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Introduction: Drug resistance remains a major clinical challenge in EGFR-mutant NSCLC tumors owing to pathway reactivation, pathway bypass, and pathway indifference resistance mechanisms to evade tyrosine kinase inhibitor (TKI) suppression. Fusion of receptor tyrosine kinases (RTKs), such as RET, ALK, and FGFR3, has been reported to mediate EGFR TKI resistance. Given the rarity of these fusions and the heterogeneous nature of the condition, no prospective clinical trials evaluated the incidence, safety, and therapeutic benefit of dual EGFR-RTK inhibition., Methods: We queried clinical databases from multiple institutions to identify patients who had RTK fusions detected on next-generation sequencing testing results from tissue or blood at five institutions: the Second Affiliated Hospital Zhejiang University School of Medicine, Hunan Cancer Hospital, Prince of Wales Hospital Chinese University of Hong Kong, Chao Family Cancer Center, and the University of Texas MD Anderson Cancer Center from March 1, 2016, to September 30, 2023. The data analyzed included objective response rate (ORR) to treatment post RTK fusion detection, duration of treatment, and safety. A comprehensive literature search was conducted to identify patients with RTK fusion as the primary resistance mechanism in EGFR-mutated NSCLC patients., Results: Twenty-seven patients were identified to be eligible in the analysis. ALK fusions were most reported (42.9%), followed by RET fusions (35.7%). Fifteen patients received dual TKI after fusion detection and nine received fusion targeting single TKIs. The median time on treatment was 169 days or 5.8 months (35-1050 d). ORR by the Response Evaluation Criteria in Solid Tumors in the evaluable 25 patients was 24% and the disease control rate was 80%. In 14 evaluable patients who received dual TKI therapy, ORR by the Response Evaluation Criteria in Solid Tumors was 21.4%, and the disease control rate was 78.6%. No new toxicities were observed with dual EGFR-RTK inhibition. In the literature review, after pooling 291 patients from 59 studies, RET fusions were the most common (50.0%), followed by BRAF (13.3%), ALK (13.3%), FGFR (10%), NTRK (5.3%), EGFR (1.7%), ROS1 (1.3%), MET (1%), and ERBB (0.7%)., Conclusion: The emergence of RTK fusions is one of the mechanisms of bypass resistance of EGFR TKI. Dual inhibition of EGFR-RTK was safe and efficacious in patients with targetable RTK fusion after progression to EGFR TKIs., Competing Interests: Disclosure Dr. Wang received consulting fees from BluPrint Oncology. Dr. Elamin received grants to institution from Spectrum Pharmaceuticals, AstraZeneca, Takeda, Xcovery, Eli Lilly, Elevation Oncology, and Turning Point Therapeutics; received consulting fees from Eli Lilly, AstraZeneca, and Turning Point Therapeutics; received travel support from Eli Lilly. Dr. Gay received consulting fees from Catalyst, Kisoii, StCube; received honoraria or payment for lectures and speaker bureaus from AstraZeneca, BeiGene, MJH, OncLive, PeerView, and Targeted Healthcare; participated on data safety monitoring board or advisory board with AstraZeneca, Abdera, Daiichi Sankyo, Bristol Myers Squibb, G1 Therapeutics, Jazz Pharmaceuticals, Monte Rosa and Roche/Genentech. Dr. Skoulidis reports consultant for: Astra Zeneca, Amgen Inc, Revolution Medicines, Novartis, BridgeBio, Beigene, BergenBio, Guardant Health, Calithera Biosciences, Tango Therapeutics, Hookipa Pharma, Novocure, Merck Sharp & Dohme, Roche; grant/research support to institution from: Amgen Inc, Mirati Therapeutics, Revolution Medicines, Pfizer, Novartis, Merck& Co; stockholder in: BioNTech SE, Moderna Inc.; honoraria from: ESMO, Japanese Lung Cancer Society, Medscape LLC, Intellishpere LLC, VSPO McGill Universite de Montreal, RV Mais Promocao Eventos LTDS, MJH Life Sciences, IDEOlogy Health, MI&T, PER LLC, CURIO LLC, DAVA Oncology, American Association for Cancer Research, International Association for the Study of Lung Cancer. Dr. Tsao received research funding to institution from Ariad, Bristol Myer Squibb, Eli Lilly, Genentech, Millennium, Polaris, AstraZeneca, Boehringer-Ingelheim, Epizyme, Merck, Novartis, and Seattle Genetics to institution; received consulting fees from Ariad, Bristol Myers Squibb, Eli Lilly, Genentech, Merck, Pfizer, Seattle Genetics, AstraZeneca, Boehringer-Ingelheim, EMD Serono, GlaxoSmithKline, Novartis, and Roche. Dr. Cascone reports (over the past 36 mo) speaker fees/honoraria from ASCO Post, AstraZeneca, Bio Ascend, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medical Educator Consortium INC, Medscape, OncLive, PEAK Medical, PeerView, Physicians' Education Resource, Society for Immunotherapy of Cancer, Targeted Oncology; advisory role/consulting fees from AstraZeneca, Bristol Myers Squibb, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, Regeneron; institutional research funding from AstraZeneca and Bristol Myers Squibb; and travel, food and beverage expenses from AstraZeneca, Bristol Myers Squibb, Dava Oncology, European Society for Medical Oncology, Genentech, IDEOlogy Health, International Association for the Study of Lung Cancer, OncLive, Parker Institute for Cancer Immunotherapy, Physicians’ Education Resource, Society for Immunotherapy of Cancer. Dr. Gibbons received grants to institution from AstraZeneca, NGM Biopharmaceuticals, Mirati Therapeutics, Boehringer Ingelheim, and Astellas; received consulting fees from 4D Pharma, Onconova, Menarini Richerche, Eli Lilly, and AstraZeneca; held leadership role in Rexnanna’s Foundation for Fighting Lung Cancer. Dr. Zhang reports research funding from Helius, Johnson and Johnson, Merck, Novartis, Summit, and honoraria and consulting fees from AstraZeneca, Bristol Myers Squibb, Catalyst, GenePlus, Johnson and Johnson, Novartis, Hengrui, Innovent, Takeda and Varian outside the submitted work. Dr. Nagasaka is on the advisory board for AstraZeneca, Daiichi Sankyo, Takeda, Novartis, EMD Serono, Janssen, Pfizer, Eli Lilly and Company, Bayer, Regeneron, BMS, and Genentech; consultant for Caris Life Sciences (virtual tumor board); speaker for Blueprint Medicines, Janssen, Mirati and Takeda; and reports travel support from AnHeart Therapeutics; Reports stock/stock options from MBrace Therapeutics. Dr. Heymach received grants to institution from AstraZeneca, Spectrum Pharmaceuticals and GSK; owned intellectual property for treatment of EGFR and HER exon20 mutations between MD Anderson and Spectrum; received consulting fees from AstraZeneca, BMS, Spectrum Pharmaceuticals, Guardant Health, Takeda, Genentech/Roche, Catalyst Biotech, Novartis, BrightPath Biotherapeutics, Nexus Health Systems, Kairos Ventures, Leads Biolabs, Roche, Hengrui Pharmaceutical, GSK, EMD Serono, Eli Lilly, Sanofi/Aventis, Boehringer Ingelheim, Foundation Medicine, Mirati Therapeutics, Janssen and Pneuma Respiratory; stock options in Cardinal Spine and Bio-Tree. Dr. Ou reports consulting fee from AnHeart Therapeutics, Pfizer, Janssen, Daiichi Sankyo, BMS and Merus; honoraria from Pfizer, Janssen, DAVA Oncology, OncLive and Caris Life Science; participated on advisory board from Elevation Oncology and AnHeart Therapeutics; stockholder in MBrace Therapeutics, Blossom Hill Therapeutics, Elevation Oncology, Turning Point Therapeutics, Nuvalent, Lilly, Nuvation; research funding to institution from Pfizer, Janssen, Nuvalent, Mirati, Revolution Medicine, Merus, Daiichi Sankyo, Erasca, Merck, BluePrint Medicines, Takeda and Roche. Dr. Li received grants to instutition from Gilead, MSD, AstraZeneca and Takeda; received honoraria from AstraZeneca, Novartis, Amgen, Pfizer, Takeda, ACE Oncology, Merck, Guardant Health, Gilead, Janssen and MSD; receive travel support from AstraZeneca, Pfizer, Daiichi Sankyo, Roche, MSD and Amgen; participated in advisory board on AstraZeneca, Pfizer, AnHeart Therapeutics, Amgen, Takeda, Yuhan and Blossomhill therapeutics. Dr. Le received grants to institution from Eli Lilly, ArriVent, Regeneron, Teligene and Boehringer Ingelheim; received consulting fees from EMD Serono, AstraZeneca, Spectrum, Eli Lilly, Novartis, Janssen, Blueprint, Boehringer Ingelheim, Hengrui Therapeutics, Abion, Sensi and Abbvie; received travel support from Spectrum. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Germline mutations driving lung cancer have been infrequently reported in the literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLCs. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become a standard-of-care treatment for EGFR T790M-positive lung cancer., Methods: We perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the University of Texas MD Anderson Cancer Center. Of the patients that underwent cell-free DNA analysis, germline mutations were identified by those with high variant allelic fraction approximating 50%, followed by further confirmation on genetic testing., Results: We identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and an EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), white (86.4%), had a family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%). Among the 18 with advanced-stage NSCLC, 12 patients (66.7%) were treated with first-line osimertinib, demonstrating a median progression-free survival (PFS) of 16.9 months (95% confidence interval [CI]: 6.3-not reached [NR]). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), median PFS was 20.4 months (95% CI: 6.3-NR) and median overall survival was 82.0 months (95% CI: 28.4-NR)., Conclusions: Based on our institutional cohort, NSCLC driven by EGFR germline mutations occurs more frequently in non-smoking, white females with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC., Competing Interests: Disclosure Dr. Elamin reports receiving research support from AstraZeneca, Spectrum Pharmaceuticals, and Takeda Pharmaceuticals; and has served on scientific advisory Boards for AstraZeneca, Eli Lilly, Novartis, Spectrum Pharmaceuticals, Sanofi, Takeda Pharmaceuticals, Turning Point Therapeutics, and Bristol-Myers Squibb. Dr. Zhang reports serving on the consulting/advisory board of Bristol-Myers Squibb, AstraZeneca, Novartis, Johnson & Johnson, GenePlus, Innovent, Varian, and Catalyst; receiving research grants to the institution from Merck, Novartis, and Johnson & Johnson. Dr. Negrao reports receiving research funding to institution from Mirati, Novartis, Checkmate, Alaunos, AstraZeneca, Pfizer, Genentech, and Navire; serving on the consultant/advisory board of Mirati, Merck/Merck Sharp & Dohme, Novartis, and Genentech; and receiving other support from Ziopharm Oncology, Apothecom, and Ashfield Healthcare. Dr. Altan reports research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, Gilead, Lyell, and Insightec and speaker fees from AstraZeneca, Nektar Therapeutics, SITC, and ASTRO, as well as participation on the safety review committee for the Nanobiotix-MDA Alliance, and is on the Hengenix Advisory Board for GlaxoSmithKline, Shattuck Lab, Bristol Myers Squibb, and AstraZeneca. Dr. Skoulidis reports receiving research grants to the institution from Revolution Medicines, Mirati Therapeutics, Pfizer, Merck, Amgen, and Novartis; serving on the consulting/advisory board of AstraZeneca, Amgen, Novartis, BeiGene, Guardant Health, Bergen Bio, Navire Pharma, Tango Therapeutics, Calithera Biosciences, Intellisphere LLC, and Medscape LLC; receiving honoraria from VSPO Mc Gill Universite de Montreal and RV Mais Promocao Eventos LTDS; receiving meeting support/travel grant from Amgen, Tango Therapeutics, and Dava Oncology; and having stock from Moderna and BioNTech SE. Dr. Tsao reports receiving research funding to the institution from Ariad, Bristol-Myers Squibb, Eli Lilly, Genentech, Millennium, Polaris, AstraZeneca, Boehringer Ingelheim, Epizyme, Merck, Novartis, and Seattle Genetics; serving on the consulting/advisory board of Ariad, Bristol-Myers Squibb, Eli Lilly, Genentech, Merck, Pfizer, Seattle Genetics, AstraZeneca, Boehringer Ingelheim, EMD Serono, GlaxoSmithKline, Novartis, and Roche. Dr. Cascone reports receiving speaker fees/honoraria from Society for Immunotherapy of Cancer (SITC), Mark Foundation for Cancer Research, Bristol-Myers Squibb, Roche, Medscape, IDEOlogy Health, Physicians' Education Resource LLC (PER), OncLive, and PeerView; having consulting/advisory role from MedImmune/AstraZeneca, Bristol-Myers Squibb, Merck, Genentech, Arrowhead Pharmaceuticals, Pfizer Inc., and Regeneron; receiving travel, food, and beverage expenses from Physicians' Education Resource LLC (PER), Dava Oncology, SITC, International Association for the Study of Lung Cancer, Parker Institute for Cancer Immunotherapy, IDEOlogy Health, OncLive, MedImmune/AstraZeneca, and Bristol-Myers Squibb; and receiving research funding to institution from MedImmune/AstraZeneca, Bristol-Myers Squibb, and EMD Serono. Dr. Heymach reports having stock and other ownership interests from Cardinal Spine and Bio-Tree; having consulting or advisory roles from AstraZeneca, Bristol-Myers Squibb, Spectrum Pharmaceuticals, Guardant Health, Hengrui Pharmaceutical, GlaxoSmithKline, EMD Serono, Lilly, Takeda, Sanofi/Aventis, Genentech/Roche, Boehringer Ingelheim, Catalyst Biotech, Foundation medicine, Novartis, Mirati Therapeutics, BrightPath Biotherapeutics, Janssen, Nexus Health Systems, Pneuma Respiratory, Kairos Ventures, Roche, and Leads Biolabs; receiving research funding to institution from AstraZeneca (Inst), Spectrum Pharmaceuticals, and GlaxoSmithKline; having patents, royalties, and other intellectual property on licensing agreement between Spectrum and MD Anderson (including Dr. Heymach himself) regarding intellectual property for treatment of EGFR and HER2 exon 20 mutations. Dr. Ostrin reports consulting/ travel fees from GeneSystems, participation on the scientific advisory board of Grail, and receiving an honorarium from the Texas Association of Family Practitioners. Dr. Le reports consulting/advisory fees from Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, Abion, and AbbVie, research funding to Institution from Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, ThermoFisher, Takeda, and Boehringer Ingelheim, and Travel Support from EMD Serono, Janssen, and Spectrum Pharmaceutics. The remaining authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer commissioned a diverse multidisciplinary international expert panel to evaluate the current landscape and provide diagnostic, staging, and therapeutic recommendations for patients with rNSCLC, with particular emphasis on patients with American Joint Committee on Cancer-Union for International Cancer Control TNM eighth edition stages II and III disease. Using a team-based approach, we generated 19 recommendations, of which all but one achieved greater than 85% consensus among panel members. A public voting process was initiated, which successfully validated and provided qualitative nuance to our recommendations. Highlights include the following: (1) the critical importance of a multidisciplinary approach to the evaluation of patients with rNSCLC driven by shared clinical decision-making of a multispecialty team of expert providers; (2) biomarker testing for rNSCLC; (3) a preference for neoadjuvant chemoimmunotherapy for stage III rNSCLC; (4) equipoise regarding the optimal management of patients with stage II between upfront surgery followed by adjuvant therapy and neoadjuvant or perioperative strategies; and (5) the robust preference for adjuvant targeted therapy for patients with rNSCLC and sensitizing EGFR and ALK tumor alterations. Our primary goals were to provide practical recommendations sensitive to the global differences in biology and resources for patients with rNSCLC and to provide expert consensus guidance tailored to the individualized patient needs, goals, and preferences in their cancer care journey as these are areas where physicians must make daily clinical decisions in the absence of definitive data. These recommendations will continue to evolve as the treatment landscape for rNSCLC expands and more knowledge is acquired on the best therapeutic approach in specific patient and disease subgroups., Competing Interests: Disclosure Dr. Spicer reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Amgen, Roche, Regeneron, and Pfizer; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eisai, Daiichi Sankyo, and Merck Sharp & Dohme; honoraria from AstraZeneca, Amgen, Bristol-Myers Squibb, Merck Sharp & Dohme, and Pfizer; meeting support from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme; data safety monitoring board for AstraZeneca; and receipt of other services from AstraZeneca, Bristol-Myers Squibb, and Merck Sharp & Dohme, outside the submitted work. Dr. Cascone reports receiving speaker fees and/or honoraria from the American Society for Clinical Oncology Post, AstraZeneca, Bio Ascend, Bristol-Myers Squibb, Clinical Care Options, IDEOlogy Health, Medical Educator Consortium, Medscape, OncLive, PEAK Medical, PeerView, Physicians' Education Resource, Society for Immunotherapy of Cancer, and Targeted Oncology; advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Mark Foundation for Cancer Research, Merck, oNKo-innate, Pfizer, RAPT Therapeutics, and Regeneron; and institutional research funding from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. Dr.Ahn reports receiving consulting fees from AstraZeneca, Alpha Pharmaceuticals, Genxin, and Pfizer; and honoraria from Takeda, Roche, Merck, Merck Sharp & Dohme, AstraZeneca, Amgen, Boronoi, Arcus, Daiichi Sankyo, Bayer, and Janssen, outside the submitted work. Dr.Dacic reports receiving consulting fees from AstraZeneca, Genentech, and Medscape, outside the submitted work. Dr. Felip reports receiving consulting fees from AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Pfizer, Regeneron, Sanofi, Takeda, Turning Point, and Daiichi Sankyo; honoraria from Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffmann-La Roche, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, PeerVoice, Pfizer, Sanofi, Takeda, and Touch Oncology; travel support from AstraZeneca, Janssen, and Roche; and other from Grifols as an independent member of the board, outside the submitted work. Dr. Forde reports receiving grants or contracts from AstraZeneca, Bristol-Myers Squibb, Novartis, Regeneron, and BioNTech; consulting fees from Ascendis, AstraZeneca, Bristol-Myers Squibb, Curevac, Novartis, Regeneron, G1, Genlux, Genentech, Gritstone, Merck, Janssen, F Star, Sanofi, Amgen, Fosun, Teva, Synthekine, Flame, Iteos, and Tavotek. Dr. Higgins reports receiving grants or contracts from Jazz Pharmaceuticals, RefleXion Medicalx; consulting fees from AstraZeneca and Janssen; positions on the NRG Oncology Board of Directors and RTOG Foundation Board of Directors; and stock or stock options in Picture Health. Dr. Kris reports receiving grant or contracts from BerGenBio, Merus, AstraZeneca, Mirati, Pfizer, Janssen, Sanofi, and Novartis; honoraria from Pfizer and AstraZeneca; and personal fees from AstraZeneca and Roche/Genentech, outside the submitted work. Dr. Mitsudomi reports receiving grants or contracts from Boehringer Ingelheim, AstraZeneca, Chugai, Pfizer, Ono, Daiichi Sankyo, and Eli Lilly; consulting fees from AstraZeneca, Novartis, Chugai, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Thermo Fisher, Roche Diagnostics, Bristol-Myers Squibb, Ono Pharmaceuticals, Taiho, Takeda, Janssen, Daiichi Sankyo, and Regeneron; honoraria from AstraZeneca, Chugai, Boehringer Ingelheim, Pfizer, Taiho, Eli Lilly, Daiichi Sankyo, Thermo Fisher, Merck Sharp & Dohme, Bristol-Myers Squibb, Ono Pharmaceuticals, Invitae, Guardant, Novartis, Amgen, Merck biopharma, and Kyorin; data safety monitoring board for Taiho Pharmaceutical, outside the submitted work. Dr. Provencio reports receiving grants or contracts from Bristol-Myers Squibb, AstraZeneca, Roche, Janssen, and Takeda; consulting fees from Bristol-Myers Squibb, Roche, AstraZeneca, Merck Sharp & Dohme, and Takeda; honoraria from Bristol-Myers Squibb, Takeda, Roche, AstraZeneca, and Merck Sharp & Dohme; and meeting attendance support from Merck Sharp & Dohme, Roche, and Bristol-Myers Squibb, outside the submitted work. Dr. Senan reports receiving grants or contracts from AstraZeneca, Merck Sharp & Dohme, and Bristol-Myers Squibb; consulting fees from AstraZeneca and Bristol-Myers Squibb; honoraria from AstraZeneca; advisory board participation for AstraZeneca and Merck Sharp & Dohme; and membership on ETOP scientific committee, outside the submitted work. Dr. Solomon reports receiving travel support from IASLC to attend meeting related to manuscript; consulting fees from AstraZeneca, Bristol-Myers Squibb, Eli Lily, Merck Sharp & Dohme, Pfizer, Roche, GlaxoSmithKline, Janssen, and Amgen; honoraria from AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Roche, and GlaxoSmithKline; unpaid leadership roles at the IASLC, Thoracic Oncology Group of Australasia, and Cancer Council of Victoria. Dr. Tsao reports receiving travel support from IASLC to attend meeting related to manuscript; grants or contracts from AstraZeneca, Bayer, and Lily; consulting fees from AstraZeneca, Bayer, Amgen, AbbVie, Regeneron, Sanofi, Daiichi Sankyo, and Lily; honoraria from AbbVie and Sanofi; and board of directors for IASLC. Dr. Tsuboi reports receiving grant from AstraZeneca KK, Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb KK, Novartis Japan, BMG KK, MiRXES, and Johnson & Johnson Japan; honoraria from Amgen KK, Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Chugai Pharmaceutical Co., Ltd., Taiho Pharma, Medtronic Japan, Ono Pharmaceutical Co., Ltd., Merck Sharp & Dohme KK, Bristol-Myers Squibb KK, Daiichi Sanko KK, and Novalis; advisory committee participation for Chugai Pharmaceutical Co., Ltd., and AstraZeneca KK; and Board of Directors for Japan Lung Cancer Society (JLCS), Bronchology Committee Chair for JLCS, and Educational Committee working group chair for IASLC, outside the submitted work. Dr. Wakelee reports receiving grants or contracts from ACEA Biosciences, Arrys Therapeutics, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Genentech/Roche, Merck, Novartis, SeaGen, Xcovery, and Helsinn; advisory board participation for AstraZeneca, Blueprint, Mirati, Merck, and Genentech/Roche; and leadership positions on the IASLC Board of Directors and ECOG-ACRIN executive committee. Dr. Wu reports receiving grants and contracts form AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Henqrui, and Roche; honoraria from AstraZeneca, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi; and unpaid leadership role for Chinese Thoracic Oncology Group. Dr. Yang reports receiving personal fees and other from Amgen, Bayer Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche/Genentech, Takeda Oncology, and Yuhan Pharmaceuticals; grants, personal fees, and other from AstraZeneca; other from Eli Lilly; personal fees from Ono Pharmaceuticals and Pfizer; and other from JNJ, Puma Technology, Gilead, and GlaxoSmithKline, outside the submitted work. Dr. Zhou reports receiving consulting fees from Innovent Biologics, Hengrui, Qila, and TopAlliance Biosciences; honoraria from Lily China, Sanofi, Boehringer Ingelheim, Roche, Merck Sharp & Dohme, Qilu, Hengrui, Innovent Biologics, Alice, C-Stone, LUYE Pharma, TopAlliance Biosciences, Amoy Diagnostics, and AnHeart. Dr. Kelly reports receiving grants from AstraZeneca, during the conduct of the study; grants and personal fees from Genentech and Bristol-Myers Squibb; and personal fees from AstraZeneca, outside the submitted work. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC., Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R 2 with 95% confidence interval were calculated by the bootstrapping approach., Results: Seven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R 2 of pCR and MPR with 2-year EFS were 0.82 (0.66-0.94) and 0.81 (0.63-0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07-0.19) and 0.11 (0.05-0.22), respectively. For the 2-year OS, the R 2 of pCR and MPR were 0.55 (0.09-0.98) and 0.52 (0.10-0.96), respectively. At the trial level, the R 2 for the association of OR for response and HR for EFS was 0.58 (0.00-0.97) and 0.61 (0.00-0.97), respectively., Conclusions: Our analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed., Competing Interests: Disclosure Drs. Hines and Cameron were supported by the National Institute for General Medical Sciences (T32 GM07019). Dr. Bestvina reports receiving institutional research funding from AstraZeneca and Bristol Myers Squibb; and advisory board membership/consulting for Amgen, AstraZeneca, Bristol Myers Squibb, CVS, Daiichi Sankyo, EMD Serono, Gilead, JNJ, Mirati, Novocure, Regeneron, Sanofi, Takeda, and Tempus. Dr. Garassino reports receiving personal financial support from AstraZeneca, Abion, Merck Sharp & DohmeInternational GmbH, Bayer, Bristol-Myers Squibb, 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; received institutional financial support from Eli Lilly, Merck Sharp & Dohme, Pfizer (MISP), AstraZeneca, Merck Sharp & Dohme International GmbH, Bristol-Myers Squibb, Boehringer Ingelheim Italia S.p.A, Celgene, Eli Lilly, Ignyta, Incyte, MedImmune, Novartis, Pfizer, Roche, Takeda, Tiziana, Foundation Medicine, GlaxoSmithKline, and Spectrum pharmaceuticals; received other forms of support from AIRC, AIFA, Italian Moh, and Transcan; and received research funding from Horizon 2020. Dr. Veronesi has received honoraria from Ab Medica Spa, AstraZeneca, Roche, and Merck Sharp & Dohme outside the submitted work. Dr. Cascone reports receiving speaker fees/honoraria from ASCO Post, AstraZeneca, Bristol Myers Squibb, Clinical Care Options, IDEOlogy Health, Mark Foundation for Cancer Research, Medscape, OncLive, PeerView, Physicians’ Education Resource, Roche, and Society for Immunotherapy of Cancer; has advisory role/consulting fees from Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Genentech, Merck & Co., Pfizer, and Regeneron; and received institutional research funding from AstraZeneca and Bristol Myers Squibb. Dr. Taube reports having an advisory role or have received consulting fees from Akoya Biosciences, AstraZeneca, Bristol Myers Squibb, Merck & Co., Genentech, Lunaphore, Compugen, Elephas, and Regeneron; received institutional research funding from Bristol Myers Squibb and Akoya Biosciences; and received reagents and equipment loan and has stock options from Akoya Biosciences. The remaining authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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.)

Background: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome., Patients and Methods: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation., Results: Our results showed that patients with detectable ctDNA at baseline or after treatment and patients who did not clear ctDNA after treatment had a significantly worse clinical outcome. Integrating radiological analysis allowed the stratification in risk groups prognostic of clinical outcome as confirmed in an independent cohort of 32 patients., Conclusions: Our findings suggest ctDNA and radiological monitoring could be valuable tools for guiding follow-up care and treatment decisions for early-stage NSCLC patients., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria., Methods: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion., Results: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma., Conclusions: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy., (Copyright © 2023. Published by Elsevier Inc.)

Background: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC., Methods: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (T any N any M0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment., Findings: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity., Interpretation: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required., Funding: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center., Competing Interests: Declaration of interests ABC reports grants from Blue Halo, Proteus Consortium/Pfizer, and Novocure. YYE reports consulting fees from Takeda, Bristol-Myers Squibb, AstraZeneca, Spectrum, and Sanofi. AT reports consulting fees from Ariad, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Eli Lilly, EMD Serono, Genentech, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Seattle Genetics, Gilead Sciences, and Summit Therapeutics. PAB reports grants from Raysearch and Varian; and is a member of the advisory board for Raysearch/Raycare. CMG reports grants from AstraZeneca; royalties from UpToDate; honoraria from AstraZeneca, BeiGene, MJH Healthcare, and Targeted Oncology; patents pending related to small cell lung cancer; and advisory board payments from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, G1 Therapeutics, Jazz Pharmaceuticals, and MonteRosa Therapeutics. TC reports funding from Bristol-Myers Squibb; grants from Bristol-Myers Squibb, MedImmune/AstraZeneca, and EMD Serono; consulting fees from MedImmune/AstraZeneca, Bristol-Myers Squibb, Regeneron, EMD Serono, Merck, Genentech, Arrowhead Pharmaceuticals, and Mark Foundation for Cancer Research; honoraria from Bristol-Myers Squibb and IDEOlogy Health; travel grants from IDEOlogy Health, Bristol-Myers Squibb, and Dava Oncology; and advisory fees from MedImmune/AstraZeneca, Bristol-Myers Squibb, Regeneron, EMD Serono, Merck, Genentech, and Arrowhead Pharmaceuticals. SGC reports grant funding from the National Institutes for Health (R50CA275822); consulting fees from AstraZeneca, CurioScience, and Norton Healthcare; honoraria from Binaytara Foundation; and travel grants from ViewRay and AstraZeneca. GB reports grant funding from Amgen, Bayer, Adaptimmune, Elelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myer Squib, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Sanofi, Xcovery, Tmunity Therapeutics, Regeneron, BeiGene, Repertoire Immune Medicines, Verastem. CytomX Therapeutics, Duality Biologics, Mythic Therapeutics, Takeda, and Aulos Bioscience; consulting fees from AbbVie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Genzyme, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Sanofi, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics, BeiGene, Rgeneron, Cytomx Therapeutics, Intervenn Biosciences, Onconova Therapeutics, Seagen, and Scorpion Therapeutics; advisory fees from Maverick Therapeutics and Virogin Biotech; stock or stock options in Virogin Biotech; and has an immediate family member employed by Johnson & Johnson (Janssen). XL reports grants from Eli Lilly, EMD Serono, Boehringer Ingelheim, and Regeneron; and consulting fees from EMD Serono, AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics AstraZeneca, Janssen, Blueprint Medicines, Sensei Biotherapeutics, Daiichi Sankyo, Regeneron, AbbVie, and AMVent. SJG reports grants from Bristol-Myers Squibb, Nanobiotix, and Bristol-Myers Squibb Foundation; and travel grants from AstraZeneca. JZ reports funding from the National Cancer Institute of the National Institutes for Health Research Project Grant (R01CA234629), the AACR-Johnson & Johnson Lung Cancer Innovation Science Grant (18-90-52-ZHAN), the MD Anderson Physician Scientist Programme, and the MD Anderson Lung Cancer Moon Shot Programme; consulting fees from Johnson and Johnson, AstraZeneca, and Novartis; honoraria from Novartis, Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, and Hengrui; advisory fees from Novartis, AstraZeneca, GenePlus, and Catalyst; and receipt of other services from Novartis, Johnson and Johnson, and Merck. JJL reports grant funding from the National Cancer Institute (P30CA016672). SHL reports grants from Nektar Therapeutics, Beyond Spring Pharmaceuticals, and STCube Pharmaceuticals; consulting fees from XRAD Therapeutics; travel grants from AstraZeneca; advisory fees from AstraZeneca and Merck; and stock or stock options from SEEK Diagnostics. MA reports research funding from Genentech, Nektar Therapeutics, Merck, GlaxoSmithKline, Novartis, Jounce Therapeutics, Bristol Myers Squibb, Eli Lilly, Adaptimmune, Shattuck Lab, and Gilead; consulting fees from GlaxoSmithKline, Shattuck Lab, Bristol Myers Squibb, and AstraZeneca; honoraria from AstraZeneca, Nektar Therapeutics, and the Society for Immunotherapy of Cancer; and advisory fees from Nanobiotix-MDA Alliance, and Hengenix. JWW reports grant funding from Alkermes, Nanobiotix, Merck, GlaxoSmithKline, Checkmate Pharmaceuticals, Varian, Bristol Myers Squibb, Reflexion, Artidis, Takeda, Gilead, HotSpot Therapeutics, and Kiromic; travel grants from Ventana, Aileron, Nanobiotix, Varian, and Reflexion; advisory fees from Alpine Immune Sciences, Reflexion, Aileron, Molecular Match, OncoResponse, Checkmate Pharmaceuticals, and Marvu Pharmaceuticals; a consultant role for Alpine Immune Sciences, Reflexion, Merck, Molecular Match, OncoResponse, Checkmate Pharmaceuticals, Marvu Pharmaceuticals, Incyte, Nanobiotix, Aileron, GI Innovation, Legion Healthcare, Roche, and Ventana Medical Systems; and stock options in Alpine Immune Sciences, Reflexion, Legion Healthcare, Molecular Match, OncoResponse, and Nanorobotix. IIW reports research funding from 4D Molecular Therapeutics, Adaptimmune, Adaptive Biotechnologies, Akoya Biosciences, Amgen, Bayer, EMD Serono, Genentech, Guardant Health, HTG Molecular Diagnostics, Lovance Biotherapeutics, Johnson & Johnson, Karus Therapeutics, MedImmune, Merck, Novartis, OncoPlex Diagnostics, Pfizer, and Takeda; personal fees from Asuragen, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca/MedImmune, HTG Molecular, Merck, Guardant Health, Oncocyte, Daiichi-Sankyo, Pfizer, and Bayer; and consulting fees from Asuragen, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca/MedImmune, Bayer, GlaxoSmithKline, Guardant Health, HTG Molecular Diagnostics, Merck, MSD Oncology, OncoCyte, Novartis, Flame, Pfizer, Regeneron, Merus, G1 Therapeutics, and AbbVie. ZL reports grant funding from the National Institutes for Health and National Cancer Institute (5 R01 HL157273-03 and P01 CA261669). JVH reports research funding from Bristol-Myers Squibb; and advisory fees from Bristol-Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Although first-line immunotherapy approaches are standard, in patients with non-small cell lung cancer (NSCLC) previously treated with programmed cell death protein-1 or programmed death-(ligand)1 (PD-[L]1) inhibitors, the activity of combined CTLA-4 plus PD-(L)1 inhibition is unknown. This phase 1b study evaluated the safety and efficacy of durvalumab plus tremelimumab in adults with advanced NSCLC who received anti-PD-(L)1 monotherapy as their most recent line of therapy., Methods: Patients with PD-(L)1-relapsed or refractory NSCLC were enrolled between October 25, 2013, and September 17, 2019. Durvalumab 20 mg/kg plus tremelimumab 1 mg/kg was administered intravenously every 4 weeks for four doses, followed by up to nine doses of durvalumab monotherapy every 4 weeks for up to 12 months of treatment or disease progression. Primary end points included safety and objective response rate (ORR) on the basis of Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) per blinded independent central review; secondary end points were ORR on the basis of RECIST v1.1 per investigator; duration of response, disease control, and progression-free survival on the basis of RECIST v1.1 per blinded independent central review and investigator; and overall survival., Clinicaltrials: gov identifier: NCT02000947., Results: PD-(L)1-refractory (n = 38) and PD-(L)1-relapsed (n = 40) patients were treated. The most common treatment-related adverse events were fatigue (26.3%, PD-(L)1-refractory patients) and diarrhea (27.5%, PD-(L)1-relapsed patients). Grade 3 to 4 treatment-related adverse events occurred in 22 patients. Median follow-up duration was 43.6 months for PD-(L)1-refractory patients and 41.2 months for PD-(L)1-relapsed patients. The ORR was 5.3% for PD-(L)1-refractory patients (one complete response, one partial response) and 0% for PD-(L)1-relapsed patients., Conclusions: Durvalumab plus tremelimumab had a manageable safety profile, but the combination did not have efficacy after PD-(L)1 treatment failure., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established., Patients and Methods: Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features., Results: While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8 + T cells expressing cytolytic enzymes, CD4 + T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas., Conclusions: Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care., Competing Interests: Disclosure CB has received research funding from Iovance Biotherapeutics and has participated in advisory committees for Myst Therapeutics and Turnstone Biologics. DLG has received research funding from AstraZeneca, Astellas, Janssen, Ribon Therapeutics, Takeda, and NGM Biopharmaceuticals, reports advisory role/consulting fees from AstraZeneca, Sanofi, Menarini Ricerche, and Eli Lilly, and research funding to MD Anderson Cancer Center from Boehringer Ingelheim. CH served on the advisory board for Briacell. SS has participated in advisory committees for Ethicon and for the Peter MacCallum Cancer Center. JVH has received research support from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum; participated in advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui, Lilly, Novartis, Specrtum, EMD Serono, and Synta; and received royalties and/or licensing fees from Spectrum. TC has received speaker fees/honoraria from The Society for Immunotherapy of Cancer, Bristol Myers Squibb, Roche and Medscape Oncology, reports advisory role/consulting fees from MedImmune, AstraZeneca, Bristol Myers Squibb, EMD Serono, Merck & Co., Genentech, and Arrowhead Pharmaceuticals, and research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune, AstraZeneca, Bristol Myers Squibb, and EMD Serono. JZ served on advisory board for AstraZeneca and Geneplus and received speaker’s fees from BMS, Geneplus, OrigMed, Innovent, grants from Merck, Johnson and Johnson from outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: Subgroup analyses from clinical studies have suggested that among patients with metastatic NSCLC receiving chemotherapy, females may derive less benefit from the addition of the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (BV) than males. This has raised the question of whether estrogen may affect the response to antiangiogenic therapy., Methods: To address this, we investigated the effects of estrogen on tumor growth, angiogenesis, and the response to BV in human xenograft models of NSCLC., Results: We observed that estrogen induced marked resistance to BV, which was accompanied by a 2.3-fold increase in tumor vascular pericyte coverage (p = 0.01) and an up-regulation of proangiogenic factors, VEGF and platelet-derived growth factor-BB. We also investigated the role of infiltrating myeloid cells, a population that has been associated with resistance to anti-VEGF therapies. We observed that estrogen induced a greater than twofold increase (p = 0.001) in the recruitment of tumor-infiltrating myeloid cells and concomitant increases in the myeloid recruitment factors, G-CSF and CXCL1. Blockade of the estrogen receptor pathway using fulvestrant resensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in our NSCLC xenograft models., Conclusions: Collectively, these data provide evidence that estrogen may promote resistance to VEGF-targeted therapies, potentially by enhancing pericyte coverage and myeloid recruitment, and suggest that estrogen receptor blockade merits further investigation as an approach to enhance the effects of antiangiogenic therapy., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Major pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the significance of pathologic response in lymph nodes harboring metastatic tumors in such patients remains uncertain. Therefore, we studied the effect of neoadjuvant chemotherapy on resected positive lymph nodes and determined if the degree of pathologic response in the lymph nodes alone (LN-MPR) or in combination with that of the primary tumor (PT-MPR) was able to predict the outcome., Methods: A total of 75 patients with NSCLC who underwent neoadjuvant chemotherapy and completed surgical resection were included in this study. Tissue specimens were retrospectively evaluated by two pathologists blinded to the patients' treatments and outcomes. Specimens were reviewed for the degree of pathologic response in the primary tumor and in any involved lymph nodes. The prognostic performance of LN-MPR alone or in combination with PT-MPR with respect to overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression model., Results: LN-MPR was significantly predictive of long-term OS after neoadjuvant chemotherapy. A combination of PT-MPR with LN-MPR was significantly associated with outcome and allowed stratification of patients into three prognostic groups (p = 0.001)., Conclusions: LN-MPR in isolation is a reliable predictor of OS in patients with NSCLC receiving neoadjuvant chemotherapy. A combination of LN-MPR with PT-MPR seems to correlate well with the outcome and can be used to predict prognosis in this patient population., (Published by Elsevier Inc.)

Background: Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways., Patients and Methods: Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies., Results: Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling., Conclusions: The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors., Competing Interests: Disclosure TC: speaker's fees from Society for Immunotherapy of Cancer and Bristol Myers Squibb; consulting/advisory role fees from MedImmune/AstraZeneca, EMD Serono, and Bristol Myers Squibb, research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune/AstraZeneca, and Bristol Myers Squibb. SAP-P: research/grant funding (institutional) from AbbVie, Inc.; Aminex Therapeutics; Amphivena Therapeutics, Inc.; BioMarin Pharmaceutical, Inc.; Boehringer Ingelheim; Bristol Myers Squib; Cerulean Pharma Inc.; Chugai Pharmaceutical Co., Ltd.; Curis, Inc.; Five Prime Therapeutics; Genmab A/S; GlaxoSmithKline; Helix BioPharma Corp.; Incyte Corp.; Jacobio Pharmaceuticals Co., Ltd.; Medimmune, LLC; Medivation, Inc.; Merck Sharp and Dohme Corp.; NewLink Genetics Corporation/Blue Link Pharmaceuticals; Novartis Pharmaceuticals; Pieris Pharmaceuticals, Inc.; Pfizer; Principia Biopharma, Inc.; Puma Biotechnology, Inc.; Rapt Therapeutics, Inc.; Seattle Genetics; Syneos Health; Taiho Oncology; Tesaro, Inc.; TransThera Bio; and Xuanzhu Biopharma. DSH: research/grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, Astra-Zeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Fate Therapeutics, Genentech, Genmab, Ignyta, Infinity, Kite, Kyowa, Lilly, LOXO, Merck, MedImmune, Mirati, miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartis, Pfizer, Seattle Genetics, Takeda, and Turning Point Therapeutics; funding for travel, accommodations, and expenses from Bayer, LOXO, miRNA, Genmab, AACR, ASCO, and SITC; consultant/advisor for Alpha Insights, Amgen, Axiom, Adaptimmune, Baxter, Bayer, Genentech, GLG, Group H, Guidepoint, Infinity, Janssen, Merrimack, Medscape, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; ownership interests in Molecular Match (Advisor), OncoResponse (Founder), Presagia Inc. (Advisor). SF: clinical trial research support through the institution from NIH/NCI; AstraZeneca; Abbisko; Anaeropharma Science; Arrien Pharmaceuticals; BeiGene; BioAtla, LLC; Boehringer Ingelheim; Eli Lilly & Co.; Hookipa Biotech; Huya Bioscience International; IMV, Inc.; Innovent Biologics, Co., Ltd.; Lyvgen Biopharma, Co., Ltd.; MacroGenics; Medivir AB; Millennium Pharmaceuticals, Inc.; Nerviano Medical Sciences; Neupharma, Inc.; Novartis; OncoMed Pharmaceuticals; Parexel International, LLC; Sellas Life Sciences Group; Soricimed Biopharma, Inc.; Tolero Pharmaceuticals; NovoCure; Turnstone Biologics; Taiho Oncology; and NCCN. AN: Research funding from NCI, EMD Serono, MedImmune, Healios, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, Top Alliance Biosciences, Kymab, PsiOxus, Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology; on advisory board of CytomX Therapeutics, Novartis, and Genome & Company, OncoSec KEYNOTE-695, STCube Pharmaceuticals, Kymab; travel and accommodation expense from ARMO BioSciences. Spouse: Research funding from Immune Deficiency Foundation, Jeffery Modell Foundation and Chao Physician-Scientist, and Baxalta; advisory board from Takeda, CSL Behring, Horizon Pharma. FJ: grant/research funding (institutional) from Novartis, Genentech, Biomed Valley Discoveries, Plexxikon, Deciphera, PIQUR Therapeutics, Symphogen, Bayer, Fujifilm Corporation and Upsher-Smith Laboratories, Astex, Asana, Astellas, Agios, Proximagen, and Bristol Myers Squibb; advisory board member for Deciphera, IFM Therapeutics, Synlogic, Guardant Health, IDEAYA, PureTech Health, and Jazz pharmaceuticals; consultant fees from Trovagene, Immunomet, Primmune Therapeutics, Jazz Pharmaceuticals, and SOTIO; ownership interests in Trovagene. GSF: research funding from 3-V Biosciences, AbbVie, ADC Therapeutics, Aileron, American Society of Clinical Oncology, Amgen, ARMO, AstraZeneca, BeiGene, BioAtla, Biothera, Celldex, Celgene, CicloMed, Curegenix, Curis, Cyteir, Daiichi, Delmar, eFFECTOR, Eli Lilly, EMD Serono, Exelixis, Fujifilm, Genmab, GlaxoSmithKline, Hutchison MediPharma, Ignyta, Incyte, Jacobio, Jounce, Kolltan, LOXO, MedImmune, Millennium, Merck, miRNA Therapeutics, National Institutes of Health, Novartis, OncoMed, Oncothyreon, Precision Oncology, Regeneron, Rgenix, Ribon, Strategia, Syndax, Taiho, Takeda, Tarveda, Tesaro, Tocagen, Turning Point Therapeutics, U.T. MD Anderson Cancer Center, VEGENICS, and Xencor; advisor fees from Fujifilm and EMD Serono; royalties from Wolters Kluwer; funding for travel from Bristol Myers Squibb, EMD Serono, Fujifilm, Millennium, and Sarah Cannon Research Institute; speaker's bureau fees from Total Health Conferencing. APC: consultant fees from Deciphera Pharmaceuticals, Guidepoint Global, Genentech, Inc., Bayer Healthcare Pharmaceuticals, OncLive, Novartis Pharmaceuticals, and Ignyta, Inc.; speaker fees from Medscape. SIS: research support from Exelixis; consultant fees from Fortress Biotech and LOXO oncology; honoraria from Eisai. FM-B: Consulting fees from Aduro Biotech Inc., Alkermes, AstraZeneca, Debiopharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks; advisory committee fees from Immunomedics, Inflection Biosciences, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; sponsored research from Aileron Therapeutics, Inc., AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Millennium Pharmaceuticals Inc., Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.; honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey; other (Travel Related) from Beth Israel Deaconess Medical Center. JVH: research support from AstraZeneca, GlaxoSmithKline, and Spectrum; consultant/advisory board member for AstraZeneca, Boehringer Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs; royalties and patents from Spectrum. VS and IMS: research funding/grant support from Novartis, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berg Health, Incyte, Fujifilm, PharmaMar, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, LOXO oncology, MedImmune, ALTUM, Dragonfly therapeutics, Takeda, and Roche/ Genentech, National Comprehensive Cancer Network, NCI-CTEP, and UT MD Anderson Cancer Center; consultant/advisory board for Helsinn, LOXO Oncology/ Eli Lilly, R-Pharma US, INCYTE, QED pharma, MedImmune, Novartis; funding for travel from Novartis, PharmaMar, ASCO, ESMO, Helsinn, Incyte. All other authors have declared no conflicts of interest. Data sharing The data supporting the findings presented in this manuscript are available upon reasonable academic request to the study principal investigator (VS)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: The treatment of patients with EGFR-mutant NSCLC with vascular endothelial growth factor (VEGF) inhibitors in combination with EGFR inhibitors provides a greater benefit than EGFR inhibition alone, suggesting that EGFR mutation status may define a patient subgroup with greater benefit from VEGF blockade. The mechanisms driving this potentially enhanced VEGF dependence are unknown., Methods: We analyzed the effect of EGFR inhibition on VEGF and HIF-1α in NSCLC models in vitro and in vivo. We determined the efficacy of VEGF inhibition in xenografts and analyzed the impact of acquired EGFR inhibitor resistance on VEGF and HIF-1α., Results: NSCLC cells with EGFR-activating mutations exhibited altered regulation of VEGF compared with EGFR wild-type cells. In EGFR-mutant cells, EGFR, not hypoxia, was the dominant regulator of HIF-1α and VEGF. NSCLC tumor models bearing classical or exon 20 EGFR mutations were more sensitive to VEGF inhibition than EGFR wild-type tumors, and a combination of VEGF and EGFR inhibition delayed tumor progression. In models of acquired EGFR inhibitor resistance, whereas VEGF remained overexpressed, the hypoxia-independent expression of HIF-1α was delinked from EGFR signaling, and EGFR inhibition no longer diminished HIF-1α or VEGF expression., Conclusions: In EGFR-mutant NSCLC, EGFR signaling is the dominant regulator of HIF-1α and VEGF in a hypoxia-independent manner, hijacking an important cellular response regulating tumor aggressiveness. Cells with acquired EGFR inhibitor resistance retained elevated expression of HIF-1α and VEGF, and the pathways were no longer EGFR-regulated. This supports VEGF targeting in EGFR-mutant tumors in the EGFR inhibitor-naive and refractory settings., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade., Methods: Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73)., Results: NCT was associated with increased infiltration of cytotoxic CD8 + T cells and CD20 + B cells. Moreover, NCT was associated with increases in CD8 + CD103 + and CD4 + CD103 + PD-1 + TIM3 - tissue resident memory T cells. Gene expression profiling supported memory function of CD8 + and CD4 + T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery., Conclusions: Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8 + and CD4 + memory helper T cells., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC., Methods: PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed., Results: PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (<1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival., Conclusions: PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The standard of care for stage IIIA (N2) non-small-cell lung cancer (NSCLC) includes concurrent definitive chemoradiation (dCRT) followed by durvalumab, thus challenging the role of surgery in resectable patients. We assessed locoregional disease control and survival in patients with surgically resected and unresected stage IIIA (N2) NSCLC disease., Patients and Methods: We conducted a retrospective analysis from prospectively collected databases at MD Anderson Cancer Center. Patients undergoing neoadjuvant chemotherapy and surgery or dCRT for clinical stage IIIA (N2) disease (2004-2014) were evaluated. Primary outcomes included locoregional disease control, disease-free survival (DFS), and overall survival (OS). Kaplan-Meier outcome analyses were performed., Results: Of the 159 resected patients, the majority had lobectomy (82.4%), followed by pneumonectomy (11.9%) and sublobar resection (5.7%). The 30- and 90-day mortality rates were 0.6% and 1.3%, respectively. At median follow-up of 52.8 months, recurrence was 55.3%, with 44.0% having distant and 15.1% locoregional recurrence. At 5 years, OS was 50.8% and DFS was 33.1% Median OS was 61.2 months. A total of 366 patients underwent dCRT, with intensity-modulated radiation in 64.5%, proton therapy in 26.0%, and 3-dimensional conformal radiotherapy in 9.6%. The mean dose was 68.1 Gy. At median follow-up of 20.8 months, recurrence was 53.6%, with distant and locoregional recurrence of 40.7% and 30.3%, respectively. At 5 years, OS was 29.2% and DFS was 20.5%. Median OS was 27.5 months., Conclusion: Stage IIIA (N2) NSCLC continues to be a heterogeneous disease, and patients with surgically resected and unresected disease represent different risk populations. Ongoing immunotherapy trials may further redefine treatment algorithms in this complex patient population., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: We have suggested that major pathologic response (MPR) could serve as a surrogate endpoint for survival and provide rapid means of comparing different neoadjuvant treatment regimens. Here, we confirm that MPR is predictive of long-term overall survival (OS) in patients with non-small-cell lung cancer (NSCLC) who underwent neoadjuvant chemotherapy and surgical resection, to assess agreement on MPR between 2 observers, and to determine the minimum number of slides needed to obtain an accurate determination of MPR., Patients and Methods: We identified 151 patients with NSCLC who had been treated with neoadjuvant chemotherapy followed by complete surgical resection from 2008 to 2012. Tissue specimens were retrospectively evaluated by 2 pathologists who had been blinded to patients' treatment and outcome. We assessed the relationships between MPR and OS, the levels of agreement between the pathologists, and determined the number of slides needed to obtain an accurate determination of MPR., Results: Our results reveal that MPR examined by either observer 1 (experienced) or by observer 2 (trained) was significantly predictive of long-term OS after neoadjuvant chemotherapy. MPR was associated with long-term OS in patients with NSCLC undergoing neoadjuvant chemotherapy on multivariable analysis (hazard ratio 2.68; P = .01). The levels of agreement between 2 pathologists were high after direct in-person training by one pathologist or the other (R 2  = 0.994). Our data suggest that at least 3 slides should be read to accurately determine MPR., Conclusions: MPR is significantly predictive of long-term OS in neoadjuvant chemotherapy-treated patients with NSCLC. MPR may serve as a surrogate endpoint for evaluating novel chemotherapies and immunotherapy response in biomarker-driven translational clinical trials., (Published by Elsevier Inc.)

Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years. The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response., (Copyright © 2020. Published by Elsevier Inc.)

Background: High tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are leading biomarkers in metastatic non-small cell lung cancer (NSCLC) and predict favorable response to checkpoint inhibitors. We sought to identify clinicopathologic characteristics associated with elevated TMB and PD-L1 expression among patients who underwent resection for NSCLC., Methods: NSCLC patients undergoing primary resection (2016-2018) were prospectively enrolled in an immunogenomic profiling project. Multiplex immunofluorescence quantified densities (cells/mm 2 ) of CD3 + , CD3 + CD8 + , CD3 + CD8 + PD-1 + , malignant cells (MCs), MCsPD-L1 + , CD68 + , CD68 + PD-L1 + , and CD20 + cells. Whole-exome sequencing quantified TMB (mutations/megabase). TMB and MCsPD-L1 + were dichotomized according to the median of each., Results: A total of 55 patients completed multiplex immunofluorescence and whole-exome sequencing profiling. In this sample, 41.8% (23 of 55) had pathologic stage I disease. Median TMB and MCsPD-L1 + were 3.91 and 0.62 cells/mm 2 , respectively. TMB was higher among smokers (P = .001) and tumors with lymphovascular invasion (LVI) (P = .051). TMB was positively correlated with densities of MCsPD-L1 + (r = 0.293, P = .030), CD68 + PD-L1 + (r = 0.289, P = .033), and CD20 + (r = 0.310, P = .043) cells. The density of MCsPD-L1 + was associated with increased CD3 + CD8 + (r = 0.319, P = .018) and CD68 + PD-L1 + (r = 0.371, P = .005) cells. Patients with PD-L1 High TMB High tumors (30.9%, 17 of 55) had higher intratumoral densities of CD3 + , CD3 + CD8 + , CD68 + , CD68 + PD-L1 + , and CD20 + cells. On multivariable analysis LVI was associated with synchronous elevated TMB and PD-L1 expression (odds ratio 3.53, P = .039)., Conclusions: NSCLC tumors with elevated TMB and PD-L1 expression are associated with LVI and increased intratumoral immune cell infiltration. These findings may potentially improve patient selection for checkpoint inhibitor therapy trials in the adjuvant setting., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Data from meta-analyses support the use of induction or adjuvant platinum-based chemotherapy for locally advanced non-small cell lung cancers (NSCLCs). This phase 2 study assessed the role of induction cisplatin and docetaxel followed by surgery in patients with resectable stage I to III NSCLCs, followed by 12 months of adjuvant erlotinib., Methods: Patients with resectable stage I to III NSCLCs received cisplatin 80 mg/m 2 , docetaxel 75 mg/m 2 every 21 days for 3 cycles, followed by surgery, followed by adjuvant erlotinib for 12 months. The primary endpoint included safety. Long-term efficacy outcomes and exploratory analysis of intermediary endpoints are also reported (NCT00254384)., Results: Forty-seven eligible patients received a median of 3 cycles of induction treatment, 37 underwent surgical resection, and only 21 received adjuvant erlotinib. Two patients died in the perioperative period (1 sepsis during chemotherapy, 1 acute respiratory distress syndrome postoperatively). Most common grade 3 to 5 toxicities during chemotherapy included hypokalemia (8%), infection (7%), and granulocytopenia (25%). During adjuvant erlotinib, 14% of patients experienced grade 2 rash. Median overall survival was 3.4 years. Major pathologic responses in the primary tumor were observed in 19% (7 of 37) of patients and correlated with improved long-term overall survival. Complete pathologic response in mediastinal/hilar nodes also correlated with superior survival., Conclusions: Induction cisplatin and docetaxel was well tolerated. Adjuvant erlotinib did not improve outcomes compared with historical controls. Major pathologic response predicted for improved long-term survival and is a suitable intermediary endpoint for future phase 2 studies., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Over the last decade, the concept of targeted biological therapy for the treatment of cancer has emerged. However, a better understanding of these targets and their role in tumor cells and in the surrounding stromal cells is required. Two interesting biological targets are the epidermal growth factor receptor (EGFR) and the vascular endothelia growth factor (VEGF) and its receptors. A number of agents that target these pathways have been described. Many of these are currently in clinical trials and a few have recently been approved by the regulatory authorities in USA and in the European Union. The molecular pathways involved in the proliferation of cancer cells and in tumor-related angiogenesis are very complex and the interference with only a single step of these pathways may often reveal an insufficient therapeutic approach. Moreover, cancer cells have an inherent ability to harness different growth factor signaling pathways for growth advantage and cell survival, a process that may even be facilitated by the use of selective targeted agents. Because of these escape mechanisms, monotherapy with selective targeted agents is unlikely to be a fully effective cancer treatment. For these reasons, targeting different pathways is an attractive and effective therapeutic strategy with a strong rationale for investigating this approach in the clinic. This review focuses on the preclinical rationale of combining targeted agents such as EGFR and VEGF inhibitors in the treatment of cancer and on the clinical trials that have emerged from these studies.

Despite recent developments in the diagnosis and conventional treatment of non small cell lung cancer (NSCLC), the prognosis remains unsatisfactory, with 5-year survival rates of approximately 15% for all stages. To date, chemotherapy represents the standard treatment for advanced-non small lung cancer, but efficacy of currently available cytotoxic drugs is modest. Median survival does not exceed 8-10 months. New treatment strategies are needed and considerable hope has been placed in therapies that specifically target the molecular mechanisms of tumour growth. One molecular target of particular relevance to lung cancer pathogenesis is the epidermal growth factor receptor (EGFR), a cell membrane receptor tyrosine kinase. Several inhibitors of EGFR fuctinonal activation have been developed. Amon these, erlotinib (Tarceva) and gefitinib (Iressa) are two orally bioavailable, small molecule EGFR inhibitors of the tyrosine kinase enzymatic activity which prevent EGFR autophosphorylation and activation. In monotherapy, gefitinib and erlotinib have determinated a 10-20% response rate and a 30-50% symptom improvement in previously treated, chemotherapy refractory, advanced NSCLC patients. Furthermore, a randomized, placebo controlled, multicenter phase III study has shown a two months improvement in median survival with erlotinib in the second or third line treatment of metastatic NSCLC patients. We will summarize the clinical evidence on the anticancer activity of small molecule EGFR inhibitors.

Background: Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials., Materials and Methods: The effects on proliferation, cell cycle distribution and induction of apoptosis of three different anti-EGFR agents (gefitinib, ZD6474, cetuximab) were evaluated in different sequences of combination with either a platinum derivative (cisplatin, carboplatin, oxaliplatin) or a taxane (docetaxel, paclitaxel) in KYSE30 cells, a model of a human cancer cell line with a functional EGFR autocrine pathway., Results: The combination of a cytotoxic drug with an EGFR inhibitor caused different antiproliferative effects on KYSE30 cancer cells depending on the treatment schedule. An antagonistic effect was observed when treatment with each EGFR inhibitor was done before chemotherapy. In contrast, a synergistic antiproliferative activity was obtained when chemotherapy was followed by treatment with EGFR antagonists. This effect was accompanied by potentiation of apoptosis and arrest of the surviving cancer cells in the G(2)/M phases of the cell cycle., Conclusions: This study provides a rationale for the evaluation of a potentially synergistic sequence of cytotoxic drugs and EGFR inhibitors in a clinical setting.