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Alexa B Schrock,1 Russell Madison,1 Mark Rosenzweig,2 Justin M Allen,2 Rachel L Erlich,2 Siao-Yi Wang,3 Tarek Chidiac,4 Vodur Suresh Reddy,5 Jonathan W Riess,6 Ahmet Ersin Yassa,6 Abdur Shakir,7 Vincent A Miller,1 Brian M Alexander,1 Jeffrey Venstrom,1 Kimberly McGregor,1 Siraj M Ali1 1Foundation Medicine, Department of Clinical Development, Cambridge, MA, USA; 2Foundation Medicine, Department of Translational Oncology and Clinical Reporting, Cambridge, MA, USA; 3Loyola University Medical Cancer, Department of Hematology and Oncology, Maywood, IL, USA; 4Zangmeister Cancer Center, Department of Hematology and Oncology, Columbus, OH, USA; 5Cancer Care Specialists, Department of Hematology and Oncology, Reno, NV, USA; 6UC Davis Comprehensive Cancer Center, Department of Hematology and Oncology Sacramento, CA, USA; 7Sarah Bush Lincoln Health System, Department of Medical Oncology, Mattoon, IL, USACorrespondence: Alexa B SchrockFoundation Medicine, 150 Second Street, Cambridge, MA 02141, USATel +1617-418-2200Email aschrock@foundationmedicine.comBackground: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin‐fixed paraffin‐embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.Conclusion: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.Keywords: ALK rearrangement, inversion, deletion, genomic profiling, targeted therapy

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).)

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.

Abstract: Accidental intra-arterial injections of radiotracers are rare events resulting in a specific imaging pattern, described as "hot-forearm," "hot-hand," "glove-phenomenon," or "glove-like pattern." We present a case 68 Ga-DOTATATE total-body PET/CT for restaging of a neuroendocrine tumor, where intra-arterial misinjection resulted in a glove phenomenon. Since patients may present with minimal symptoms, like in this case, and PET findings may only be seen at the distal upper extremity (placed above the head), these accidental injections may be more frequently detected with total-body PET/CT due to the longer field-of-view. Radiologists and technologists should be aware of this possibility to avoid accidental misinjections., Competing Interests: Conflicts of interest and sources of funding: L.N. is principal investigator of service agreement with United Imaging Healthcare. L.N. is site principal investigator of clinical trials supported by Novartis Pharmaceuticals Corporation. L.N. is principal investigator of a clinical trial supported by Telix Pharmaceuticals. L.N. is principal investigator of a clinical trial supported by Lantheus Medical Imaging. L.N. is principal investigator of a clinical trial supported by GE Healthcare. L.N. is coinvestigator of a clinical trial supported by Lilly. L.N. has a speaker engagement agreement with Lilly. UC Davis has a revenue sharing agreement with United Imaging Healthcare. All other authors have no conflicts of interest to report. F.S. is site principal investigator of clinical research supported by Biogen. J.W.R. has received fees for consulting/advisory board from Novartis, Janssen, Catalyst, Biodesix, Amgen, Seattle Genetics, Merck, BMS, Beigene, Regeneron, Sanofi, Turning Point, Bayer, Merus NV, Daiichi Sankyo, and OncoHost; travel support from AstraZeneca and IO Biotech; and research funding to institution from ArriVent, Merck, Novartis, Nuvalent, Revolution Medicines, Spectrum, Calithera, Kinnate, AstraZeneca, and IO Biotech., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: MET tyrosine kinase inhibitor (TKI) therapy is associated with improved outcomes in patients with nonsmall cell lung cancer (NSCLC) harboring a MET alteration, including MET exon 14 (METex14) skipping mutation, MET amplification, or MET fusion. However, primary or acquired resistance to TKI therapy ultimately develops. In preclinical models, hyperactivation of MAPK signaling was shown to promote resistance to MET TKI; resistance was overcome by co-treatment with a MET inhibitor and a MEK inhibitor. This phase I/Ib study offers a potential combination strategy simultaneously targeting MET (with capmatinib) and MEK signaling (with trametinib) to overcome resistance to MET inhibitor monotherapy in METex14 NSCLC., Methods: In the dose escalation phase, a minimum of 6 and maximum of 18 patients will be enrolled using a conventional 3+3 design with the primary endpoint of identifying a recommended phase 2 dose (RP2D) of capmatinib in combination with trametinib. Once the RP2D is identified, patients will continue to enroll in a dose expansion phase to a total of 15 patients. The primary endpoint of the dose expansion phase is to further characterize the safety profile of the combination., Conclusion: This phase I/Ib clinical trial will assess the safety and efficacy of combination capmatinib and trametinib in NSCLC patients whose tumors harbor METex14 skipping mutations, MET amplification, or MET fusion and had developed progressive disease on single agent MET inhibitor therapy., Competing Interests: Disclosure C.M.B. receives institutional research funding from Novartis, AstraZeneca, Mirati, Verastem, and Puma. J.W.R. received institutional research funding from AstraZeneca, Boehringer Ingelheim, Merck, Novartis, Revolution Medicines, Arrivent and Spectrum; consulting fees from Blueprint, Boehringer Ingelheim, EMD Serono, and Novartis; participation on an Advisory Board for Bayer, Beigene, Biodesix, Regeneron, Turning Point, Bristol Myers Squibb, Daiichi Sankyo, Roche/Genentech, Janssen, Jazz Pharmaceuticals, Mervus, Seattle Genetics, Summit and Sanofi., (Copyright © 2024. Published by Elsevier Inc.)

Introduction: EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC., Methods: Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood., Results: A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells ( p  = 0.027, p  = 0.01) increased and exhausted CD8+ T-cells decreased on treatment ( p  = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p  = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p  = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment., Conclusions: Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs., Competing Interests: Dr. Riess reports receiving grants or contracts from ArriVent, Merck, Novartis, Nuvalent, Revolution Medicines, Kinnate, AstraZeneca, IO Biotech, Summit, Seattle Genetics; consulting fees from Novartis, Janssen, Catalyst, Biodesix, Amgen, Seattle Genetics, Merck, BMS, Beigene, Regeneron, Sanofi, Turning Point, Bayer, Merus NV, Daiichi Sankyo, OncoHost and support for attending meetings and/or travel from IO Biotech and AstraZeneca. Dr. Monjazeb reports grants or contracts from Merck, BMS, Transgene, Genentech, Incyte, Trisalus, IO Biotech, receipt of equipment, materials, drugs, medical writing, gifts or other services from Merck, Transgene and Incyte. Dr. Gandara reports consulting fees from Merck. Dr. Schalper reports receiving grants or contracts from Akoya Biosciences; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; F. Hoffmann-La Roche; Lilly; Merck Sharpe & Dohme; Ribon Therapeutics; Surface Oncology; Takeda Pharmaceutical Company Limited; and Tesaro Inc./GSK; consulting fees from AbbVie Inc.; Agenus Inc.; AstraZeneca; Bristol Myers Squibb; CDR-Life Inc.; Clinica Alemana de Santiago; EMD Serono Inc.; F.Hoffmann-La Roche; Genmab A/S; Indaptus Therapeutics; Janssen Pharmaceuticals, Inc.; Merck Sharpe & Dohme; Moderna, Inc.; Molecular Templates, Inc.; OnCusp Therapeutics; Parthenon/Incendia Therapeutics; Repertoire Therapeutics; Sanofi; Sensei Biotherapeutics; Shattuck Labs, Inc.; and Takeda Pharmaceutical Company Limited; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Squibb; Fluidigm Corporation; Genmab A/S; Merck & Co., Inc.; Sanofi; PeerView and Takeda Pharmaceutical Company Limited and payment for expert testimony from AstraZeneca., (© 2024 The Authors.)

Competing Interests: Disclosure The authors have stated that they have no conflicts of interest.

Competing Interests: Disclosure This case report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. WAF, FS, VH, and MK have no conflicts of interest to report. MK receives funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, under award number K23AR074530. JWR has consulting or advisory roles with Blueprint, Beigene, Daiichi Sankyo, EMD Serano, Janssen, Regeneron, Sanofi, Biodesix, Bayer, Turning Point, Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Roche/Genentech, Boehringer Ingelheim, Merck, and SeaGen. JWR also receives research funding to institution from Merck, Novartis, AstraZeneca, Spectrum, Revolution Medicines, Arrivent, IO Biotech, and Vitrac.

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response., (© 2024. The Author(s).)

NSCLC w/EGFRex19del & MET amp: durable intracranial + systemic response to amivantamab/osimertinib.

The mitogen-activated protein kinase (MAPK or MEK) pathway modulates tumor cell survival and proliferation in non-small cell lung cancer (NSCLC). Unlike RAS or EGFR, activating mutations in MEK are exceedingly rare in NSCLC. Instead, enhanced activation of the MEK pathway is often linked to increased signaling by upstream oncogenic driver mutations. Thus far, MEK inhibitor monotherapy has shown little promise. However, treatment strategies involving MEK inhibition in combination with other targeted therapies in other oncogene-driven NSCLC has proven to be encouraging. For example, MEK inhibition - when combined with BRAF inhibition, - has shown strong anti-tumor activity in BRAF V600 mutated NSCLC. In this review, recent data on MEK inhibitor strategies in NSCLC are summarized. Furthermore, ongoing early phase trials investigating MEK inhibitor combination therapy with immunotherapy, chemotherapy and other oncogene drivers are highlighted. These and other studies could help inform future rational combination strategies of MEK-ERK inhibition in oncogene-driven NSCLC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: For Dr. Jonathan Riess: Consulting/Advisory board. SeaGen Amgen Catalyst Genentech BMS Regeneron Sanofi EMD Serano Daiichi Sankyo Beigene Merus NV Biodesix OncoCyte Janssen Bayer Research Funding to Institution AstraZeneca ArriVent IO Biotech Summit Novartis Revolution Medicines Travel IO Biotech AstraZeneca For Dr. Blakely Novartis, AstraZeneca, Puma, Mirati, Spectrum. Honararia/consulting from BMS, Janssen, Bayer, Gilead. For Matthew Lara No disclosures, (Copyright © 2024. Published by Elsevier Inc.)

Introduction: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known., Methods: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups., Results: A total of 61 patients received amivantamab. Median age was 65 (31-81) years old; 72.1% were female; and 77% were patients with never smoking history. Median number of prior lines of therapies was four. On the basis of tumor's EGFR mutation, 39 patients were in the classical mutation cohort, 15 patients in the exon 20 cohort, and seven patients in the atypical cohort. There were 37 patients (58.7%) who received amivantamab concomitantly with osimertinib and 25 patients (39.1%) who received concomitant radiation. Furthermore, 54 patients were assessable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 assessable patients, 12 (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 assessable patients in the exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation with or without osimertinib., Conclusions: Our real-world multicenter analysis revealed that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also seems safe when administered sequentially or concurrently with amivantamab., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: The spatial arrangement of lymphocytes in the tumor bed (e.g., immune infiltrated, immune excluded, immune desert) is expected to reflect distinct immune evasion mechanisms and to associate with immunotherapy outcomes. However, data supporting these associations are scant and limited by the lack of a clear definition for lymphocyte infiltration patterns and the subjective nature of pathology-based approaches., Experimental Design: We used multiplexed immunofluorescence to study major tumor-infiltrating lymphocyte (TIL) subsets with single-cell resolution in baseline whole-tissue section samples from NSCLC patients treated with immune checkpoint inhibitors (ICI). The spatial TIL patterns were analyzed using a qualitative pathologist-based approach, and an objective analysis of TIL density ratios in tumor/stromal tissues. The association of spatial patterns with outcomes was studied for different TIL markers., Results: The analysis of CD8+ TIL patterns using qualitative assessment identified prominent limitations including the presence of a broad spectrum of phenotypes within most tumors and limited association with outcomes. The utilization of an objective method to classify NSCLCs showed the existence of at least three subgroups with partial overlap with those defined using visual patterns. Using this strategy, a subset of cases with "immune excluded-like" tumors showed prominently worse outcomes, suggesting reduced sensitivity to ICI; however, these results need to be validated. The analysis for other TIL subsets showed different results, underscoring the relevance of the marker selected for spatial TIL pattern evaluation and opportunities for market integration., Conclusions: Our results identified major challenges associated with the qualitative spatial TIL pattern evaluation. We devised a novel objective strategy to overcome some of these limitations that has strong biomarker potential., (©2023 American Association for Cancer Research.)

Background: FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles., Materials and Methods: Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, and diagnostic genomic alterations and signatures, determined in accordance with professional guidelines. Interventional clinical trials with targeted therapies or immune checkpoint inhibitors were matched to tumor profiles based on evidence that the genomic finding may be an actionable, investigational, or hypothetical target in the patient's tumor type., Results: In 14 predefined cancer types (80.7% of analyzed solid tumors), predictive, prognostic, and diagnostic markers were reported in 47.6%, 13.2%, and 4.5% of samples, respectively, accounting for a total of 51.2% of tumor profiles. Pan-cancer predictive markers of tumor mutational burden (TMB) of 10 or more mutations per megabase, high microsatellite instability (MSI), or NTRK1/2/3 fusions were observed in 15.6%, 2.0%, and 0.1% of solid tumors, respectively. Most solid tumor profiles (89.2%) had genomic results that could theoretically inform decisions on the selection of immunotherapy and targeted therapy clinical trials., Conclusion: For this real-world population of patients with FoundationOneCDx solid tumor profiles in the routine course of clinical care, clinically significant findings were reported for approximately half of patients with genomic results., (© The Author(s) 2023. Published by Oxford University Press.)

Obesity, a condition of excess adiposity usually defined by a BMI > 30, can have profound effects on both metabolism and immunity, connecting the condition with a broad range of diseases, including cancer and negative outcomes. Obesity and cancer have been associated with increased incidence, progression, and poorer outcomes of multiple cancer types in part due to the pro-inflammatory state that arises. Surprisingly, obesity has also recently been demonstrated in both preclinical models and clinical outcomes to be associated with improved response to immune checkpoint inhibition (ICI). These observations have laid the foundation for what has been termed the "obesity paradox". The mechanisms underlying these augmented immunotherapy responses are still unclear given the pleiotropic effects obesity exerts on cells and tissues. Other important variables such as age and sex are being examined as further affecting the obesity effect. Sex-linked factors exert significant influences on obesity biology, metabolism as well as differential effects of different immune cell-types. Age can be another confounding factor contributing to the effects on both sex-linked changes, immune status, and obesity. This review aims to revisit the current body of literature describing the immune and metabolic changes mediated by obesity, the role of obesity on cancer immunotherapy, and to highlight questions on how sex-linked differences may influence obesity and immunotherapy outcome., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2024.)

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.

Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations., Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity., Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status., Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients., Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication., Clinical Trial Number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701., Competing Interests: GN, SV, AK, TS, NK, DA, JA, JA, ZB, NB, TB, BB, SB, MB, PB, SB, BB, HB, CC, HC, JD, AD, NE, LF, DF, CF, MG, CG, PG, SG, MH, HH, DH, CH, CJ, SJ, MJ, VK, EK, NK, VK, AK, DK, CL, PL, KL, ML, XL, GL, GL, DM, AM, MM, SM, RM, IM, VM, RN, SN, RN, TN, TO, OP, KP, JP, KP, JP, HP, MP, YR, PR, SR, JR, DR, MR, SR, AR, LS, PS, MS, LS, MS, DS, MS, LT, MT, ST, LW, GW, MW, EW, SM, BF, JW, ML, MA, DS No competing interests declared

Purpose: Efficacy of MEK inhibitors in KRAS+ NSCLC may differ based on specific KRAS mutations and comutations. Our hypothesis was that docetaxel and trametinib would improve activity in KRAS+ NSCLC and specifically in KRAS G12C NSCLC., Patients and Methods: S1507 is a single-arm phase II study assessing the response rate (RR) with docetaxel plus trametinib in recurrent KRAS+ NSCLC and secondarily in the G12C subset. The accrual goal was 45 eligible patients, with at least 25 with G12C mutation. The design was two-stage design to rule out a 17% RR, within the overall population at the one-sided 3% level and within the G12C subset at the 5% level., Results: Between July 18, 2016, and March 15, 2018, 60 patients were enrolled with 53 eligible and 18 eligible in the G12C cohort. The RR was 34% [95% confidence interval (CI), 22-48] overall and 28% (95% CI, 10-53) in G12C. Median PFS and OS were 4.1 and 3.3 months and 10.9 and 8.8 months, overall and in the subset, respectively. Common toxicities were fatigue, diarrhea, nausea, rash, anemia, mucositis, and neutropenia. Among 26 patients with known status for TP53 (10+ve) and STK11 (5+ve), OS (HR, 2.85; 95% CI, 1.16-7.01), and RR (0% vs. 56%, P = 0.004) were worse in patients with TP53 mutated versus wild-type cancers., Conclusions: RRs were significantly improved in the overall population. Contrary to preclinical studies, the combination showed no improvement in efficacy in G12C patients. Comutations may influence therapeutic efficacy of KRAS directed therapies and are worthy of further evaluation. See related commentary by Cantor and Aggarwal, p. 3563., (©2023 American Association for Cancer Research.)

Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial., (© 2023. Springer Nature Limited.)

Introduction: ERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions., Methods: ZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end points included disease control rate, duration of response, progression-free survival, and safety., Results: A total of 80 patients (16 mg QD, n = 47; 8 mg BID, n = 33) were treated in ZENITH20-C4. ORR was 39% (95% confidence interval [CI]: 28%-50%; 31 of 80), with a disease control rate of 73% (95% CI: 61%-82%; 58 of 80); 80% of the patients experienced tumor reduction. Median duration of response was 5.7 (95% CI: 4.6-11.9) months, and median progression-free survival was 5.6 (95% CI: 5.4-7.3) months. The most common grade 3 treatment-related adverse events were rash (QD, 45%; BID, 39%), stomatitis (QD, 21%; BID, 15%), and diarrhea (QD, 15%; BID, 21%). Among all subtypes of HER2 exon 20 insertions, seven patients (9%) harboring tumors with G778_P780dupGSP had the best clinical outcomes (ORR, 71%)., Conclusions: Poziotinib was found to have clinically meaningful efficacy with a manageable toxicity profile for patients with treatment-naive NSCLC harboring HER2 exon 20 mutations., (Copyright © 2023. Published by Elsevier Inc.)

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies., Significance: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501., (©2023 American Association for Cancer Research.)

This review article illuminates the role of liquid biopsy in the continuum of care for non-small cell lung cancer (NSCLC). We discuss its current application in advanced-stage NSCLC at the time of diagnosis and at progression. We highlight research showing that concurrent testing of blood and tissue yields faster, more informative, and cheaper answers than the standard stepwise approach. We also describe future applications for liquid biopsy including treatment response monitoring and testing for minimal residual disease. Lastly, we discuss the emerging role of liquid biopsy for screening and early detection., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Osimertinib sensitive and resistant NSCLC NCI-H1975 clones are used to model osimertinib acquired resistance in humanized and non-humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation are found in resistant clones. Resistant tumors grown under continuous osimertinib pressure both in humanized and non-humanized mice show aggressive tumor regrowth which is significantly less sensitive to osimertinib as compared with parental tumors. 3-phosphoinositide-dependent kinase 1 (PDK1) is identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitizes resistant clones. In-vivo inhibition of PDK1 enhances the osimertinib sensitivity against osimertinib resistant xenograft and a patient derived xenograft (PDX) tumors. PDK1 knock-out dysregulates PI3K/Akt/mTOR signaling, promotes cell cycle arrest at the G1 phase. Yes-associated protein (YAP) and active-YAP are upregulated in resistant tumors, and PDK1 knock-out inhibits nuclear translocation of YAP. Higher expression of PDK1 and an association between PDK1 and YAP are found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP., (© 2023. The Author(s).)

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together, results from this cohort demonstrate the complexity of biological determinants underlying immunotherapy outcomes and reinforce the discovery potential of integrative analysis within large, well-curated, cancer-specific cohorts., (© 2023. The Author(s).)

Lung cancer is the leading cause of cancer-related mortality globally. Imaging is essential in the screening, diagnosis, staging, response assessment, and surveillance of patients with lung cancer. Subtypes of lung cancer can have distinguishing imaging appearances. The most frequently used imaging modalities include chest radiography, computed tomography, magnetic resonance imaging, and positron emission tomography. Artificial intelligence algorithms and radiomics are emerging technologies with potential applications in lung cancer imaging., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohammad H. Madani: None. Jonathan W. Riess: Research Funding to Institution: AstraZeneca, IO Biotech, Boehringer Ingelheim, Merck, Arrivent, Novartis, Kinnate, Revolution Medicines, Spectrum; Consulting fees: Blueprint, Boehringer Ingelheim, EMD Serono, Novartis, Regeneron; Advisory Board: Bayer, Beigene, Biodesix, Regeneron, Turning Point, Bristol Myers Squibb, Daiichi Sankyo, Roche/Genentech, Janssen, Jazz Pharmaceuticals, Sanofi, Merus NV. Lisa M. Brown: None. David T. Cooke: None. H. Henry Guo: None., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: CD47 is a tumor antigen that inhibits phagocytosis leading to immune evasion. Anti-CD47 therapy is a promising new immunotherapy across numerous tumor types, but it has not been tested in thymic epithelial tumors (TETs): thymomas and thymic carcinomas. TETs are rare tumors that are difficult to treat, especially with programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors, owing to the excessive rates of immune-related adverse events. This study investigated the levels of CD47 expression in TETs to explore the possibility of anti-CD47 therapy., Methods: A total of 67 thymic tumors (63 thymomas and 4 thymic carcinomas) and 14 benign thymus controls and their clinical data were included. Samples were stained for CD47 expression (rabbit monoclonal antibody SP279, Abcam, Waltham, MA) and scored for both intensity and H-score (intensity multiplied by the percentage of tumor involved). Intensity was defined as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. H-scores ranged from 0 to 300. Samples with an intensity score below 2 or an H-score below 150 were considered CD47 low , whereas the rest were CD47 high ., Results: Compared with normal thymic tissues, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was positive in 79.1% of TETs compared with 57.1% of normal thymus. The level of CD47 expression was 16-fold higher in TETs (mean H-score 75.0 versus 4.6, p  = 0.003). Multivariate analysis adjusted for age, sex, stage, resection status, and performance status revealed that CD47-high tumors were highly correlated with WHO histology type ( p  = 0.028). The most frequent CD47 high tumors, in contrast to CD47 low tumors, were types A (28.6% versus 7.5%) and AB (57.1% versus 13.2%), and the least frequent were B1 (7.1% versus 24.5%), B2 (0% versus 35.8%), B3 (7.1% versus 11.3%), and C (0% versus 7.5%)., Conclusions: In contrast to normal thymus, TETs had significantly higher levels of CD47 expression. Tumor samples with high CD47 expression were mostly WHO types A and AB. This is the first study to explore CD47 expression in thymic cancers and lends support for ongoing investigation of anti-CD47 macrophage checkpoint inhibitor therapy in these tumors., (© 2023 The Authors.)

Introduction: EGFR mutations drive a subset of NSCLC. Patients harboring the common EGFR mutations, deletion of exon 19 and L858R, respond well to osimertinib, a third-generation tyrosine kinase inhibitor. Nevertheless, the effect of osimertinib on NSCLC with atypical EGFR mutations is not well described. This multicenter retrospective study evaluates the efficacy of osimertinib among patients with NSCLC harboring atypical EGFR mutations., Methods: Patients with metastatic NSCLC treated with osimertinib, harboring at least one atypical EGFR mutation, excluding concurrent deletion of exon 19, L858R, or T790M mutations, from six U.S. academic cancer centers were included. Baseline clinical characteristics were collected. The primary end point was the time to treatment discontinuation (TTD) of osimertinib. Objective response rate by the Response Evaluation Criteria in Solid Tumors version 1.1 was also assessed., Results: A total of 50 patients with NSCLC with uncommon EGFR mutations were identified. The most frequent EGFR mutations were L861Q (40%, n = 18), G719X (28%, n = 14), and exon 20 insertion (14%, n = 7). The median TTD of osimertinib was 9.7 months (95% confidence interval [CI]: 6.5-12.9 mo) overall and 10.7 months (95% CI: 3.2-18.1 mo) in the first-line setting (n = 20). The objective response rate was 31.7% (95% CI: 18.1%-48.1%) overall and 41.2% (95% CI: 18.4%-67.1%) in the first-line setting. The median TTD varied among patients with L861Q (17.2 mo), G719X (7.8 mo), and exon 20 insertion (1.5 mo) mutations., Conclusions: Osimertinib has activity in patients with NSCLC harboring atypical EGFR mutations. Osimertinib activity differs by the type of atypical EGFR -activating mutation., (© 2023 The Authors.)

Introduction: In patients with NSCLC harboring oncogenic ALK or ROS1 rearrangements, tyrosine kinase inhibitors have yielded high response rates and improvements in progression-free survival compared with cytotoxic chemotherapy; however, acquired resistance eventually develops. In preclinical models, ALK and MEK coinhibition was able to overcome ALK inhibitor resistance., Methods: A phase 1 study of the ALK/ROS1 inhibitor ceritinib and the MEK inhibitor trametinib in patients with refractory NSCLC harboring ALK or ROS1 fusions was initiated. A three plus three dose-escalation scheme was used. Two dose levels were investigated. The primary end point was to determine the safety and tolerability of the combination., Results: Nine patients (n = 8 ALK+, n = 1 ROS1+) were enrolled in the study and completed at least one cycle of therapy. The most common adverse events (all grades) were diarrhea (n = 9; 100%), rash (n = 8; 89%), abdominal pain (n = 5; 56%), and elevated aspartate transaminase/alanine transaminase level (n = 4; 44%). The overall response rate was 22%, whereas disease control rate was 56%. Median duration of response was 7.85 months. The median progression-free survival was 3.0 months (95% confidence interval: 1.5-7.0 mo). The median overall survival was 8.9 months (95% confidence interval: 2.0-not reached)., Conclusions: Data from this trial indicate that the combination of ceritinib and trametinib had no unexpected toxicities and that a tolerable dose could be identified. A subset of patients seemed to obtain clinical benefit from this treatment after progression on prior ALK/ROS1 inhibitor treatment.ClinicalTrials.gov Identifier: NCT03087448., (© 2022 The Authors.)

Patient-derived xenograft (PDX) models are an effective preclinical in vivo platform for testing the efficacy of novel drugs and drug combinations for cancer therapeutics. Here we describe a repository of 79 genomically and clinically annotated lung cancer PDXs available from The Jackson Laboratory that have been extensively characterized for histopathologic features, mutational profiles, gene expression, and copy-number aberrations. Most of the PDXs are models of non-small cell lung cancer (NSCLC), including 37 lung adenocarcinoma (LUAD) and 33 lung squamous cell carcinoma (LUSC) models. Other lung cancer models in the repository include four small cell carcinomas, two large cell neuroendocrine carcinomas, two adenosquamous carcinomas, and one pleomorphic carcinoma. Models with both de novo and acquired resistance to targeted therapies with tyrosine kinase inhibitors are available in the collection. The genomic profiles of the LUAD and LUSC PDX models are consistent with those observed in patient tumors from The Cancer Genome Atlas and previously characterized gene expression-based molecular subtypes. Clinically relevant mutations identified in the original patient tumors were confirmed in engrafted PDX tumors. Treatment studies performed in a subset of the models recapitulated the responses expected on the basis of the observed genomic profiles. These models therefore serve as a valuable preclinical platform for translational cancer research., Significance: Patient-derived xenografts of lung cancer retain key features observed in the originating patient tumors and show expected responses to treatment with standard-of-care agents, providing experimentally tractable and reproducible models for preclinical investigations., (©2022 The Authors; Published by the American Association for Cancer Research.)

Purpose: Aurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion., Methods: Key inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1-4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m 2 on days 1, 8, and 15 in 28-day cycles., Results: In total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1-4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration., Conclusions: This trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent., (© 2022. The Author(s).)

Background: Tumor infiltrating lymphocytes (TILs) reflect adaptive antitumor immune responses in cancer and are generally associated with favorable prognosis. However, the relationships between TILs subsets and their spatial arrangement with clinical benefit from immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) remains less explored., Methods: We used multiplexed quantitative immunofluorescence panels to determine the association of major TILs subpopulations, CD8 + cytotoxic T cells, CD4 + helper T cells and CD20 + B cells, and T cell exhaustion markers, programmed cell death protein-1 (PD-1),lymphocyte-activation gene 3 (LAG-3) and T cell immunoglobulin mucin-3 (TIM-3) with outcomes in a multi-institutional cohort of baseline tumor samples from 179 patients with NSCLC treated with ICI. The analysis of full-face tumor biopsies including numerous fields of view allowed a detailed spatial analysis and assessment of tumor immune heterogeneity using a multiparametric quadratic entropy metric (Rao's Q Index (RQI))., Results: TILs were preferentially located in the stromal tissue areas surrounding tumor-cell nests and CD8 + T cells were the most abundant subset. Higher density of stromal CD8 + cytotoxic T cells was significantly associated with longer survival, and this effect was more prominent in programmed death ligand-1 (PD-L1) positive cases. The role of baseline T cell infiltration to stratify PD-L1 expressing cases was confirmed measuring the T cell receptor-burden in an independent NSCLC cohort studied with whole-exome DNA sequencing. High levels of LAG-3 on T cells or elevated RQI heterogeneity index were associated with worse survival in the cohort., Conclusion: Baseline T cell density and T cell exhaustion marker expression can stratify outcomes in PD-L1 positive patients with NSCLC treated with ICI. Spatial immune heterogeneity can be measured using the RQI and is associated with survival in NSCLC., Competing Interests: Competing interests: JG has served as a compensated consultant or received honoraria from Bristol Myers Squibb, Takeda, Loxo/Lilly, Blueprint, Oncorus, Regeneron, Gilead, Moderna, AstraZeneca, EMD Serono, Pfizer, Novartis, Merck, and GlydeBio; research support from Novartis; institutional research support from Bristol Myers Squibb, Tesaro, Moderna, Blueprint, Jounce, Array Biopharma, Merck, Adaptimmune, Novartis, and Alexo; and has an immediate family member who is an employee with equity at Ironwood Pharmaceuticals. AR has served as a consultant for Halo and Tyra. AM is an equity holder in Elucid Bioimaging and in Inspirata. In addition, he has served as a scientific advisory board member for Inspirata, AstraZeneca, Bristol Meyers Squibb and Merck. Currently he serves on the advisory board of Aiforia and currently consults for Caris, Roche, Cernostics and Aiforia. He also has sponsored research agreements with Philips, AstraZeneca, Boehringer-Ingelheim and Bristol Meyers Squibb. His technology has been licensed to Elucid Bioimaging. He is also involved in three different R01 grants with Inspirata. MM-K has served as a compensated consultant for H3 Biomedicine and AstraZeneca and has received research (institutional) funding from Novartis and royalty from Elsevier, all of which are not related to this work. JWR reports institutional research support from Spectrum, AstraZeneca, Novartis, Merck, Revolution Medicines. JWR has received honoraria for consultant/advisory roles from EMD Serono, Daiichi Sankyo, BMS, Beigene, Turning Point, Janssen, Novartis, Boehringer Ingelheim, Blueprint, Regeneron. KAS reports research funding from Navigate Biopharma, Tesaro/GlaxoSmithKline, Moderna, Takeda, Surface Oncology, Pierre-Fabre Research Institute, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Ribon Therapeutics, Eli Lilly, Boehringer Ingelheim and Akoya Biosciences. KAS has received honoraria for consultant/advisory/speaker roles from Moderna, Shattuck Labs, Pierre-Fabre, AstraZeneca, EMD Serono, Ono Pharmaceuticals, Clinica Alemana de Santiago, Dynamo Therapeutics, PeerView, AbbVie, Fluidigm, Takeda/Millenium Pharmaceuticals, Merck Sharp & Dohme, Bristol Myers Squibb, Agenus, Torque Therapeutics, Genmab, Parthenon Therapeutics and OnCusp. AM’s research efforts are supported by grants from the National Cancer Institute under award numbers R01CA249992-01A1, R01CA202752-01A1, R01CA208236-01A1, R01CA216579-01A1, R01CA220581-01A1, R01CA257612-01A1, 1U01CA239055-01, 1U01CA248226-01, 1U54CA254566-01, National Heart, Lung and Blood Institute 1R01HL15127701A1, R01HL15807101A1, National Institute of Biomedical Imaging and Bioengineering 1R43EB028736-01, National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the US Department of Veterans Affairs Biomedical Laboratory Research and Development Service the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program (W81XWH-19-1-0668), the Prostate Cancer Research Program (W81XWH-15-1-0558, W81XWH-20-1-0851), the Lung Cancer Research Program (W81XWH-18-1-0440, W81XWH-20-1-0595), the Peer Reviewed Cancer Research Program (W81XWH-18-1-0404, W81XWH-21-1-0345), the Kidney Precision Medicine Project (KPMP) Glue Grant and sponsored research agreements from Bristol Myers Squibb, Boehringer-Ingelheim, and AstraZeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Afatinib and pembrolizumab have separately shown survival benefit in patients with squamous cell carcinoma (SqCC) of the lung, and there is biological rationale for concurrent inhibition of the programmed death ligand-1 and epidermal growth factor receptor (EGFR) pathways in this patient population., Materials and Methods: This open-label, single-arm study enrolled patients with SqCC of the lung who had progressed during/after first-line chemotherapy and comprised two parts: a safety run-in to establish the recommended phase II dose (RP2D; afatinib 40 mg or 30 mg once daily with pembrolizumab 200 mg every 3 weeks); and the main part assessing efficacy and safety of the RP2D. The primary endpoint was objective response rate (ORR); secondary endpoints included the RP2D, progression-free survival (PFS) and overall survival (OS)., Results: Twenty-four patients were treated in the safety run-in (afatinib 40 mg/30 mg cohorts: n = 12/12). Median age was 63.5 years; 79.2% of patients were male. All patients discontinued afatinib and pembrolizumab, most commonly due to disease progression (58.3% and 75.0%, respectively) or adverse events (AEs; 37.5% and 25.0%, respectively). The study was discontinued early after completion of the safety run-in, and no patients entered the main part. ORR was 12.5%; median PFS and OS were 13.1 and 29.3 weeks, respectively. All patients had ≥ 1 drug-related AE (grade ≥ 3: 45.8%)., Conclusion: While there were no new or unexpected safety findings, exploratory analysis of antitumor activity indicated limited efficacy with afatinib plus pembrolizumab in patients with SqCC of the lung who had progressed during/after first-line chemotherapy., Clinical Trial Registration Number: NCT03157089., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Onalespib is a novel heat shock protein 90 inhibitor (HSP90i). Previous preclinical and clinical studies with HSP90i have demonstrated activity in EGFR-mutant non-small cell lung cancer (NSCLC). This study sought to determine the safety and tolerability of onalespib plus erlotinib in EGFR-mutant NSCLC and to evaluate the preliminary efficacy of the combination in epidermal growth factor receptor exon 20 insertion (EGFRex20ins) NSCLC., Patients and Methods: Standard 3+3 dose escalation was followed by a phase II expansion in EGFRex20ins. The phase II component targeted a response rate of 25% versus a background rate of 5%. Prospective next-generation sequencing (NGS) of 70 cancer-related genes, including EGFR, via plasma circulating tumor DNA (ctDNA) was performed. Toxicity was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4, and response was determined by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1., Results: Eleven patients were treated (nine dose escalation, two dose expansion). Two dose-limiting toxicities (DLTs) occurred in dose level (DL) 0 and zero in DL -1 (minus). In 10 EGFRex20ins patients, no responses were observed, median progression-free survival was 5.4 months (95% confidence interval, 0.9-5.7), and the disease control rate (DCR) was 40% (median, 3.5 months). EGFRex20ins was detected in nine of 10 ctDNA samples at baseline; on-treatment ctDNA clearance was not observed. Grade 3 diarrhea was the predominant toxicity in 45% of patients. The recommended phase II dose is DL -1 (minus): erlotinib 150 mg orally every morning and onalespib 120 mg/m 2 intravenously on days 1, 8, and 15 every 28 days., Conclusion: Overlapping toxicities of erlotinib and onalespib, mainly diarrhea, limited the tolerability of this combination, and limited clinical activity was observed, so the trial was closed early. Plasma EGFRex20ins ctDNA was detected in the majority of patients; failure to clear ctDNA was consistent with lack of tumor response (NCT02535338)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Osimertinib, a third-generation, irreversible, epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selectively inhibits both EGFR-TKI sensitizing (EGFRm) and EGFR T790M resistance mutations and has demonstrated efficacy in non-small cell lung cancer (NSCLC) CNS metastases. Most patients with EGFRm NSCLC treated with osimertinib will eventually develop resistance. ORCHARD (NCT03944772) is a phase II study aiming to characterize first-line osimertinib resistance and identify post-progression treatments., Methods: Adults aged ≥ 18 years (Japan ≥ 20 years), with EGFRm locally advanced/metastatic NSCLC will be allocated to one of three groups after first-line osimertinib progression, based on molecular profiling from a post-progression tumor biopsy. Group A will evaluate patients with protocol-determined biomarkers of resistance treated with novel osimertinib combination therapies, Group B will evaluate patients without a detectable protocol-determined biomarker treated with non-biomarker selected therapies that are chemotherapy- or EGFR-TKI-based, and Group C (observational) includes patients with histologically transformed disease, and/or a biomarker with an available therapy not investigated in ORCHARD. Group C patients will be treated as per local practice and followed to assess overall survival. The study's platform design allows for adaptability to include emerging treatments related to novel resistance mechanisms. The primary endpoint is confirmed objective response rate (investigator assessed). Other endpoints are progression-free survival, duration of response, overall survival, pharmacokinetics and safety., Conclusions: ORCHARD aims to characterize mechanisms of resistance to first-line osimertinib and explore treatments to overcome acquired resistance. The modular design allows for additional biomarker-directed cohorts and treatment options as understanding of osimertinib resistance mechanisms evolves., Competing Interests: Disclosure H Yu has received research funding to her institution from AstraZeneca, Pfizer, Cullinan, Daiichi, Novartis, Lilly and advisory board fees from AstraZeneca, Blueprint Medicine and Janssen. S Goldberg has received research funding from AstraZeneca and Boehringer Ingelheim, received advisory board/personal fees from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Genentech and Spectrum. Z Piotrowska has received research funding to her institution from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro, Cullinan, Daiichi and AbbVie and has received advisory board fees from AstraZeneca, Blueprint Medicines, Janssen, Takeda, Jazz Pharmaceuticals and C4 Therapeutics. X Le receives consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Eli Lilly, Boehringer Ingelheim, and Research Funding from Eli Lilly and Boehringer Ingelheim. JW Riess has received research funding from AstraZeneca, Merck, Spectrum, Revolution Medicines and Novartis, received advisory board/personal fees from Novartis, Medtronic, Blueprint Medicines, Boehringer Ingelheim and Spectrum. G Patel is an employee of AstraZeneca. H Ambrose, J Chmielecki, G Doughton, S Kraljevic, X Li-Sucholeiki, J Maidment and P Szekeres are employees of AstraZeneca and hold stock/stock options., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The translocation t(15:19) produces the oncogenic BRD4-NUT fusion which is pathognomonic for NUT carcinoma (NC), which is a rare, but extremely aggressive solid tumor. Comprehensive genomic profiling (CGP) by hybrid-capture based next generation sequencing of 186+ genes of a cohort of advanced cancer cases with a variety of initial diagnoses harboring BRD4-NUT may shed further insight into the biology of these tumors and possible options for targeted treatment., Case Presentation: Thirty-one solid tumor cases harboring a BRD4-NUT translocation are described, with only 16% initially diagnosed as NC and the remainder carrying other diagnoses, most commonly NSCLCNOS (22%) and lung squamous cell carcinoma (NSCLC-SCC) (16%). The cohort was all microsatellite stable and harbored a low Tumor Mutational Burden (TMB, mean 1.7 mut/mb, range 0-4). In two index cases, patients treated with immune checkpoint inhibitors (ICPI) had unexpected partial or better responses of varying duration. Notably, four cases - including the two index cases - were negative for PD-L1 expression. Neo-antigen prediction for BRD4-NUT and then affinity modeling of the peptide-MHC (pMHC) complex for an assessable index case predicted very high affinity binding, both on a ranked (99.9%) and absolute (33 nM) basis., Conclusions: CGP identifies BRD4-NUT fusions in advanced solid tumors which carry a broad range of initial diagnoses and which should be re-diagnosed as NC per guidelines. A hypothesized mechanism underlying responses to ICPI in the low TMB, PD-L1 negative index cases is the predicted high affinity of the BRD4-NUT fusion peptide to MHC complexes. Further study of pMHC affinity and response to immune checkpoint inhibitors in patients with NC harboring BRD4-NUT is needed to validate this therapeutic hypothesis., (Copyright © 2021. Published by Elsevier Inc.)

Purpose: Aurora kinases are overexpressed or amplified in numerous malignancies. This study was designed to determine the safety and tolerability of the Aurora A kinase inhibitor alisertib (MLN8237) when combined with weekly irinotecan., Methods: In this single-center phase 1 study, adult patients with refractory advanced solid tumors received 100 mg/m 2 irinotecan intravenously on day 1 and 8 of a 21-day cycle. Alisertib at planned escalating dose levels of 20-60 mg was administered orally twice per day on days 1-3 and 8-10. Patients homozygous for UGT1A1*28 were excluded. The primary objective was the safety of alisertib when combined with irinotecan to determine the maximum tolerated dose (MTD). Secondary objectives included overall response rate by RECIST and pharmacokinetics in a planned expansion cohort of patients with colorectal cancer treated at the MTD., Results: A total of 17 patients enrolled at three dose levels. Dose-limiting toxicities included diarrhea, dehydration, and neutropenia. The MTD of alisertib combined with weekly irinotecan was 20 mg twice per day on days 1-3 and 8-10. One fatal cardiac arrest at the highest dose level tested was deemed possibly related to drug treatment. One partial response in 11 efficacy evaluable patients (9%) occurred in a patient with small cell lung cancer. The study was terminated prior to the planned expansion in patients with colorectal cancer., Conclusion: In contrast to prior results in a pediatric population, adult patients did not tolerate alisertib combined with irinotecan at clinically meaningful doses due to hematologic and gastrointestinal toxicities. The study was registered with ClinicalTrials.gov under study number NCT01923337 on Aug 15, 2013.

Purpose: We report the first 5-year follow-up of any first-line phase III immunotherapy trial for non-small-cell lung cancer (NSCLC). KEYNOTE-024 (ClinicalTrials.gov identifier: NCT02142738) is an open-label, randomized controlled trial of pembrolizumab compared with platinum-based chemotherapy in patients with previously untreated NSCLC with a programmed death ligand-1 (PD-L1) tumor proportion score of at least 50% and no sensitizing EGFR or ALK alterations. Previous analyses showed pembrolizumab significantly improved progression-free survival and overall survival (OS)., Methods: Eligible patients were randomly assigned (1:1) to pembrolizumab (200 mg once every 3 weeks for up to 35 cycles) or platinum-based chemotherapy. Patients in the chemotherapy group with progressive disease could cross over to pembrolizumab. The primary end point was progression-free survival; OS was a secondary end point., Results: Three hundred five patients were randomly assigned: 154 to pembrolizumab and 151 to chemotherapy. Median (range) time from randomization to data cutoff (June 1, 2020) was 59.9 (55.1-68.4) months. Among patients initially assigned to chemotherapy, 99 received subsequent anti-PD-1 or PD-L1 therapy, representing a 66.0% effective crossover rate. Median OS was 26.3 months (95% CI, 18.3 to 40.4) for pembrolizumab and 13.4 months (9.4-18.3) for chemotherapy (hazard ratio, 0.62; 95% CI, 0.48 to 0.81). Kaplan-Meier estimates of the 5-year OS rate were 31.9% for the pembrolizumab group and 16.3% for the chemotherapy group. Thirty-nine patients received 35 cycles (ie, approximately 2 years) of pembrolizumab, 82.1% of whom were still alive at data cutoff (approximately 5 years). Toxicity did not increase with longer treatment exposure., Conclusion: Pembrolizumab provides a durable, clinically meaningful long-term OS benefit versus chemotherapy as first-line therapy for metastatic NSCLC with PD-L1 tumor proportion score of at least 50%., Competing Interests: Martin ReckConsulting or Advisory Role: Lilly, MSD Oncology, Merck Serono, Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Pfizer, Novartis, Roche/Genentech, Abbvie, Amgen, Mirati Therapeutics, Samsung BioepisSpeakers' Bureau: Roche/Genentech, Lilly, MSD Oncology, Merck Serono, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Pfizer, Novartis, Amgen, Mirati Therapeutics Delvys Rodríguez-AbreuConsulting or Advisory Role: Roche, Bristol Myers Squibb, MSD, AstraZeneca Spain, NovartisSpeakers' Bureau: Roche, Bristol Myers Squibb, MSDTravel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD Andrew G. RobinsonHonoraria: MerckConsulting or Advisory Role: AstraZeneca, Merck, AmgenResearch Funding: AstraZeneca, Merck, Bristol Myers Squibb, Roche Canada Rina HuiHonoraria: Merck Sharp & Dohme, Novartis, Roche, AstraZeneca, Bristol Myers Squibb, Lilly, Pfizer, SeagenConsulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Roche, Bristol Myers Squibb, Novartis, Lilly, Pfizer, SeagenResearch Funding: AstraZeneca, Lilly, Novartis, MSD, Roche, Seagen, OncoSecTravel, Accommodations, Expenses: Novartis Tibor CsősziConsulting or Advisory Role: NovartisSpeakers' Bureau: Ipsen, Janssen-CilagTravel, Accommodations, Expenses: Sanofi, Pfizer Andrea FülöpResearch Funding: MSD, AstraZeneca, Janssen Nir PeledHonoraria: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, MSD, Novartis, Pfizer, Roche, TakedaConsulting or Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, MSD, Novartis, Pfizer, RocheResearch Funding: MSD Oncology, Roche/Genentech, AstraZeneca, Takeda, Merck Serono, NovartisTravel, Accommodations, Expenses: Roche/Genentech, MSD Oncology, AstraZeneca, Pfizer Sinead CuffeTravel, Accommodations, Expenses: MSD Oncology, Roche, Pfizer, Bristol Myers Squibb Mary O'BrienHonoraria: Merck, Merck Serono, Abbvie, Bristol Myers SquibbConsulting or Advisory Role: MerckTravel, Accommodations, Expenses: Bristol Myers Squibb Suman RaoHonoraria: Merck, AstraZenecaConsulting or Advisory Role: Galvanize TherapeuticsSpeakers' Bureau: AstraZenecaTravel, Accommodations, Expenses: Merck Katsuyuki HottaHonoraria: AZD, MSD Oncology, Pfizer, Lilly, Taiho Pharmaceutical, Chugai Pharma, TakedaResearch Funding: MSD, Chugai Pharma, Lilly Japan, Bristol Myers Squibb, AZD Ticiana A. LealConsulting or Advisory Role: BeyondSpring Pharmaceuticals, Bristol Myers Squibb, Merck, Takeda, Genentech, InvisionFirst Lung, Novocure, Jazz Pharmaceuticals, AstraZeneca, Bayer, EMD Serono, Boehringer Ingelheim, Blueprint Medicines, Daiichi Sankyo/Lilly, Debiopharm Group, Genentech, LillyTravel, Accommodations, Expenses: Takeda, Abbvie, Bristol Myers Squibb, Genentech, Mirati Therapeutics, AstraZeneca, MerckUncompensated Relationships: Mirati Therapeutics Jonathan W. RiessConsulting or Advisory Role: Medtronic, Boehringer Ingelheim, Novartis, Blueprint Medicines, Genentech, EcoR1 Capital, Teladoc, Daiichi Sankyo, EMD SeronoResearch Funding: Merck, AstraZeneca/MedImmune, Spectrum Pharmaceuticals, Boehringer Ingelheim, Novartis, Revolution Medicines, GlaxoSmithKline Erin JensenEmployment: MerckStock and Other Ownership Interests: Merck Bin ZhaoEmployment: Merck Sharp & DohmeStock and Other Ownership Interests: Merck Sharp & Dohme M. Catherine PietanzaEmployment: MerckStock and Other Ownership Interests: Merck Sharp & Dohme Julie R. BrahmerHonoraria: Roche/GenentechConsulting or Advisory Role: Bristol Myers Squibb, Lilly, Merck, Amgen, Genentech, GlaxoSmithKline, AstraZeneca, Regeneron, SanofiResearch Funding: Bristol Myers Squibb, AstraZeneca, Spectrum Pharmaceuticals, Revolution, RAPT Therapeutics, Genentech/RocheTravel, Accommodations, Expenses: Bristol Myers Squibb, Roche/GenentechOther Relationship: Bristol Myers Squibb, Merck, Janssen OncologyNo other potential conflicts of interest were reported.

Introduction: In 2018, durvalumab was approved by the U.S. Food and Drug Administration as consolidation immunotherapy for patients with stage III NSCLC after definitive chemoradiotherapy (CRT). However, whether durvalumab benefits patients with EGFR-mutated NSCLC remains unknown., Methods: We conducted a multi-institutional retrospective analysis of patients with unresectable stage III EGFR-mutated NSCLC who completed concurrent CRT. Kaplan-Meier analyses evaluated progression-free survival (PFS) between patients who completed CRT with or without durvalumab., Results: Among 37 patients, 13 initiated durvalumab a median of 20 days after CRT completion. Two patients completed 12 months of treatment, with five patients discontinuing durvalumab owing to progression and five owing to immune-related adverse events (irAEs). Of 24 patients who completed CRT without durvalumab, 16 completed CRT alone and eight completed CRT with induction or consolidation EGFR tyrosine kinase inhibitors (TKIs). Median PFS was 10.3 months in patients who received CRT and durvalumab versus 6.9 months with CRT alone (log-rank p = 0.993). CRT and EGFR TKI was associated with a significantly longer median PFS (26.1 mo) compared with CRT and durvalumab or CRT alone (log-rank p = 0.023). Six patients treated with durvalumab initiated EGFR TKIs after recurrence, with one developing grade 4 pneumonitis on osimertinib., Conclusions: In this study, patients with EGFR-mutated NSCLC did not benefit with consolidation durvalumab and experienced a high frequency of irAEs. Patients who initiate osimertinib after durvalumab may be susceptible to incident irAEs. Consolidation durvalumab should be approached with caution in this setting and concurrent CRT with induction or consolidation EGFR TKIs further investigated as definitive treatment., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Plasma circulating tumor DNA (ctDNA) analysis is routine for genotyping of advanced non-small-cell lung cancer (NSCLC); however, early response assessment using plasma ctDNA has yet to be well characterized., Materials and Methods: Patients with advanced EGFR -mutant NSCLC across three phase I NCI osimertinib combination trials were analyzed in this study, and an institutional cohort of patients with KRAS- , EGFR- , and BRAF -mutant advanced NSCLC receiving systemic treatment was used for validation. Plasma was collected before treatment initiation and serially before each cycle of therapy, and key driver mutations in ctDNA were characterized by droplet digital polymerase chain reaction. Timing of plasma versus imaging response was compared in a separate cohort of patients with EGFR -mutant NSCLC treated with osimertinib. Across cohorts, we also studied ctDNA variability before treatment start., Results: In the NCI cohort, 14/16 (87.5%) patients exhibited ≥ 90% decrease in mutation abundance by the first on-treatment timepoint (20-28 days from treatment start) with minimal subsequent change. Similarly, 47/56 (83.9%) patients with any decrease in the institutional cohort demonstrated ≥ 90% decrease in mutation abundance by the first follow-up draw (7-30 days from treatment start). All 16 patients in the imaging cohort with radiographic partial response showed best plasma response within one cycle, preceding best radiographic response by a median of 24 weeks (range: 3-147 weeks). Variability in ctDNA levels before treatment start was observed., Conclusion: Plasma ctDNA response is an early phenomenon, with the majority of change detectable within the first cycle of therapy. These kinetics may offer an opportunity for early insight into treatment effect before standard imaging timepoints., (© 2021 by American Society of Clinical Oncology.)

Introduction: Remote consent and enrollment offer a unique opportunity to provide rare cancer populations with access to clinical research. The genomic analysis of plasma cell-free DNA (cfDNA) permits remote characterization of the cancer genome. We hypothesized we could leverage these approaches to remotely study drug resistance in patients with metastatic ALK -positive NSCLC., Methods: The SPACEWALK study (Study of Plasma Next-Generation Sequencing for Remote Assessment, Characterization, Evaluation of Patients With ALK Drug Resistance) enrolled patients with ALK -positive NSCLC and progression on a next-generation ALK inhibitor who could participate remotely. Plasma was collected for next-generation sequencing (NGS) of cfDNA before initiating subsequent therapy, with results returned and subsequent therapy studied., Results: Of the 62 patients enrolled, an ALK fusion was detected in 27 (44%) with a median allelic fraction of 2.6%. Among these 27 patients, a potential resistance mechanism was identified in 17 patients (63%): eight cases (30%) had secondary ALK kinase domain resistance mutations, three cases (11%) had bypass track resistance, and six cases (22%) had both ALK resistance mutations and bypass resistance. The most frequently detected mechanism of bypass resistance was MET amplification. Repeat plasma NGS was performed in 14 patients after subsequent treatment was initiated, with seven (50%) patients exhibiting greater than 50% reductions in ALK fusion allelic fraction., Conclusions: Through the leveraging of remote participation, plasma NGS offers an optimal mechanism for characterizing resistance to emerging targeted therapies in rare cancer populations, though sensitivity depends on adequate tumor DNA samples. Repeat cfDNA analysis on therapy may offer an objective monitoring approach to remotely study treatment response., (© 2021 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer.)