M.R., J.C., S.C.T., J.M.C., R.B., N.C.R., P.A.B., J.C.F., E.K., M.N., and Y.S. report no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Newer-generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR ) mutations and anaplastic lymphoma kinase ( ALK ) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited., Materials and Methods: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine & Gray and Cox proportional hazards models for clinically relevant factors., Results: From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm ( P < .001) and neurologic symptoms ( P < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P < .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival., Conclusion: The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR - and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.

Our purpose was to provide an understanding of current functional lung imaging (FLI) techniques and their potential to improve dosimetry and outcomes for patients with lung cancer receiving radiation therapy (RT). Excerpta Medica dataBASE (EMBASE), PubMed, and Cochrane Library were searched from 1990 until April 2023. Articles were included if they reported on FLI in one of: techniques, incorporation into RT planning for lung cancer, or quantification of RT-related outcomes for patients with lung cancer. Studies involving all RT modalities, including stereotactic body RT and particle therapy, were included. Meta-analyses were conducted to investigate differences in dose-function parameters between anatomic and functional RT planning techniques, as well as to investigate correlations of dose-function parameters with grade 2+ radiation pneumonitis (RP). One hundred seventy-eight studies were included in the narrative synthesis. We report on FLI modalities, dose-response quantification, functional lung (FL) definitions, FL avoidance techniques, and correlations between FL irradiation and toxicity. Meta-analysis results show that FL avoidance planning gives statistically significant absolute reductions of 3.22% to the fraction of well-ventilated lung receiving 20 Gy or more, 3.52% to the fraction of well-perfused lung receiving 20 Gy or more, 1.3 Gy to the mean dose to the well-ventilated lung, and 2.41 Gy to the mean dose to the well-perfused lung. Increases in the threshold value for defining FL are associated with decreases in functional parameters. For intensity modulated RT and volumetric modulated arc therapy, avoidance planning results in a 13% rate of grade 2+ RP, which is reduced compared with results from conventional planning cohorts. A trend of increased predictive ability for grade 2+ RP was seen in models using FL information but was not statistically significant. FLI shows promise as a method to spare FL during thoracic RT, but interventional trials related to FL avoidance planning are sparse. Such trials are critical to understanding the effect of FL avoidance planning on toxicity reduction and patient outcomes., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Prior research demonstrates that nearly all (95 %) people with lung cancer (PwLC) report stigma, and approximately half (48 %) PwLC experience stigma during clinical encounters with oncology care providers (OCPs). When stigma is experienced in a medical context, it can have undesirable consequences including patients' delaying and underreporting of symptoms, misreporting of smoking behavior, and avoiding help-seeking such as psychosocial support and cessation counseling. Multi-level interventions are needed to prevent and mitigate lung cancer stigma. One promising intervention for reducing patient perception and experience of stigma is to train OCPs in responding empathically to patient emotions and promoting empathic communication within clinical encounters., Methods: This paper describes the study protocol for a cluster randomized trial comparing Usual Care (waitlist control group) with Empathic Communication Skills (ECS) training (intervention group). For this study, we will recruit 16 community oncology practice sites, 9-11 OCPs per site, and 6 PwLCs per OCP., Results: The goal of this trial is to investigate the effect of the ECS training on (a) OCP primary outcomes (communication and empathic skill uptake) and secondary outcomes (ECS training appraisal - relevance, novelty, clarity; self-efficacy, attitude towards communication with patients); and (b) patient-reported primary outcomes (lung cancer stigma), and secondary outcomes (perceived clinician empathy, satisfaction with OCP communication, psychological distress, social isolation, and appraisal of care)., Conclusion: Findings from this trial will advance understanding of the effectiveness of the ECS training intervention and inform future provider-level training interventions that may reduce lung cancer stigma and improve cancer care delivery., Clinicaltrials: govIdentifier: NCT05456841., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Minimally invasive resection for non-small cell lung cancer has been linked to decreased postoperative morbidity. This work sought to characterize factors associated with receiving minimally invasive surgery for surgically resectable non-small cell lung cancer., Methods: All adults undergoing lobectomy/sublobar resection for stage I non-small cell lung cancer were identified using the 2010-2020 National Cancer Database. Those undergoing thoracoscopic/robotic procedures comprised the minimally invasive resection cohort (others: open). Hospitals were stratified by minimally invasive resection procedure volume, with the top quartile considered high minimally invasive resection volume centers. Multivariable models were constructed to assess the independent association between the patients, diseases, and hospital factors and the likelihood of receiving minimally invasive resection., Results: Of 217,762 patients, 112,304 (52%) underwent minimally invasive resection. The proportion of minimally invasive resection procedures increased from 27% in 2010 to 72% in 2020 (P < .001). After adjustment, several factors were independently associated with decreased odds of receiving minimally invasive resection, including lower quartiles of median neighborhood income (51st-75th percentile adjusted odds ratio, 0.92, 95% CI, 0.89-0.94; 26th-50th percentile adjusted odds ratio, 0.86, CI, 0.83-0.89; 0-25th percentile adjusted odds ratio, 0.78, CI, 0.75-0.81; reference: 76th-100th percentile income) and care at community hospitals (adjusted odds ratio, 0.70, CI, 0.68-0.71; reference: academic centers). Among patients receiving care at high minimally invasive resection volume centers, lowest income remained linked with reduced likelihood of undergoing minimally invasive resection from 2010 to 2015 (adjusted odds ratio, 0.85, CI, 0.77-0.94), but did not alter the odds of minimally invasive resection in later years (adjusted odds ratio, 1.01, CI, 0.87-1.16; reference: highest income)., Conclusions: This study identified significant community income-based disparities in the likelihood of undergoing minimally invasive resection as definitive surgical treatment. Novel interventions are warranted to expand access to high-volume minimally invasive resection centers and ensure equitable access to minimally invasive surgery., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: A novel form of lung function imaging has been developed that uses 4-dimensional computed tomography (4DCT) data to generate lung ventilation images (4DCT-ventilation). Functional avoidance uses 4DCT-ventilation to reduce doses to functional lung with the aim of reducing pulmonary side effects. A phase 2, multicenter 4DCT-ventilation functional avoidance clinical trial was completed. The purpose of this work was to quantify changes in patient-reported outcomes (PROs) for patients treated with functional avoidance and determine which metrics are predictive of PRO changes., Materials and Methods: Patients with locally advanced lung cancer receiving curative-intent radiation therapy were accrued. Each patient had a 4DCT-ventilation image generated using 4DCT data and image processing. PRO instruments included the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire administered pretreatment; at the end of treatment; and at 3, 6, and 12 months posttreatment. Using the FACT-Trial Outcome Index and the FACT-Lung Cancer Subscale results, the percentage of clinically meaningful declines (CMDs) were determined. A linear mixed-effects model was used to determine which patient, clinical, dose, and dose-function metrics were predictive of PRO decline., Results: Of the 59 patients who completed baseline PRO surveys. 83% had non-small cell lung cancer, with 75% having stage 3 disease. The median dose was 60 Gy in 30 fractions. CMD FACT-Trial Outcome Index decline was 46.3%, 38.5%, and 26.8%, at 3, 6, and 12 months, respectively. CMD FACT-Lung Cancer Subscale decline was 33.3%, 33.3%, and 29.3%, at 3, 6, and 12 months, respectively. Although an increase in most dose and dose-function parameters was associated with a modest decline in PROs, none of the results were significant (all P > .053)., Conclusions: The current work presents an innovative combination of use of functional avoidance and PRO assessment and is the first report of PROs for patients treated with prospective 4DCT-ventilation functional avoidance. Approximately 30% of patients had clinically significant decline in PROs at 12 months posttreatment. The study provides additional data on outcomes with 4DCT-ventilation functional avoidance., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To assess the safety and efficacy of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib as neoadjuvant therapy in patients with surgically resectable stage I-IIIA EGFR -mutated non-small cell lung cancer (NSCLC)., Patients and Methods: This was a multi-institutional phase II trial of neoadjuvant osimertinib for patients with surgically resectable stage I-IIIA (American Joint Committee on Cancer [AJCC] V7) EGFR -mutated (L858R or exon 19 deletion) NSCLC (ClinicalTrials.gov identifier: NCT03433469). Patients received osimertinib 80 mg orally once daily for up to two 28-day cycles before surgical resection. The primary end point was major pathological response (MPR) rate. Secondary safety and efficacy end points were also assessed. Exploratory end points included pretreatment and post-treatment tumor mutation profiling., Results: A total of 27 patients were enrolled and treated with neoadjuvant osimertinib for a median 56 days before surgical resection. Twenty-four (89%) patients underwent subsequent surgery; three (11%) patients were converted to definitive chemoradiotherapy. The MPR rate was 14.8% (95% CI, 4.2 to 33.7). No pathological complete responses were observed. The ORR was 52%, and the median DFS was 40.9 months. One treatment-related serious adverse event (AE) occurred (3.7%). No patients were unable to undergo surgical resection or had surgery delayed because of an AE. The most common co-occurring tumor genomic alterations were in TP53 (42%) and RBM10 (21%)., Conclusion: Treatment with neoadjuvant osimertinib in surgically resectable (stage IA-IIIA, AJCC V7) EGFR -mutated NSCLC did not meet its primary end point for MPR rate. However, neoadjuvant osimertinib did not lead to unanticipated AEs, surgical delays, nor result in a significant unresectability rate.

Purpose: Clinical guidelines recommend early palliative care for patients with advanced lung cancer. In rural and underserved community oncology practices with limited resources, both primary palliative care from an oncologist and specialty palliative care are needed to address patients' palliative care needs. The aim of this study is to describe community oncology clinicians' primary palliative care practices and perspectives on integrating specialty palliative care into routine advanced lung cancer treatment in rural and underserved communities., Methods: Participants were clinicians recruited from 15 predominantly rural community oncology practices in Kentucky. Participants completed a one-time survey regarding their primary palliative care practices and knowledge, barriers, and facilitators to integrating specialty palliative care into advanced-stage lung cancer treatment., Results: Forty-seven clinicians (30% oncologists) participated. The majority (72.3%) of clinicians worked in a rural county. Over 70% reported routinely asking patients about symptom and physical function concerns, whereas less than half reported routinely asking about key prognostic concerns. Roughly 30% held at least one palliative care misconception (e.g., palliative care is for only those who are stopping cancer treatment). Clinician-reported barriers to specialty palliative care referrals included fear a referral would send the wrong message to patients (77%) and concern about burdening patients with appointments (53%). Notably, the most common clinician-reported facilitator was a patient asking for a referral (93.6%)., Conclusion: Educational programs and outreach efforts are needed to inform community oncology clinicians about palliative care, empower patients to request referrals, and facilitate patients' palliative care needs assessment, documentation, and standardized referral templates., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: The randomized clinical trial Cancer and Leukemia Group B (CALGB) 140503 showed that for patients with clinically staged T1N0 non-small cell lung cancer (NSCLC; ≤2 cm), sublobar resections were associated with similar oncological outcomes to those after lobar resection. The association of the extent of parenchymal resection with recurrence and survival in patients with tumors pathologically upstaged to T2 based on visceral pleural invasion (VPI) is controversial., Objective: To determine survival and recurrence rates in patients with small peripheral pT2 NSCLC (≤2 cm) that was treated by either lobar or sublobar resection in CALGB 140503., Design, Participants, and Setting: CALGB 140503, a randomized multicenter noninferiority trial, included 697 patients with small peripheral NSCLC that was clinically staged as T1N0. Enrollment was from June 2007 through March 2017 at 83 participating institutions, and after a median follow-up of 7 years, the primary outcome of disease-free survival after sublobar resection was noninferior to that after lobar resection., Intervention: Lobar or sublobar resection., Main Outcomes and Measures: Survival end points were estimated by the Kaplan-Meier estimator. Hazard ratios and 95% CIs were estimated using stratified Cox proportional hazard models., Results: Of 679 participants, 390 (57.4%) were female, and the median (range) age was 67.8 (37.8-89.7) years. Among 697 patients randomized, 566 (81.2%) had pT1 tumors (no VPI) and 113 (16.2%) had pT2 tumors (VPI). Five-year disease-free survival was 65.9% (95% CI, 61.9%-70.2%) in patients with pT1 compared with 53.3% (95% CI, 44.3%-64.1%) in patients with pT2 tumors (stratified log-rank: P = .02). Disease recurrence developed in 27.6% of patients with pT1 (locoregional only: 60 [10.8%]; distant only: 81 [14.6%]) and 41.6% of those with pT2 (locoregional only: 17 [15.0%]; distant only: 27 [23.9%]). Five-year recurrence-free survival was 73.1% (95% CI, 69.2%-77.1%) for pT1 tumors and 58.2% (95% CI, 49.2%-68.8%) for pT2 tumors (stratified log-rank: P = .01). There were no intergroup differences in disease-free or recurrence-free survival based on the extent of parenchymal resection., Conclusions and Relevance: The results of this secondary analysis suggest that compared with patients with tumors without VPI, patients who had tumors with VPI had worse disease-free and recurrence-free survival and a higher rate of local and distant disease recurrence. These high rates of recurrence were independent of the extent of parenchymal resection, and these data support the inclusion of these patients in adjuvant therapy trials., Trial Registration: ClinicalTrials.gov Identifier: NCT0049933.

Purpose: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor ( EGFR )-wildtype NSCLC., Methods: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR -wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review., Results: In total, 172 patients with nonsquamous EGFR -wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%)., Conclusion: Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR -wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

The American Cancer Society National Lung Cancer Roundtable strategic plan for provider engagement and outreach addresses barriers to the uptake of lung cancer screening, including lack of provider awareness and guideline knowledge about screening, concerns about potential harms from false-positive examinations, lack of time to implement workflows within busy primary care practices, insufficient infrastructure and administrative support to manage a screening program and patient follow-up, and implicit bias based on sex, race/ethnicity, social class, and smoking status. Strategies to facilitate screening include educational programming, clinical reminder systems within the electronic medical record, decision support aids, and tools to track nodules that can be implemented across a diversity of practices and health care organizational structures. PLAIN LANGUAGE SUMMARY: The American Cancer Society National Lung Cancer Roundtable strategic plan to reduce deaths from lung cancer includes strategies designed to support health care professionals, to better understand lung cancer screening, and to support adults who are eligible for lung cancer screening by providing counseling, referral, and follow-up., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Nonsmokers account for 10% to 13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose CT (LDCT)., Experimental Design: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA), were analyzed and quantified using liquid chromatography-mass spectrometry to determine if nonsmoker cases can be distinguished from sex and age-matched controls in comparison with tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening., Results: Urinary levels of CR and NANA were significantly higher and comparable in nonsmokers and tobacco smoker cases than population controls in both cohorts. Receiver operating characteristic analysis for combined CR and NANA levels in nonsmokers of the exploratory cohort resulted in better predictive performance with the AUC of 0.94, whereas the validation cohort nonsmokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in nonsmokers as well as tobacco smoker cases in both cohorts., Conclusions: Measuring CR and NANA in urine liquid biopsies could identify nonsmokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: A significantly lower rate of non-small cell lung cancer (NSCLC) screening, greater health care avoidance, and changes to oncologic recommendations were some consequences of the Coronavirus disease 2019 (COVID-19) pandemic affecting the medical environment. We sought to determine how the health care environment during the COVID-19 pandemic affected the oncologic treatment of patients diagnosed with non-small cell lung cancer (NSCLC)., Methods: This was a retrospective cohort study evaluating patients with NSCLC in the National Cancer Database (2019-2020). Patients were divided into prepandemic (2019) and pandemic (2020) cohorts, and patient, oncologic, and treatment variables were compared. Multivariable logistic regression was performed to control for the impact of demographic characteristics on oncologic variables and the impact of oncologic variables on treatment variables., Results: The study population comprised 250,791 patients, including 114,533 patients (45.7%) in the pandemic cohort. There were 15% fewer new NSCLC diagnoses during the pandemic compared with prepandemic. Patients diagnosed during the pandemic had more advanced clinical TNM stage on presentation (P < .0001) and were more likely to have tumors in overlapping lobes or in a main bronchus (P = .0002). They were less likely to receive cancer treatment (P < .0001) and to undergo primary resection (P < .0001) and more likely to receive adjuvant systemic therapy (P = .004) and a combination of palliative treatment regimens (P < .0001). After risk adjustment, all these differences remained statistically significant (P < .05)., Conclusions: The COVID-19 pandemic was associated with increased clinical stage at presentation for patients with NSCLC, which impacted subsequent treatment strategies. However, treatment differed minimally when controlling for cancer stage. Future studies will examine the impact of these differences on overall survival and cancer-free survival., Competing Interests: Conflict of Interest Statement E.A.D. reports honoraria from Astra Zeneca. R.A.M. reports consulting fees from Medtronic (payments made to institution). The other authors have no conflicts of interest to report. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC)., Patients and Methods: Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m 2 every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m 2 daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR)., Results: Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade ≥3 related treatment-emergent adverse events (TEAEs). The most common grade ≥3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan., Conclusion: Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged.

Bronchial premalignant lesions (PMLs) precede the development of invasive lung squamous cell carcinoma (LUSC), posing a significant challenge in distinguishing those likely to advance to LUSC from those that might regress without intervention. This study followed a novel computational approach, the Graph Perceiver Network, leveraging hematoxylin and eosin-stained whole slide images to stratify endobronchial biopsies of PMLs across a spectrum from normal to tumor lung tissues. The Graph Perceiver Network outperformed existing frameworks in classification accuracy predicting LUSC, lung adenocarcinoma, and nontumor lung tissue on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium datasets containing lung resection tissues while efficiently generating pathologist-aligned, class-specific heatmaps. The network was further tested using endobronchial biopsies from two data cohorts, containing normal to carcinoma in situ histology. It demonstrated a unique capability to differentiate carcinoma in situ lung squamous PMLs based on their progression status to invasive carcinoma. The network may have utility in stratifying PMLs for chemoprevention trials or more aggressive follow-up., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Small-cell lung cancer (SCLC) is the most fatal form of lung cancer. Intratumoral heterogeneity, marked by neuroendocrine (NE) and non-neuroendocrine (non-NE) cell states, defines SCLC, but the cell-extrinsic drivers of SCLC plasticity are poorly understood. To map the landscape of SCLC tumor microenvironment (TME), we apply spatially resolved transcriptomics and quantitative mass spectrometry-based proteomics to metastatic SCLC tumors obtained via rapid autopsy. The phenotype and overall composition of non-malignant cells in the TME exhibit substantial variability, closely mirroring the tumor phenotype, suggesting TME-driven reprogramming of NE cell states. We identify cancer-associated fibroblasts (CAFs) as a crucial element of SCLC TME heterogeneity, contributing to immune exclusion, and predicting exceptionally poor prognosis. Our work provides a comprehensive map of SCLC tumor and TME ecosystems, emphasizing their pivotal role in SCLC's adaptable nature, opening possibilities for reprogramming the TME-tumor communications that shape SCLC tumor states., Competing Interests: Declaration of interests A.T. received grants to NCI from EMD Serono Research & Development, AstraZeneca, Gilead Sciences, and ProLynx during the conduct of the study., (Published by Elsevier Inc.)

Background: Innovations in lung cancer control and care have started to transform the landscape of lung cancer outcomes, but lung cancer stigma and biases have been implicated as a deterrent to realizing the promise of these innovations. Research has documented lung cancer stigma among the general public and lung cancer survivors (self-blame), as well as clinicians across many disciplines. However, studies have not explored lung cancer stigma in health-care trainees. These data seek to address that gap and inform efforts to prevent the emergence or mitigate the presence of lung cancer stigma among future clinicians., Methods: Using clinical vignettes and a 2x2 factorial design, this investigation evaluated the impact of a history of smoking (yes vs no) and cancer diagnosis (lung vs colorectal) on perceptions of the described patient among 2 groups of preclinical health-care trainees (medical = 94 and nursing = 138). A charitable giving paradigm also asked participants to donate provided funds to 1 of 2 cancer advocacy organizations: one serving the lung cancer community and one serving the colorectal cancer community., Results: In study 1, results revealed a consistent pattern of statistically significant and medium to large effect size differences regarding stigmatized perceptions (eg, higher stigmatizing behavior, increased pity, greater anger, and less helping) for individuals with a history of smoking but no reliable differences regarding cancer diagnosis. Analysis of data from nursing trainees in study 2 showed a similar pattern of statistically significant and medium to large effects pertaining to stigma behavior and perceptions of individuals who had a history of smoking depicted in the vignettes. The charitable giving paradigm did not identify any reliable difference between the groups in either study., Conclusions: Findings revealed a consistent pattern of health-care trainee perceptions that varied by smoking status but much less evidence that the cancer diagnosis contributed to different perceptions. This suggests that efforts to integrate consideration of stigma and biases in health-care training needs to adopt an approach that seeks to mitigate or eliminate stigmatizing perceptions and behaviors toward individuals with a history of smoking., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Alterations in the highly actionable lung cancer oncogenes, EGFR, ALK, and ROS1, occur across the age spectrum. Pregnancy and plans for motherhood consequently overlap with diagnoses of advanced oncogene-driven NSCLC. Guidelines for cytotoxic agents and pregnancy are well established. Nevertheless, accessible data on targeted lung cancer therapy during pregnancy or egg retrieval has not been collated previously, nor have the issues of reproduction in the setting of specific oncogene-addicted advanced NSCLC been widely discussed., Methods: We performed a narrative review of ex vivo placenta perfusion studies, pharmacologic characteristics, mutagenicity, animal embryo-fetal development studies, and case reports of pathways to motherhood, pregnancies, and egg retrieval while on EGFR-, ALK-, or ROS1-targeted therapy., Results: EGFR inhibitors may reduce female fertility while on therapy owing to decrease in corpora lutea. Odds of pregnancy in women on EGFR and ALK inhibitors may be reduced owing to potential increase in postimplantation loss found in animals. Crizotinib and entrectinib exhibit in vitro mutagenic potential. Several effects on human pregnancies have been noted; however, 11 EGFR and ALK tyrosine kinase inhibitor-exposed infants have been documented free of substantial adverse health effects by ages 4 months to 2 years. Successful gestational surrogacy has been reported in two women treated with crizotinib. Adoption and termination approaches have also been undertaken by some patients., Conclusions: Reproduction may not be out of reach for some patients with advanced NSCLC. Additional explorations of the impact and optimal timing of targeted therapy in egg capture and pregnancy are needed. Wider scientific and societal discussion about the issues of reproduction in advanced NSCLC is warranted., Competing Interests: Disclosure Dr. Simons reports receiving honorarium from Sanofi and Janssen. Dr. Camidge reports receiving honoraria from AbbVie, Anheart, Appolomics, AstraZeneca/Daiichi, Beigene, Dizal, Elevation, Eli Lilly, EMD Serono, Hengrui, Hummingbird, Imagene, Immunocore, Janssen, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Prelude, Regeneron, Roche, Sanofi, Seattle Genetics, Takeda, Theseus, Valence, and Xcovery; and having clinical trials (institutional) sponsored by AbbVie, AstraZeneca, Blueprint, Dizal, Inhibrx, Karyopharm, Nuvalent, Pfizer, Phosplatin, Psioxus, Rain, Roche/Genentech, Seattle Genetics, Takeda, Turning Point, and Verastem., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Adjuvant chemotherapy is underutilized in clinical practice, in part, because its anticipated survival benefit is limited. We evaluated the impact of AC on overall and recurrence-free survival among completely resected pN1 NSCLC patients enrolled in the North American Intergroup phase III (JBR10) trial. A post-hoc subgroup analysis of pN1 NSCLC patients was performed. Participants were randomized to cisplatin+vinorelbine (AC) (n = 118) or observation (n = 116) following complete resection. The primary endpoint was overall survival (OS). The secondary endpoint was recurrence free survival (RFS). Kaplan-Meier methods were used to compare OS and RFS between the two treatment groups. Cox regression was used to identify factors associated with OS and RFS endpoints. Both groups had similar baseline characteristics. AC patients had improved 5-year OS (AC 61.4% vs observation 41.0%, log-rank p = .008) and 5-year RFS (AC 56.2% vs observation 39.9%, log-rank p = .011) rates compared to observation. Cox regression analyses confirmed the OS (HR 0.583, 95% CI 0.402-0.846, p = .005) and RFS (HR 0.573, 95% CI 0.395-0.830, p = .003) benefit associated with AC. AC was associated with a lower risk (HR 0.648, 95% CI 0.435-0.965, p = .0326) and a lower cumulative incidence (Subdistribution Hazard Ratio [SHR], 0.67, 95% CI 0.449-0.999, p = .0498) of lung cancer deaths. In the JBR10 trial, treatment with AC conferred a significant OS and RFS advantage over observation for pN1 NSCLC patients. These data suggest that pN1 NSCLC patients may experience a disproportionately greater clinical benefit from AC than the 6% survival advantage estimated by the LACE meta-analysis., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown., Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used., Results: Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3)., Conclusions: This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib., Competing Interests: Disclosure Dr. Nassar receives honoraria from OncLive, TEMPUS, and Korean Society for Medical Oncology and consulting fees from Guidepoint Global. Dr. Kim is on the advisory board for Amgen. Dr. Shepherd reports having stock and other ownership interests from Eli Lilly and AstraZeneca; receiving honoraria from AstraZeneca, Merck Serono, Takeda, and Daiichi Sankyo; having consulting/advisory role at AstraZeneca and Merck Serono; and receiving research funding from Eli Lilly (inst), Pfizer (inst), Bristol-Myers Squibb (inst), AstraZeneca/MedImmune (inst), and Roche Canada (inst). Dr. Gray reports receiving grants from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, G1 Therapeutics, Ludwig Institute of Cancer Research, Merck & Co., Inc., Novartis, and Pfizer; receiving consulting fees from AbbVie, AstraZeneca, Blueprint Medicines, EMD Serono, Gilead Sciences, Inc., Janssen Scientific Affairs, LLC, Jazz Pharmaceuticals, Loxo Oncology Inc., Merck & Co., Inc., Novartis, OncoCyte Biotechnology, Spectrum ODAC, Takeda Pharmaceuticals, and Triptych Health Partners; and having leadership role as SWOG Lung Committee Chair, IASLC Board of Director member, and ASCO Education Committee Ex-Chair. Dr. Dilling reports receiving consulting fees from AstraZeneca and support for travel from NCCN. Dr. Neal reports receiving grants from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GlaxoSmithKline, Janssen, AbbVie, and Novocure; receiving consulting fees from AstraZeneca, Genentech/Roche, Exelixis, Takeda Pharmaceuticals, Eli Lilly and Company, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics, Mirati Therapeutics, Gilead Sciences, AbbVie, Summit Therapeutics, Novartis, Novocure, Janssen Oncology, and AnHeart Therapeutics; and receiving honorarium from CME Matters, Clinical Care Options CME, Research to Practice CME, Medscape CME, Biomedical Learning Institute CME, MLI Peerview CME, Prime Oncology CME, Projects in Knowledge CME, Rockpointe CME, MJH Life Sciences CME, Medical Educator Consortium, and HMP Education. Dr. Wakelee reports receiving grants from Arrys Therapeutics Research, AstraZeneca/Medimmune, Bristol-Myers Squibb, Genentech/Roche, Merck, Helsinn, Seagen, and Xcovery; and serving on the advisory board of Mirati (compensated)—ended November 2022, IOBiotech (compensated)—October 2023, Merck (NOT compensated), and Genentech/Roche/Bristol-Myers Squibb/AstraZeneca (NOT compensated). Dr. S.H. Lin reports receiving grants from STCube Pharmaceuticals, Beyond Spring, and Nektar Therapeutics; consulting fees from XRAD Therapeutics; serving on the advisory board of AstraZeneca; having stock/stock options from Apple, Google, Amazon, Tesla, Meta, Rivian, and CreatvMicrotech; and having other support from SEEK Diagnostics (co-founder). Dr. Patil reports receiving grants from Gilead Research Scholars and LUNGevity Foundation Award; consulting fees from AstraZeneca, Boehringer Ingelheim, Bicara, Daiichi, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Pfizer, Sanofi, Regeneron, Roche/Genentech, Takeda, Gilead Research Scholars, and LUNGevity Foundation Award; and honorarium from Janssen. Dr. Bar reports receiving grants from Merck Sharp & Dohme, AstraZeneca, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Bayer, Boehringer Ingelheim, and Pfizer; receiving consulting fees from AstraZeneca, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Takeda, AbbVie, Pfizer, Bayer, and VBL; and having leadership role from Lung Ambition Consortium, Israel Lung Cancer Group, and IASLC committee. Dr. Marron receives grants from Regeneron, Bristol-Myers Squibb, Merck, Boehringer Ingelheim, NCI, and Cancer Research Institute; and serving on the advisory board of AbbVie, Celldex, and Rockefeller University. Dr. Yu receives grants/contracts from AstraZeneca, Pfizer, Daiichi Cullinan Oncology, Janssen, Novartis, Blueprint med, Black Diamond, and Systimmune and consulting fees from AstraZeneca, Daiichi, Taiho, Takeda, Janssen, Amgen, AbbVie, Novocure, and Ipsen. Dr. Owen receives grants/contracts from Bristol-Myers Squibb, Merck, Palobiofarma, Genentech, Onc.AI, and Pfizer; and travel support from Amgen, AstraZeneca, and Genentech. Rocha receives grants/contracts from SEOM, ESMO Fellowship, and AECC; and travel support from Merck Sharp & Dohme, AstraZeneca, and Bristol-Myers Squibb. Dr. Arriola receives grants/contracts from AstraZeneca and Bristol-Myers Squibb; honorarium from Eli Lilly, AstraZeneca, Roche, Takeda, Merck Sharp & Dohme, Pfizer, Janssen, and Bristol-Myers Squibb; and travel support from AstraZeneca, Roche, and Pfizer. Dr. Cheng receives grants/contracts from AstraZeneca and Genentech; and serving on the advisory board of Janssen, G1 Therapeutics, and AstraZeneca. Dr. Parikh receives consulting fees from Jazz Pharmaceuticals, Guardant Health, and AstraZeneca; and honorarium from MJH Life Sciences. Dr. Harris receives grants/contract from NIH P30CA062203, the UC Irvine Comprehensive Cancer Center using UCI Anti-Cancer Challenge Grant, and ACS Seed Grant 129801-IRG-16-187-13-IRG; and serving on the advisory board of UC Irvine as DSMB member. Dr. Nagasaka receives consulting fees from Caris Life Sciences; honorarium/speaker fees from AstraZeneca, Daiichi, Novartis, EMD Serono self, Pfizer, Eli Lilly, Genentech, Regeneron, Takeda, Janssen, Blueprint, and Mirati; travel support from AnHeart Therapeutics; and stock/stock options from Mbrace Therapeutics. Dr. Valazquez receives grants/contracts from ASCO, American Association for Cancer Research (AACR), LUNGevity, NIA P30AG015272, NCI 5U54CA242646-03 Conquer Cancer and Niarchos Foundation, UCSF Clinical Practice Group, and AAMC; consulting fees from AstraZeneca, Merus, Novocure, and Cadence Communications & Research; and having stock/stock options from Corbus Pharmaceuticals. Dr. J.J. Lin receives grants/contracts from Hengrui Therapeutics, Turning Point Therapeutics, Neon Therapeutics, Relay Therapeutics, Bayer, Elevation Oncology, Roche, Linnaeus Therapeutics, Nuvalent, and Novartis; consulting fees from Genentech, C4 Therapeutics, Blueprint Medicines, Nuvalent, Bayer, Elevation Oncology, Novartis, Mirati Therapeutics, AnHeart Therapeutics, Takeda, CLaiM Therapeutics, Regeneron, Pfizer, Turning Point Therapeutics, Daiichi Sankyo, AstraZeneca, and Merus. Dr. Piotrowska receives grants/contracts from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GlaxoSmithKline, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, and Blueprint; consulting fees from Taiho, Janssen, Takeda, AstraZeneca, Cullinan Oncology, C4 Therapeutics, Jazz Pharmaceuticals, and Blueprint; and honorarium from Daiichi Sankyo, Janssen, and Eli Lilly (honoraria for nonpromotional educational events). Dr. Reuss receives grants/contracts from Genentech/Roche, Verastem, Nuvalent, and LUNGevity Foundation; consulting fees from Genentech/Roche, Sanofi/Genzyme, Personalis, Guardant, AstraZeneca, Bristol-Myers Squibb, Arcus, AbbVie, Daiichi Sankyo, Catalym, Seagen, and Gilead; and honorarium from AstraZeneca and Merck. Dr. Baena Espinar receives consulting fees from AstraZeneca, Roche, and Merck Sharp & Dohme; honorarium from AstraZeneca, Roche, and Merck Sharp & Dohme; payment for expert testimony from Roche; and travel support from Roche and Janssen. Leal receives research funding to institution from Pfizer, Advaxis, and Bayer, outside the submitted work. Dr. Mak receives grants/contracts from ViewRay; consulting fees from AstraZeneca, Novartis, and Sio Capital Management; and other support from Founder of HealthAI. Dr. Naqash receives grants/contracts from SWOG Hope Foundation and FDA Broad Agency Contract; serving on the advisory board of JCO Precision Oncology; receiving travel support from SITC/American Association for Cancer Research (AACR)/Conquer Cancer Foundation/BinayTara Foundation and Foundation Med/Caris Life Sciences, and Jazz Pharmaceuticals; and funding to institution for trials from Loxo@Lilly, Surface Oncology, ADC Therapeutics, IGM Biosciences, EMD Serono, Aravive, Nikang Therapeutics, Inspirna, Exelexis, Revolution Medicine, Jacobio, Pionyr, Jazz Pharmaceuticals, NGM Biopharmaceuticals, Immunophotonics, and Selexine. Dr. Goldberg receives grants/contracts from AstraZeneca, Boehringer Ingelheim, and Mirati; and serving on the advisory board of AstraZeneca, Bristol-Myers Squibb, Amgen, Sanofi, Genzyme, Daiichi Sankyo, Regeneron, Takeda, Janssen, Summit, and Merck. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Pathologic response (PathR) by histopathologic assessment of resected specimens may be an early clinical end point associated with long-term outcomes with neoadjuvant therapy. Digital pathology may improve the efficiency and precision of PathR assessment. LCMC3 (NCT02927301) evaluated neoadjuvant atezolizumab in patients with resectable NSCLC and reported a 20% major PathR rate., Methods: We determined PathR in primary tumor resection specimens using guidelines-based visual techniques and developed a convolutional neural network model using the same criteria to digitally measure the percent viable tumor on whole-slide images. Concordance was evaluated between visual determination of percent viable tumor (n = 151) performed by one of the 47 local pathologists and three central pathologists., Results: For concordance among visual determination of percent viable tumor, the interclass correlation coefficient was 0.87 (95% confidence interval [CI]: 0.84-0.90). Agreement for visually assessed 10% or less viable tumor (major PathR [MPR]) in the primary tumor was 92.1% (Fleiss kappa = 0.83). Digitally assessed percent viable tumor (n = 136) correlated with visual assessment (Pearson r = 0.73; digital/visual slope = 0.28). Digitally assessed MPR predicted visually assessed MPR with outstanding discrimination (area under receiver operating characteristic curve, 0.98) and was associated with longer disease-free survival (hazard ratio [HR] = 0.30; 95% CI: 0.09-0.97, p = 0.033) and overall survival (HR = 0.14, 95% CI: 0.02-1.06, p = 0.027) versus no MPR. Digitally assessed PathR strongly correlated with visual measurements., Conclusions: Artificial intelligence-powered digital pathology exhibits promise in assisting pathologic assessments in neoadjuvant NSCLC clinical trials. The development of artificial intelligence-powered approaches in clinical settings may aid pathologists in clinical operations, including routine PathR assessments, and subsequently support improved patient care and long-term outcomes., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer with driver alterations., Methods: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized clinical trials (RCTs), with the latest time frame spanning February to October 2023. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts were convened. The literature search included systematic reviews, meta-analyses, and randomized controlled trials. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations., Results: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Eight new RCTs were identified in the latest search of the literature to date., Recommendations: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients based on targetable driver alterations.Additional information is available at www.asco.org/living-guidelines.

Background: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC., Methods: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment)., Findings: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis., Interpretation: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC., Funding: Daiichi Sankyo and AstraZeneca., Competing Interests: Declaration of interests EFS has received provision of study materials (drug) and clinical trial funding (to their institution) from Daiichi Sankyo; consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Janssen, MSD, Roche Sanofi, and Takeda; speaker payment or honoraria from Boehringer Ingelheim and Daiichi Sankyo; and participated on a data safety monitoring board for Daiichi Sankyo. EF has received consulting fees from Amgen, AstraZeneca, Bayer, Bergenbio, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, F Hoffmann–La Roche, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Sanofi, and Takeda; speaker payment or honoraria from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Eli Lilly, F Hoffmann–La Roche, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Peervoice, Pfizer, Sanofi, Takeda, and Touch Oncology; grants or contracts from Fundación Merck Salud, Merck Healthcare, and Oncology Innovation; and has other financial interests in Grífols. DU has received consulting fees from AstraZeneca, Daiichi Sankyo, Jazz Pharmaceuticals, and Sanofi. MN has received consulting fees from Caris Life Sciences; speaker payment or honoraria from AstraZeneca, Blueprint Medicine, Daiichi Sankyo, EMD Serono, Genentech, Janssen, Lilly, Mirati, Novartis, Pfizer, and Takeda; and support for meeting attendance or travel from AnHeart Therapeutics. KN has received consulting fees from Eli Lilly Japan and Ono Pharmaceuticals; speaker payment or honoraria from Amgen, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Care Net, Chugai Pharmaceutical, CMIC, CMIC ShiftZero, Daiichi Sankyo, Eli Lilly Japan, Incyte Biosciences Japan, Janssen Pharmaceuticals, Japan Clinical Research Operations, Kyowa Kirin, Medical Mobile Communications, Medical Review, Merck Biopharma, MSD, Life Technologies Japan, Neo Communication, Nikkei Business Publications, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Pfizer Japan, Taiho Pharmaceutical, Taiyo Pharma, Takeda Pharmaceutical, Yodosha, and 3H Clinical Trial; grants or contracts from Amgen, Ascent Development Services, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Bristol Myers Squibb, Chugai Pharmaceutical, CMIC, Daiichi Sankyo, Eisai, Eli Lilly Japan, EP-CRSU, EPS Corporation, GlaxoSmithKline, IQVIA Services Japan, Janssen Pharmaceutical, Japan Clinical Research Operations, Kissei Pharmaceutical, Kobayashi Pharmaceutical, Labcorp Development Japan (Covance Japan), Mebix, Medical Research Support, Mochida Pharmaceutical, MSD, Nippon Boehringer Ingelheim, Nippon Kayaku, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Parexel International, Pfizer Japan, Pfizer R&D Japan, PPD-SNBL, Sanofi, Shionogi, SRL, SymBio Pharmaceuticals, Syneos Health Clinical, Sysmex Corporation, Taiho Pharmaceutical, and Takeda Pharmaceutical; and holds a patent with Daiichi Sankyo. LP-AR has received consulting fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, Daiichi Sankyo, GlaxoSmithKline, Janssen, Merck, Mirati, MSD, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, and Takeda; speaker payment or honoraria from AstraZeneca, Janssen, Merck, and Mirati; and grants and contracts from AstraZeneca, Bristol Myers Squibb, MSD, and Pfizer. JMP has received consulting fees from AstraZeneca, Blueprint Medicines, Jazz Pharmaceuticals, and Silverback Therapeutics. BTL has received grants or contracts from Amgen, AstraZeneca, Bolt Biotherapeutics, Daiichi Sankyo, Genentech, Jiangsu Hengrui Pharmaceuticals, Lilly, and National Institutes of Health (Cancer Center Support Grant P30 CA008748 and Research Project Grant R01CA249666); support for meeting attendance or travel from Amgen; holds a patent with Memorial Sloan Kettering Cancer Center; and has a leadership or fiduciary role in Asia Society Policy Institute Cure4Cancer and Bloomberg New Economy International Cancer Coalition. DP has received consulting fees from AstraZeneca, AbbVie, AnHeart Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Novartis, Roche, Pfizer, MSD Oncology, Celgene, BeiGene, Samsung, Janssen, Jazz Pharmaceuticals, Pierre Fabre, Seagen, Gilead Sciences, and Sanofi; speaker payment or honoraria from Prime Oncology and PeerVoice; and research grants paid to his institution from AstraZeneca/MedImmune, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Sanofi/Aventis, Taiho Pharmaceutical, Daiichi Sankyo, AbbVie, Janssen, Pierre Fabre, and Seagen. CB has received consulting fees from AstraZeneca, Boehringer, Daiichi Sankyo, Guardant, Jansen, Pfizer, Regeneron, Silverback, Takeda, and TurningPoint; and grants or contracts from AbbVie, AstraZeneca, Blueprint, Daiichi Sankyo, Jansen, Lilly, Loxo, Nuvalent, Pfizer, Rain Therapeutics, Spectrum, and TurningPoint. YG has received speaker payment or honoraria from Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Merck, MSD, Novartis, Ono, Pfizer, Taiho, and Thermo Fisher Scientific; grants or contracts from AbbVie, AZK, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Kyorin, Novartis, Ono, Pfizer, and Preferred Network; participated in advisory boards for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health, Illumina, MSD, Novartis, Ono Pharmaceutical, Pfizer, and Taiho; and has a leadership or fiduciary role in Cancer Net Japan and the Japan Association of Medical Translation for Cancer. HM has received speaker payment or honoraria from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Eisai, Lilly Japan, MSD, Nihonkayaku, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Taiho Pharmaceutical; grants or contracts from AbbVie, AstraZeneca, Bayer, Chugai Pharma, IQVIA, and Takeda; and participated in advisory boards for Amgen, Chugai Pharma, Daiichi Sankyo, GAIA BioMedicine, and Taiho Pharmaceutical. AS has received speaker payment and honoraria from HMP Global and MJH Life Sciences; grants or contracts from AstraZeneca, BioAtla, Daiichi Sankyo, Eli Lily, Genentech, Genmab, Memgen, Mersana, Novartis, and Turning Point Therapeutics; and participated in advisory boards for Daiichi Sankyo, Eli Lilly, and Zymeworks. KP and ZT are employees of Daiichi Sankyo. AT, WF, YC, and QY are employees of Daiichi Sankyo and hold stocks, stock options, or have other financial interest in Daiichi Sankyo. PAJ has received consulting fees from AbbVie, Accutar Biotech, Allorion Therapeutics, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Chugai Pharmaceuticals, Daiichi Sankyo, Duality, Eli Lilly, Esai, Frontier Medicines, Hongyun Biotechnology, Merus, Mirati Therapeutics, Monte Rosa, Novartis, Nuvalent, Pfizer, Roche/Genentech, Scorpion Therapeutics, SFJ Pharmaceuticals, Silicon Therapeutics, Syndax, Takeda Oncology, Transcenta, and Voronoi; grants and contracts from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Puma Biotechnology, Revolution Medicines, and Takeda Oncology; holds patents and royalties or licenses with LabCorp; and reports holding stocks or stock options in Gatekeeper Pharmaceuticals., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: For patients with unresectable, stage III non-small-cell lung cancer (NSCLC), current standard of care is concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab. However, earlier initiation of durvalumab simultaneously with cCRT may increase antitumor activity relative to initiation after cCRT. The phase 1 CLOVER study (NCT03509012) evaluated durvalumab combined with cCRT in patients with advanced solid tumors; we report findings from the NSCLC cohort., Methods: CLOVER comprised a dose-limiting toxicity (DLT) assessment part, followed by an expansion part. In the NSCLC cohort, patients with previously untreated, unresectable, stage III NSCLC were enrolled in three treatment arms: durvalumab every 4 weeks (Q4W) + cisplatin + etoposide + radiotherapy (Arm 1); durvalumab Q4W + carboplatin + paclitaxel + radiotherapy (Arm 2); or durvalumab Q4W + carboplatin or cisplatin + pemetrexed + radiotherapy (non-squamous histology only; Arm 3). Patients received durvalumab until disease progression or unacceptable toxicity. The primary endpoint was safety and tolerability., Results: Sixty-four patients were enrolled: 21, 22, and 21 in Arms 1, 2, and 3, respectively. One patient in Arm 1 had DLT (grade 3 aspartate aminotransferase increase and grade 4 alanine aminotransferase increase); no DLTs were observed in Arms 2 or 3. Grade 3/4 adverse events occurred in 76.6 % of patients overall; the most common were neutropenia (51.6 %), leukopenia (20.3 %), and anemia (17.2 %). In a post-hoc analysis, 7.8 % of patients had grade 3 pneumonitis/radiation pneumonitis (grouped term) events. Overall, the objective response rate was 60.9 % (95 % confidence interval [CI], 47.9-72.9); median duration of response was 15.8 months (95 % CI, 9.0-not estimable [NE]). Median progression-free survival was 13.4 months (95 % CI, 8.8-20.1) and median overall survival was not reached (95 % CI, 21.9-NE)., Conclusion: Durvalumab in combination with cCRT was well tolerated, with a manageable safety profile and showed encouraging antitumor activity in patients with unresectable, stage III NSCLC., Competing Interests: Declaration of competing interest Dong-Wan Kim reports research funding (to institution) from Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi-Sankyo, GSK, Hanmi, InnoN Janssen, Merck, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan, reports uncompensated consultation or advisory roles for Amgen, AstraZeneca, BMS/ONO Pharmaceuticals, Daiichi-Sankyo, GSK, Janssen, Meck, MSD, NoveltyNobility, Oncobix, Pfizer, SK Biopharm, and Takeda, and has received medical writing assistance from Amgen, AstraZeneca, Boehringer-Ingelheim, Bridge BioTherapeutics, Chong Keun Dang, Daiichi-Sankyo, GSK, Janssen, Merus, Mirati Therapeutics, MSD, Meck, Novartis, Pfizer, Roche, Takeda, and Yuhan. Byoung Chul Cho is an employee of Yonsei University Health System, reports stock/share ownership in TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., and J INTS BIO, reports advisory council or committee membership for KANAPH Therapeutic Inc, Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, and Oscotec Inc, is a member of the board of directors for Interpark Bio Convergence Corp., and J INTS BIO, is an invited speaker for 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, is a consultant for 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., Takeda, MSD, Janssen, Medpacto, Blueprint Medicines, RandBio, and Hanmi, reports grants or funds from MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GIInnovation, 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, Bridgebio therapeutics, Yuhan, ImmuneOncia, Illumina, Kanaph therapeutics, Therapex, JINTSbio, Hanmi, and CHA Bundang Medical Center, reports royalties from Champions Oncology, Crown Bioscience, and Imagen, and is a founder of DAAN Biotherapeutics. Sang-We Kim reports advisory meeting participation for AstraZeneca, Amgen, Boehringer Ingelheim, Janssen, Novartis, Takeda, Therapex, and Yuhan, lecture fees from Boehringer Ingelheim, and research funding from Yuhan. Gee-Chen Chang reports honoraria from F. Hoffmann–La Roche, Ltd, Eli Lilly and Company Oncology, AstraZeneca, Novartis, Pfizer, Boehringer-Ingelheim, Bristol-Myers Squibb, and Merck Sharp & Dohme. Myung-Ju Ahn reports advisory council or committee membership for AstraZeneca, YUHAN, Roche, Pfizer, Amgen, Merck, Takeda, Alpha Pharmaceutical, and VORONOI. Rosa Alvarez reports advisory council or committee membership for Astra Zeneca, Pharmamar, Boehringer Ingelheim, Novartis, Sanofi, and GSK, reports research funding (to institution) from PharmaMar, Astra Zeneca, Rain Therapeutics, GSK, Boehringer Ingelheim, Cebiotex, Roche, Philogen, MSD, Janssen, Pfizer, Daichii Sankyo, Gilead, and Seagen, speaker fees from Pharmamar, and travel support from Roche and Pharmamar. Chao-Hua Chiu reports honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Janssen, Merck KGaA, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, Shionogi, and Takeda. José Trigo reports consulting fees from AstraZeneca, MSD, Eisai, and BMS. Ana Estiva reports advisory council or committee membership for Takeda, Roche, and MSD, and honoraria from Pfizer, MSD, Roche, Takeda, Pharmamar, and GSK. Sana D. Karam reports grants or funds from AstraZeneca (clinical trial), Genentech (clinical trial), and Roche (preclinical). Cathy O’Brien is a contractor for AstraZeneca. Hema Gowda is an employee of AstraZeneca, and reports stock/share ownership in AstraZeneca and Incyte. Haiyi Jiang reports employment and stock/share ownership with AstraZeneca. Julie E. Bauman reports consulting fees from BluedotBio and Exelixis. Krishna Pachipala and Chih-Liang Wang do not have any competing interests to disclose., (Copyright © 2024. Published by Elsevier B.V.)

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. Patients with early-stage non-small-cell lung cancer (NSCLC) who undergo curative surgical resection are at risk for developing second primary lung cancer (SPLC). Cancer and Leukemia Group B 140503 (Alliance) was a multicenter, international, randomized, phase III trial in patients with stage T1aN0 NSCLC (using the TNM staging system seventh edition) and demonstrated the noninferiority for disease-free survival between sublobar resection (SLR) and lobar resection (LR). After surgery, patients underwent computed tomography surveillance as defined by the protocol. The determination of a SPLC was done by the treating physician and recorded in the study database. We performed an analysis of the rate of SPLC (per patient per year) and the 5-year cumulative incidence in the study population and within the SLR and LR arms. Median follow-up was 7 years. The rate per patient per year in the study population, in the SLR arm, and in the LR arm was 3.4% (95% CI, 2.9 to 4.1), 3.8% (95% CI, 2.9 to 4.9), and 3.1% (95% CI, 2.4 to 4.1), respectively. The estimated 5-year cumulative incidence of SPLC in the study population, SLR arm, and LR arm was 15.9% (95% CI, 12.9 to 18.9), 17.2% (95% CI, 12.7 to 21.5), and 14.7% (95% CI, 10.6 to 18.7), respectively.

Background: First-line pembrolizumab plus chemotherapy has shown clinical benefit in patients with metastatic non-small cell lung cancer (NSCLC) regardless of tissue tumor mutational burden (tTMB) status. Blood tumor mutational burden (bTMB), assessed using plasma-derived circulating tumor DNA (ctDNA), may be a surrogate for tTMB. The KEYNOTE-782 study evaluated the correlation of bTMB with the efficacy of first-line pembrolizumab plus chemotherapy in NSCLC., Methods: Previously untreated patients with stage IV nonsquamous NSCLC received pembrolizumab 200 mg plus pemetrexed 500 mg/m 2 and investigator's choice of carboplatin area under the curve 5 mg/mL/min or cisplatin 75 mg/m 2 for 4 cycles, then pembrolizumab plus pemetrexed for ≤31 additional cycles every 3 weeks. Study objectives were to evaluate the association of baseline bTMB with objective response rate (ORR) (RECIST v1.1 by investigator assessment; primary), progression-free survival (PFS; RECIST v1.1 by investigator assessment), overall survival (OS), and adverse events (AEs; all secondary). A next-generation sequencing assay (GRAIL LLC) with a ctDNA panel that included lung cancer-associated and immune gene targets was used to measure bTMB., Results: 117 patients were enrolled; median time from first dose to data cutoff was 19.3 months (range, 1.0-35.5). ORR was 40.2 % (95 % CI 31.2-49.6 %), median PFS was 7.2 months (95 % CI 5.6-9.8) and median OS was 18.1 months (95 % CI 13.5-25.6). Treatment-related AEs occurred in 113 patients (96.6 %; grade 3-5, n = 56 [47.9 %]). Of patients with evaluable bTMB (n = 101), the area under the receiver operating characteristics curve for continuous bTMB to discriminate response was 0.47 (95 % CI 0.36-0.59). Baseline bTMB was not associated with PFS or OS (posterior probabilities of positive association: 16.8 % and 7.8 %, respectively)., Conclusions: AEs were consistent with the established safety profile of first-line pembrolizumab plus chemotherapy in NSCLC. Baseline bTMB did not show evidence of an association with efficacy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.B. reports advisory roles with AbbVie, AstraZeneca, Bayer, BMS, Causalis, Merck Serono, MSD, Novartis, Roche, and Takeda and receiving research funding from Immunai, OncoHost, MSD, and AstraZeneca. D.R.A. reports personal fees/honoraria for consultancy or advisory roles and lectures from Roche, Genentech, AstraZeneca, Bristol Myers Squibb, Boehringer Ingleheim, MSD, Merck Serono, Eli Lilly, Gilead, Sanofi, Regeneron, Incyte, Pfizer, Takeda, and Novartis; and travel expenses from Roche, Bristol Myers Squibb, MSD, Sanofi, Regeneron, and Novartis. E.F. reports personal fees or honoraria for advisory roles from Abbvie, Amgen, AstraZeneca, Bayer, Bergen Bio, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, GSK, Janssen, Merck Serono, MSD, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, and Turning Point; speaker’s bureau fees from Amgen, AstraZeneca, Bristol Myers Squibb, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, Medical Trends, Medscape, Merck Serono, MSD, Peervoice, Pfizer, Sanofi, Takeda, and Touch Oncology; and independent board membership with Grifols. M.P. reports lecture fees, honoraria, or other fees from Bristol Myers Squibb, Roche, MSD, AstraZeneca, Takeda, Eli Lilly and Company, F. Hoffman-La Roche, Janssen, and Pfizer; and research funds from MSD, AstraZeneca, Roche, Boehringer Ingleheim, and Bristol Myers Squibb. D.R.C. reports lecture fees, honoraria or other fees from Roche and AstraZeneca. S.M.T, J.K., and E.J.D. report employment with MSD. M.A. reports employment and stock ownership with MSD. N.H. reports advisory or consultancy roles and stock ownership with Curve Biosciences. R.Mc. and B.J. report employment with Grail LLC. R.Ma reports employment with Grail LLC and stock ownership with Illumina. D.B. reports employment with GRAIL LLC and stock ownership with Illumina. E.E., S.P.A., M.G., A.R., A.F., S.B.R., G.S., T.C. have no conflicts of interest to disclose., (Copyright © 2024 Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To examine the influence of comorbid psychiatric disorders (PSYD) on postoperative outcomes in patients undergoing pulmonary lobectomy., Methods: A retrospective analysis of the Healthcare Cost and Utilization Project Nationwide Readmissions Database from 2016 to 2018 was performed. Patients with lung cancer with and without psychiatric comorbidities who underwent pulmonary lobectomy were collated and analyzed (International Classification of Diseases, 10th Revision, Clinical Modification Mental, Behavioral and Neurodevelopmental disorders [F01-99]). The association of PSYD with complications, length of stay, and readmissions was assessed using a multivariable regression analysis. Additional subgroup analyses were performed., Results: A total of 41,691 patients met inclusion criteria. Of these, 27.84% (11,605) of the patients had at least 1 PSYD. PSYD was associated with a significantly increased risk of postoperative complications (relative risk, 1.041; 95% CI, 1.015-1.068; P = .0018), pulmonary complications (relative risk, 1.125; 95% CI, 1.08-1.171; P < .0001), longer length of stay (PSYD mean, 6.79 days and non-PSYD mean, 5.68 days; P < .0001), higher 30-day readmission rate (9.2% vs 7.9%; P < .0001), and 90-day readmission rate (15.4% vs 12.9%; P < .007). Among patients with PSYD, those with cognitive disorders and psychotic disorders (eg, schizophrenia) appear to have the highest rates and risks of postoperative morbidity and in-hospital mortality., Conclusions: Patients with lung cancer with comorbid psychiatric disorders undergoing lobectomy experience worse postoperative outcomes with longer hospitalization, increased rates of overall and pulmonary complications, and greater readmissions suggesting potential opportunities for improved psychiatric care during the perioperative period., (Copyright © 2023. Published by Elsevier Inc.)

Objective: Observational data suggest hope is associated with the quality of life and survival of people with cancer. This trial examined the feasibility, acceptability, and preliminary outcomes of "Pathways," a hope intervention for people in treatment for advanced lung cancer., Methods: Between 2020 and 2022, we conducted a single-arm trial of Pathways among participants who were 3-12 weeks into systemic treatment. Pathways consisted of two individual sessions delivered during infusions and three phone calls in which participants discussed their values, goals, and goal strategies with a nurse or occupational therapist. Participants completed standardized measures of hope and goal interference pre- and post-intervention. Feasibility was defined as ≥60% of eligible patients enrolling, ≥70% of participants completing three or more sessions, ≥70% of participants completing post-assessments, and mean acceptability ratings ≥7 out of 10 on intervention relevance, helpfulness, and convenience. Linear regression fixed effects models with covariates modeled pre-post changes in complete case analysis and multiple imputation models., Results: Fifty two participants enrolled: female (59.6%), non-Hispanic White (84.6%), rural (75.0%), and with low educational attainment (51.9% high school degree or less). Except for enrollment (54%), feasibility and acceptability markers were surpassed (77% adherence, 77% retention, acceptability ratings ≥8/10). There was moderate improvement in hope and goal interference from pre-to post-intervention (d = 0.51, p < 0.05 for hope; d = -0.70, p < 0.005 for goal interference)., Conclusions: Strong feasibility, acceptability, and patient-reported outcome data suggest Pathways is a promising intervention to increase hope and reduce cancer-related goal interference during advanced lung cancer treatment., (© 2024 John Wiley & Sons Ltd.)

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations represent ~6%-12% of all EGFR-mutated non-small cell lung cancer (NSCLC) cases. First-, second-, and third-generation tyrosine kinase inhibitors (TKIs) have limited clinical activity against EGFR ex20ins mutations. Mobocertinib is a first-in-class oral EGFR TKI that selectively targets in-frame EGFR ex20ins mutations in NSCLC; accelerated approval in the United States was granted for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex20ins mutations whose disease has progressed on or after platinum-based chemotherapy. Accelerated approval was based on the results from the three-part, open-label, multicenter, pivotal phase I/II nonrandomized clinical trial (NCT02716116) that enrolled 114 patients with locally advanced or metastatic EGFR ex20ins mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and received mobocertinib at the recommended dosage of 160 mg once daily. At the November 1, 2021, data cutoff date, the confirmed objective response rate per independent review committee (IRC) was 28%, median duration of response was 15.8 months, median progression-free survival per IRC was 7.3 months, and median overall survival was 20.2 months. The most common treatment-emergent adverse events were gastrointestinal- and skin-related. The phase III EXCLAIM-2 study evaluated mobocertinib versus chemotherapy as first-line therapy for locally advanced or metastatic EGFR ex20ins-positive NSCLC; however, the primary end point was not met, resulting in initiating voluntary withdrawal of mobocertinib worldwide. This mini-review article summarizes the mechanism of action, pharmacokinetic characteristics, key clinical trials, and clinical efficacy and safety data for mobocertinib., (© 2024 Takeda Pharmaceuticals U.S.A., Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: Traditional methods of evaluating cardiotoxicity focus on radiation doses to the heart. Functional imaging has the potential to provide improved prediction for cardiotoxicity for patients with lung cancer. Fluorine-18 ( 18 F) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging is routinely obtained in a standard cancer staging workup. This work aimed to develop a radiomics model predicting clinical cardiac assessment using 18 F-FDG PET/CT scans before thoracic radiation therapy., Methods: Pretreatment 18 F-FDG PET/CT scans from three study populations (N = 100, N = 39, N = 70) were used, comprising two single-institutional protocols and one publicly available data set. A clinician (V.J.) classified the PET/CT scans per clinical cardiac guidelines as no uptake, diffuse uptake, or focal uptake. The heart was delineated, and 210 novel functional radiomics features were selected to classify cardiac FDG uptake patterns. Training data were divided into training (80%)/validation (20%) sets. Feature reduction was performed using the Wilcoxon test, hierarchical clustering, and recursive feature elimination. Ten-fold cross-validation was carried out for training, and the accuracy of the models to predict clinical cardiac assessment was reported., Results: From 202 of 209 scans, cardiac FDG uptake was scored as no uptake (39.6%), diffuse uptake (25.3%), and focal uptake (35.1%), respectively. Sixty-two independent radiomics features were reduced to nine clinically pertinent features. The best model showed 93% predictive accuracy in the training data set and 80% and 92% predictive accuracy in two external validation data sets., Conclusion: This work used an extensive patient data set to develop a functional cardiac radiomic model from standard-of-care 18 F-FDG PET/CT scans, showing good predictive accuracy. The radiomics model has the potential to provide an automated method to predict existing cardiac conditions and provide an early functional biomarker to identify patients at risk of developing cardiac complications after radiotherapy.

Central nervous system (CNS) metastases are frequently diagnosed in patients with non-small cell lung cancer (NSCLC). Only recently, clinical trials are broadening eligibility to include patients with brain metastases, offering the potential for some assessment of CNS efficacy to be made. In this work we aim to review the available information on the activity of small molecule targeted drugs for advanced NSCLC with respect to CNS metastases. We analyze a framework for evaluation assessment regarding trials of systemic agents being conducted in patients with, or at risk from, CNS metastases, and provide examples of NSCLC targeted therapies evaluated in the CNS., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Current treatment guidelines refer to small cell lung cancer (SCLC), one of the deadliest human malignancies, as a homogeneous disease. Accordingly, SCLC therapy comprises chemoradiation with or without immunotherapy. Meanwhile, recent studies have made significant advances in subclassifying SCLC based on the elevated expression of the transcription factors ASCL1, NEUROD1, and POU2F3, as well as on certain inflammatory characteristics. The role of the transcription regulator YAP1 in defining a unique SCLC subset remains to be established. Although preclinical analyses have described numerous subtype-specific characteristics and vulnerabilities, the so far non-existing clinical subtype distinction may be a contributor to negative clinical trial outcomes. This comprehensive review aims to provide a framework for the development of novel personalized therapeutic approaches by compiling the most recent discoveries achieved by preclinical SCLC research. We highlight the challenges faced due to limited access to patient material as well as the advances accomplished by implementing state-of-the-art models and methodologies., (© 2024. The Author(s).)

Background: Predictive biomarkers of immune checkpoint inhibitor (ICI) efficacy are currently lacking for non-small cell lung cancer (NSCLC). Here, we describe the results from the Anti-PD-1 Response Prediction DREAM Challenge, a crowdsourced initiative that enabled the assessment of predictive models by using data from two randomized controlled clinical trials (RCTs) of ICIs in first-line metastatic NSCLC., Methods: Participants developed and trained models using public resources. These were evaluated with data from the CheckMate 026 trial (NCT02041533), according to the model-to-data paradigm to maintain patient confidentiality. The generalizability of the models with the best predictive performance was assessed using data from the CheckMate 227 trial (NCT02477826). Both trials were phase III RCTs with a chemotherapy control arm, which supported the differentiation between predictive and prognostic models. Isolated model containers were evaluated using a bespoke strategy that considered the challenges of handling transcriptome data from clinical trials., Results: A total of 59 teams participated, with 417 models submitted. Multiple predictive models, as opposed to a prognostic model, were generated for predicting overall survival, progression-free survival, and progressive disease status with ICIs. Variables within the models submitted by participants included tumor mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, and gene-expression-based signatures. The best-performing models showed improved predictive power over reference variables, including TMB or PD-L1., Conclusions: This DREAM Challenge is the first successful attempt to use protected phase III clinical data for a crowdsourced effort towards generating predictive models for ICI clinical outcomes and could serve as a blueprint for similar efforts in other tumor types and disease states, setting a benchmark for future studies aiming to identify biomarkers predictive of ICI efficacy., Trial Registration: CheckMate 026; NCT02041533, registered January 22, 2014. CheckMate 227; NCT02477826, registered June 23, 2015., (© 2024. The Author(s).)

Multiple tyrosine kinase inhibitors (TKIs) are often developed for the same indication. However, their relative overall efficacy is frequently incompletely understood and they may harbor unrecognized targets that cooperate with the intended target. We compared several ROS1 TKIs for inhibition of ROS1-fusion-positive lung cancer cell viability, ROS1 autophosphorylation and kinase activity, which indicated disproportionately higher cellular potency of one TKI, lorlatinib. Quantitative chemical and phosphoproteomics across four ROS1 TKIs and differential network analysis revealed that lorlatinib uniquely impacted focal adhesion signaling. Functional validation using pharmacological probes, RNA interference, and CRISPR-Cas9 knockout uncovered a polypharmacology mechanism of lorlatinib by dual targeting ROS1 and PYK2, which form a multiprotein complex with SRC. Rational multi-targeting of this complex by combining lorlatinib with SRC inhibitors exhibited pronounced synergy. Taken together, we show that systems pharmacology-based differential network analysis can dissect mixed canonical/non-canonical polypharmacology mechanisms across multiple TKIs enabling the design of rational drug combinations., Competing Interests: Declaration of interests R.C.D. is an employee and shareholder of Rain Oncology and reports licensing fees from Voronoi, Takeda, Loxo@Lilly, Foundation Medicine, Histocyte, Black Diamond, and ThermoFisher. JMK reports support from Bristol-Myers Squibb on an unrelated project. E.B.H. serves in a consulting or advisory role to Amgen, Ellipses Pharma, Janssen Oncology, Janssen Research & Development and Revolution Medicines; reports research funding (paid to his institution) from AstraZeneca, Genentech, Incyte, Janssen, Novartis, Revolution Medicines and Spectrum Pharmaceuticals; and reports patents, royalties or other intellectual property from ProteinProtein Interactions as Biomarkers Patent., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors., Main Body: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8 + T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8 + and granzyme B + cells were observed., Conclusions: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME., Trial Registration Number: NCT02671435., Competing Interests: Competing interests: SP: scientific advisory income from: Amgen, AstraZeneca, Bristol Myers Squibb, Certis, Eli Lilly, Genentech, Illumina, Merck, Pfizer, Rakuten, and Tempus; SP’s university receives research funding from: Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, Eli Lilly, Fate Therapeutics, Iovance, Merck, Pfizer, Roche/Genentech, and SQZ Biotechnologies.TA-G has received research funding, honoraria, and non-financial or other support from IPSEN, Adacap, Pfizer, Sanofi, EISAI, Lilly, Bayer, Janssen, BMS, Astellas, Novartis, Roche, and Merck. SB: institutional grants: AstraZeneca and GlaxoSmithKline. Honoraria for Advisory boards: Amgen, AstraZeneca, Genmab, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Merck Sereno, Mersana Therapeutics, OncXerna, Seagen, and Shattuck Labs; Honoraria for lectures: Amgen, AstraZeneca, Clovis, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Mersana Therapeutics, Pfizer, and Roche. DW, JN, NES, DCP, L-YC, PK, MDH: employment by and stock ownership/options in AstraZeneca. MLA: former employment by and stock ownership/options in AstraZeneca. MD: employment by and stock ownership/options in AstraZeneca. JRD: institutional funds received from: AstraZeneca, Abbvie, Astellas, Gilead, Merck, Deciphera, Hutchison, BMS, Adlai Norte, Takeda, OnKure Therapeutics; Consulting: Gilead, OnKure Therapeutics; Equity Interest: OnKure Therapeutics. BAC: institutional research support: Astra Zeneca, Abbvie, Actuate Therapeutics, Astellas, Bayer, Dragonfly Therapeutics, Pfizer, Repare Therapeutics. Scientific advisory boards: Foundation Medicine, Tempus, Seattle Genetics, G1 therapeutics., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The Social Vulnerability Index (SVI) is a composite metric for social determinants of health. The objective of this study was to determine if SVI influences stage at presentation for non-small cell lung cancer (NSCLC) patients and subsequent therapies., Materials and Methods: NSCLC patients from our local contribution to the National Cancer Database (2011-2021) were grouped into low SVI (<75 %ile) and high SVI (>75 %ile) cohorts. Demographics, cancer-related variables, and treatment modalities were compared. Multivariable logistic regression was performed to control for the impact of demographics on cancer presentation and for the impact of oncologic variables on treatment outcomes., Results: Of 1,662 NSCLC patients, 435 (26 %) were defined as high SVI. Compared to the 1,227 (74 %) low SVI patients, highly vulnerable patients were more likely to be male (53.3 % vs 46.0 %, p = 0.009), non-White (17.2 % vs 9.7 %, p < 0.0001), have comorbidities (29.4 % vs 23.1 %, p = 0.009) and present at a higher AJCC clinical T, M and overall stage (all p < 0.05). These findings persisted on multivariable analysis, with highly vulnerable patients having 1.5x the odds (95 %CI: 1.23-1.86, p < 0.001) of presenting at more advanced stage. Patients with high SVI were less likely to be recommended for and receive surgery (40.9 % vs 53.2 %, p < 0.001), and this finding persisted after controlling for stage at presentation (OR 1.37, 95 %CI 1.04-1.80)., Conclusions: Highly vulnerable patients present at a more advanced clinical stage and are less likely to be recommended and receive surgery, even after controlling for stage at presentation. Further investigation into these findings is warranted to achieve more equitable oncologic care., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Christina M Stuart reports that this work was supported by the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32CA17468., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best prevention, 50% of lung cancer diagnoses occur in people who have quit smoking. Research into treatment options for high-risk patients is constrained to rodent models, which are time-consuming, expensive, and require large cohorts. Embedding precision-cut lung slices (PCLS) within an engineered hydrogel and exposing this tissue to vinyl carbamate, a carcinogen from cigarette smoke, creates an in vitro model of lung cancer premalignancy. Hydrogel formulations are selected to promote early lung cancer cellular phenotypes and extend PCLS viability to six weeks. Hydrogel-embedded PCLS are exposed to vinyl carbamate, which induces adenocarcinoma in mice. Analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content after six weeks reveals that vinyl carbamate induces premalignant lesions with a mixed adenoma/squamous phenotype. Putative chemoprevention agents diffuse through the hydrogel and induce tissue-level changes. The design parameters selected using murine tissue are validated with hydrogel-embedded human PCLS and results show increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human lung cancer premalignancy is the foundation for more sophisticated ex vivo models that enable the study of carcinogenesis and chemoprevention strategies., (© 2023 Wiley-VCH GmbH.)

Background: The early-generation ROS1 tyrosine kinase inhibitors (TKIs) that are approved for the treatment of ROS1 fusion-positive non-small-cell lung cancer (NSCLC) have antitumor activity, but resistance develops in tumors, and intracranial activity is suboptimal. Repotrectinib is a next-generation ROS1 TKI with preclinical activity against ROS1 fusion-positive cancers, including those with resistance mutations such as ROS1 G2032R., Methods: In this registrational phase 1-2 trial, we assessed the efficacy and safety of repotrectinib in patients with advanced solid tumors, including ROS1 fusion-positive NSCLC. The primary efficacy end point in the phase 2 trial was confirmed objective response; efficacy analyses included patients from phase 1 and phase 2. Duration of response, progression-free survival, and safety were secondary end points in phase 2., Results: On the basis of results from the phase 1 trial, the recommended phase 2 dose of repotrectinib was 160 mg daily for 14 days, followed by 160 mg twice daily. Response occurred in 56 of the 71 patients (79%; 95% confidence interval [CI], 68 to 88) with ROS1 fusion-positive NSCLC who had not previously received a ROS1 TKI; the median duration of response was 34.1 months (95% CI, 25.6 to could not be estimated), and median progression-free survival was 35.7 months (95% CI, 27.4 to could not be estimated). Response occurred in 21 of the 56 patients (38%; 95% CI, 25 to 52) with ROS1 fusion-positive NSCLC who had previously received one ROS1 TKI and had never received chemotherapy; the median duration of response was 14.8 months (95% CI, 7.6 to could not be estimated), and median progression-free survival was 9.0 months (95% CI, 6.8 to 19.6). Ten of the 17 patients (59%; 95% CI, 33 to 82) with the ROS1 G2032R mutation had a response. A total of 426 patients received the phase 2 dose; the most common treatment-related adverse events were dizziness (in 58% of the patients), dysgeusia (in 50%), and paresthesia (in 30%), and 3% discontinued repotrectinib owing to treatment-related adverse events., Conclusions: Repotrectinib had durable clinical activity in patients with ROS1 fusion-positive NSCLC, regardless of whether they had previously received a ROS1 TKI. Adverse events were mainly of low grade and compatible with long-term administration. (Funded by Turning Point Therapeutics, a wholly owned subsidiary of Bristol Myers Squibb; TRIDENT-1 ClinicalTrials.gov number, NCT03093116.)., (Copyright © 2024 Massachusetts Medical Society.)

Despite the initial benefit from tyrosine kinase inhibitors (TKI) targeting oncogenic ALK and ROS1 gene fusions in non-small cell lung cancer, complete responses are rare and resistance ultimately emerges from residual tumor cells. Although several acquired resistance mechanisms have been reported at the time of disease progression, adaptative resistance mechanisms that contribute to residual diseases before the outgrowth of tumor cells with acquired resistance are less clear. For the patients who have progressed after TKI treatments, but do not demonstrate ALK/ROS1 kinase mutations, there is a lack of biomarkers to guide effective treatments. Herein, we found that phosphorylation of MIG6, encoded by the ERRFI1 gene, was downregulated by ALK/ROS1 inhibitors as were mRNA levels, thus potentiating EGFR activity to support cell survival as an adaptive resistance mechanism. MIG6 downregulation was sustained following chronic exposure to ALK/ROS1 inhibitors to support the establishment of acquired resistance. A higher ratio of EGFR to MIG6 expression was found in ALK TKI-treated and ALK TKI-resistant tumors and correlated with the poor responsiveness to ALK/ROS1 inhibition in patient-derived cell lines. Furthermore, we identified and validated a MIG6 EGFR-binding domain truncation mutation in mediating resistance to ROS1 inhibitors but sensitivity to EGFR inhibitors. A MIG6 deletion was also found in a patient after progressing to ROS1 inhibition. Collectively, this study identifies MIG6 as a novel regulator for EGFR-mediated adaptive and acquired resistance to ALK/ROS1 inhibitors and suggests EGFR to MIG6 ratios and MIG6-damaging alterations as biomarkers to predict responsiveness to ALK/ROS1 and EGFR inhibitors., (©2023 The Authors; Published by the American Association for Cancer Research.)

Introduction: Effective communication and messaging strategies are crucial to raise awareness and support participants' efforts to adhere to lung cancer screening (LCS) guidelines. Health messages that incorporate images are processed more efficiently, and given the stigma surrounding lung cancer and cigarette smoking, emphasis must be placed on selecting imagery that is engaging to LCS-eligible individuals. This exploratory study aimed to identify person-centered themes surrounding LCS imagery., Materials and Methods: This qualitative study leveraged a modified photovoice approach and interviews to define descriptive themes about LCS imagery. Study participants eligible for annual LCS who had a CT scan within 12 months were asked to select three images and participate in a semi-structured interview about photo selection, likes, and dislikes. Participants were also asked their opinions about images from current LCS communications featuring matches, smoke, and cigarettes. Data were analyzed using an inductive thematic approach., Results: Data saturation was reached after thirteen individuals completed the photovoice activity; each participant selected three pictures resulting in a total of 39 images representing LCS. Over half (54%) of images selected contained lungs and only 4 (10%) contained smoking-related elements. Five main themes emerged: 1) images should focus on good news and early detection; 2) people should be relatable; 3) pictures with lungs can dually support lung health or invoke fear; 4) opportunity for education or awareness; and 5) should not be judgmental and induce stigma., Conclusions: These findings suggest that LCS imagery should not contain negative or stigmatizing elements but instead be relatable and educational. This information can inform communication and messaging interventions and strategies for future LCS participation, awareness, and educational research., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Hirsch reports grants from NIH/National Cancer Institute and non-financial support from NIH/National Center for Advancing Translational Sciences, during the conduct of the study. Dr. Studts reports personal fees from Johnson & Johnson and Genentech, outside the submitted work; and Dr. Studts volunteers on the Scientific Leadership Board of GO2 for Lung Cancer and the American Cancer Society National Lung Cancer Roundtable. Dr. Studts receives grant funding from National Cancer Institute, the Bristol Myers Squibb Foundation, the American Cancer Society, the Patient-Centered Outcomes Research Institute, the Colorado Department of Public Health and Environment, and the Centers for Disease Control and Prevention, outside the submitted work. Ms. Hoover has no conflicts of interest to disclose.

Background: The US National Lung Screening Trial (NLST) and Dutch-Belgian NELSON randomized controlled trials have shown significant mortality reductions from low-dose computed tomography (CT) lung cancer screening (LCS). NLST, ITALUNG, and COSMOS trials have provided detailed dosimetry data for LCS., Methods: LCS trial mortality benefit results, organ dose and effective dose data, and Biological Effects of Ionizing Radiation, Report VII (BEIR VII) organ dose-to-cancer-mortality risk data are used to estimate benefit-to-radiation-risk ratios of the NLST, ITALUNG, and COSMOS trials. Data from those trials also are used to estimate benefit-to-radiation-risk ratios for longer-term LCS corresponding to scenarios recommended by United States Preventive Services Task Force and the American Cancer Society., Results: Including only screening doses, NLST benefit-to-radiation-risk ratios are 12:1 for males, 19:1 for females, and 16:1 overall. Including both screening and estimated follow-up doses, benefit-to-radiation-risk ratios for NLST are 9:1 for males, 13:1 for females, and 12:1 overall. For the ITALUNG trial, the benefit-to-radiation-risk ratio is 58-63:1. For the COSMOS trial, assuming sex-specific mortality benefits like those of the NELSON trial, the benefit-to-radiation-risk ratio is 23:1. Assuming a conservative 20% mortality benefit, annual screening in people 50-79 years old with a 20+ pack-year history of smoking has benefit-to-radiation-risk ratios of 23:1 (with follow-up doses adding 40% to screening doses) to 29:1 (with follow-up adding 10%) based on COSMOS dose data., Conclusions: Based on linear, no threshold BEIR VII dose-risk estimates, benefit-to-radiation-risk ratios for LCS are highly favorable. Results emphasize the importance of using modern CT technologies, maintaining low diagnostic follow-up rates, and minimizing both screening and diagnostic follow-up doses., Plain Language Summary: The benefits of lung cancer screening significantly outweigh estimates of future harms associated with exposure to radiation during screening and diagnostic follow-up examinations. Our findings emphasize the importance of lung cancer screening practices using state-of-the-art computed tomography scanners and specialized low-dose lung screening and diagnostic follow-up techniques., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: We have recently reported the primary results of CALGB 140503 (Alliance), a randomized trial in patients with peripheral cT1aN0 non-small cell lung cancer (American Joint Committee on Cancer seventh) treated with either lobar resection (LR) or sublobar resection (SLR). Here we report differences in disease-free survival (DFS), overall survival (OS) and lung cancer-specific survival (LCSS) between LR, segmental resection (SR), and wedge resection (WR). We also report differences between WR and SR in terms of surgical margins, rate of locoregional recurrence (LRR), and expiratory flow rate at 6 months postoperatively., Methods: Between June 2007 and March 2017, a total of 697 patients were randomized to LR (n = 357) or SLR (n = 340) stratified by clinical tumor size, histology, and smoking history. Ten patients were converted from SLR to LR, and 5 patients were converted from LR to SLR. Survival endpoints were estimated using the Kaplan-Maier estimator and tested by the stratified log-rank test. The Kruskal-Wallis test was used to compare margins and changes in forced expiratory volume in 1 second (FEV1) between groups, and the χ 2 test was used to test the associations between recurrence and groups., Results: A total of 362 patients had LR, 131 had SR, and 204 had WR. Basic demographic and clinical and pathologic characteristics were similar in the 3 groups. Five-year DFS was 64.7% after LR (95% confidence interval [CI], 59.6%-70.1%), 63.8% after SR (95% CI, 55.6%-73.2%), and 62.5% after WR (95% CI, 55.8%-69.9%) (P = .888, log-rank test). Five-year OS was 78.7% after LR, 81.9% after SR, and 79.7% after WR (P = .873, log-rank test). Five-year LCSS was 86.8% after LR, 89.2% after SR, and 89.7% after WR (P = .903, log-rank test). LRR occurred in 12% after SR and in 14% after WR (P = .295). At 6 months postoperatively, the median reduction in % FEV1 was 5% after WR and 3% after SR (P = .930)., Conclusions: In this large randomized trial, LR, SR, and WR were associated with similar survival outcomes. Although LRR was numerically higher after WR compared to SR, the difference was not statistically significant. There was no significant difference in the reduction of FEV1 between the SR and WR groups., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Importance: Patients with relapsed small cell lung cancer (SCLC), a high replication stress tumor, have poor prognoses and few therapeutic options. A phase 2 study showed antitumor activity with the addition of the ataxia telangiectasia and Rad3-related kinase inhibitor berzosertib to topotecan., Objective: To investigate whether the addition of berzosertib to topotecan improves clinical outcomes for patients with relapsed SCLC., Design, Setting, and Participants: Between December 1, 2019, and December 31, 2022, this open-label phase 2 randomized clinical trial recruited 60 patients with SCLC and relapse after 1 or more prior therapies from 16 US cancer centers. Patients previously treated with topotecan were not eligible., Interventions: Eligible patients were randomly assigned to receive topotecan alone (group 1), 1.25 mg/m2 intravenously on days 1 through 5, or with berzosertib (group 2), 210 mg/m2 intravenously on days 2 and 5, in 21-day cycles. Randomization was stratified by tumor sensitivity to first-line platinum-based chemotherapy., Main Outcomes and Measures: The primary end point was progression-free survival (PFS) in the intention-to-treat population. Secondary end points included overall survival (OS) in the overall population and among patients with platinum-sensitive or platinum-resistant tumors. The PFS and OS for each treatment group were estimated using the Kaplan-Meier method. The log-rank test was used to compare PFS and OS between the 2 groups, and Cox proportional hazards models were used to estimate the treatment hazard ratios (HRs) and the corresponding 2-sided 95% CI., Results: Of 60 patients (median [range] age, 59 [34-79] years; 33 [55%] male) included in this study, 20 were randomly assigned to receive topotecan alone and 40 to receive a combination of topotecan with berzosertib. After a median (IQR) follow-up of 21.3 (18.1-28.3) months, there was no difference in PFS between the 2 groups (median, 3.0 [95% CI, 1.2-5.1] months for group 1 vs 3.9 [95% CI, 2.8-4.6] months for group 2; HR, 0.80 [95% CI, 0.46-1.41]; P = .44). Overall survival was significantly longer with the combination therapy (5.4 [95% CI, 3.2-6.8] months vs 8.9 [95% CI, 4.8-11.4] months; HR, 0.53 [95% CI, 0.29-0.96], P = .03). Adverse event profiles were similar between the 2 groups (eg, grade 3 or 4 thrombocytopenia, 11 of 20 [55%] vs 20 of 40 [50%], and any grade nausea, 9 of 20 [45%] vs 14 of 40 [35%])., Conclusions and Relevance: In this randomized clinical trial, treatment with berzosertib plus topotecan did not improve PFS compared with topotecan therapy alone among patients with relapsed SCLC. However, the combination treatment significantly improved OS., Trial Registration: ClinicalTrials.gov Identifier: NCT03896503.

Small cell lung cancer (SCLC) is characterized by rapid growth and high metastatic capacity. It has strong epidemiologic and biologic links to tobacco carcinogens. Although the majority of SCLCs exhibit neuroendocrine features, an important subset of tumors lacks these properties. Genomic profiling of SCLC reveals genetic instability, almost universal inactivation of the tumor suppressor genes TP53 and RB1, and a high mutation burden. Because of early metastasis, only a small fraction of patients are amenable to curative-intent lung resection, and these individuals require adjuvant platinum-etoposide chemotherapy. Therefore, the vast majority of patients are currently being treated with chemoradiation with or without immunotherapy. In patients with disease confined to the chest, standard therapy includes thoracic radiotherapy and concurrent platinum-etoposide chemotherapy. Patients with metastatic (extensive-stage) disease are treated with a combination of platinum-etoposide chemotherapy plus immunotherapy with an anti-programmed death-ligand 1 monoclonal antibody. Although SCLC is initially very responsive to platinum-based chemotherapy, these responses are transient because of the development of drug resistance. In recent years, the authors have witnessed an accelerating pace of biologic insights into the disease, leading to the redefinition of the SCLC classification scheme. This emerging knowledge of SCLC molecular subtypes has the potential to define unique therapeutic vulnerabilities. Synthesizing these new discoveries with the current knowledge of SCLC biology and clinical management may lead to unprecedented advances in SCLC patient care. Here, the authors present an overview of multimodal clinical approaches in SCLC, with a special focus on illuminating how recent advancements in SCLC research could accelerate clinical development., (© 2023 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)