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Introduction: The KRAS G12C inhibitor sotorasib was approved for treating advanced NSCLC in the second line or later on the basis of the CodeBreaK100 trial. Nevertheless, data on the real-world efficacy and safety of sotorasib, and to its optimal dose, remain limited., Methods: Patients treated with sotorasib for NSCLC through the Veterans Health Administration were retrospectively identified from the Corporate Data Warehouse. Survival, response, and toxicity data were obtained from chart review., Results: Among the 128 patients treated with sotorasib through the Veterans Health Administration, objective response rate was 34%, progression-free survival (PFS) six months, and overall survival 12 months. Similar PFS was observed among the 16 patients who received frontline sotorasib without any prior systemic therapy for NSCLC. Toxicity leading to sotorasib interruption or dose reduction occurred in 37% of patients, whereas sotorasib discontinuation for toxicity occurred in 25%. Notably, sotorasib dose reduction was associated with substantially improved PFS and OS., Conclusions: In this real-world study, the observed efficacy of sotorasib was similar to the results of CodeBreaK100. Patients who received frontline sotorasib had similar PFS to our overall cohort, suggesting that first-line sotorasib monotherapy may benefit patients who are not eligible for chemotherapy. Toxicities leading to sotorasib interruption, dose reduction, or discontinuation were common. Sotorasib dose reduction was associated with improved survival, suggesting that sotorasib dose reduction may not compromise efficacy., Competing Interests: Dr. Lin reported serving as a consultant for Rigel and on the advisory board of Autolus. Dr. Dowell participated in advisory boards for Mirati, Astra Zeneca, Catalyst, and Takeda. Dr. Kelley reported research funding (paid to his institution) from 10.13039/100004336Novartis, 10.13039/100002491Bristol-Myers Squibb, 10.13039/100009857Regeneron, and Mirati Therapeutics. The remaining authors declare no conflict of interest.

Introduction: Characteristics of long-term survivors in EGFR-mutant (EGFRm) NSCLC are not fully understood. This retrospective analysis evaluated a multi-institution cohort of patients with EGFRm NSCLC treated in the pre-osimertinib era and sought to describe characteristics of long-term survivors., Methods: Clinical characteristics and outcomes were abstracted from the electronic medical records of patients with EGFRm metastatic NSCLC who started first-line therapy before 2015. Demographics and comutations were compared between greater than or equal to 5-year survivors and less than 5-year survivors. Multivariable Cox proportional hazard and logistic regression models were used to evaluate factors associated with survival and the odds of death within 5 years, respectively., Results: Overall, 133 patients were greater than or equal to 5-year survivors; 127 were less than 5-year survivors. Burden of pathogenic comutations including TP53 and PIK3CA was similar between greater than or equal to 5-year survivors and less than 5-year survivors. Receipt of first-line chemotherapy rather than EGFR tyrosine kinase inhibitor was similar between the groups (22% of <5-y versus 31% of ≥5-y). Baseline brain metastasis and history of smoking were associated with higher odds of death within 5 years (odds ratio = 2.16, p  = 0.029 and odds ratio = 1.90, p  = 0.046, respectively). Among patients without baseline brain metastases, cumulative incidence of brain metastases at 5 years was 42.3%. Both baseline and post-baseline brain metastasis were associated with worse overall survival compared with no brain metastasis (hazard ratio = 3.26, p < 0.001 and hazard ratio = 4.99, p < 0.001, respectively)., Conclusions: Within patients treated for EGFRm metastatic NSCLC before 2015, absence of brain metastasis and nonsmoking status were predictive of 5-year survival. Our findings help to define a subset of patients with EGFRm NSCLC with excellent survival outcomes who may not require intensification of initial therapy., Competing Interests: Dr. McCoach reports working as an employee at Genentech. Dr. G. Liu reports receiving institutional grants from NCI, CIHR, CCSRI, AstraZeneca, 10.13039/100016040Takeda, Boehringer Ingelheim, AMGEN, EMD Serono, 10.13039/100004319Pfizer, and 10.13039/100004326Bayer; receiving personal honoraria from AstraZeneca, Pfizer, EMD Serono, and Takeda; and participating on the Data Safety Monitoring Board/Advisory Board for AstraZeneca, Pfizer, EMD Serono, Merck, AbbVie, Jazz, Takeda, Anheart, Roche, Bristol-Myers Squibb, Novartis, and Lilly. Dr. Nieva reports receiving institutional grants from 10.13039/100004328Genentech and Merck; receiving consulting fees from ANP Technologies, Aadi Biosciences, AstraZeneca, BioAtla, G1 Therapeutics, Genentech, Mindmed, Naveris, and Sanofi; receiving travel support from 10.13039/100004325AstraZeneca; having a patent planned with Cansera; participating on the Data Safety Monitoring Board/Advisory Board for Kalivir; and having stock in Amgen, Novartis, Johnson & Johnson, and Cansera. Dr. Marrone reports receiving grants from 10.13039/100016957Mirati Therapeutics and Bristol-Myers Squibb; receiving consulting fees from Daiichi Sankyo, Regeneron, Janssen, Mirati, Amgen, and AstraZeneca; receiving honoraria from Merck, Regeneron, Bristol-Myers Squibb, and AstraZeneca; and participating on the Data Safety Monitoring Board/Advisory Board for Puma. Dr. Lam reports receiving grants from 10.13039/100002491Bristol-Myers Squibb, Merck, SeaGen, and AstraZeneca; receiving consulting fees from SeaGen, Bristol-Myers Squibb, AstraZeneca, Guardant Health, Takeda, and Anheart Therapeutics; and participating on the Data Safety Monitoring Board/Advisory Board for Iovance Therapeutics. Dr. Velcheti reports receiving consulting fees from Bristol-Myers Squibb, Merck, OnCOC4, AstraZeneca, Roche, Novocure, Takeda, Taiho, and Regeneron. Dr. S. Liu reports receiving institutional grants from 10.13039/100006483AbbVie, 10.13039/100018529Alkermes, AstraZeneca, Elevation Oncology, Ellipses, Genentech, Gilead, Merck, Merus, Nuvalent, OSE Immunotherapeutics, Puma, RAPT, and Turning Point Therapeutics; receiving consulting fees from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, Daiichi Sankyo, Elevation Oncology, Genentech/Roche, Gilead, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati, Novartis, Pfizer, RAPT, Regeneron, Revolution Medicines, Sanofi, and Takeda; and participating on a Data Safety Monitoring Board/Advisory Board for Candel Therapeutics. Dr. Patil reports receiving research funding from 10.13039/100004755EMD Serono, 10.13039/100005565Janssen, and 10.13039/100005564Gilead; receiving consulting fees from AstraZeneca, Biocept, Boehringer Ingelheim, Bristol-Myers Squibb, Bicara, Caris, Daiichi, Guardant Health, Guidepoint, EMD Serono, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Natera, Pfizer, Sanofi, Regeneron, Roche/Genentech, and Takeda; and participating on the Data Safety Monitoring Board/Advisory Board for Elevation Oncology. Dr. Weiss reports receiving institutional grants from AstraZeneca, 10.13039/100019799G1, Loxo/10.13039/100019518Lilly, Mirati, SDP, BI, and PDS; receiving consulting fees from AZD, EMD Serono, Genentech, G1, Jounce, AbbVie, Nanobiotix, Merck, Sanofi, Gilead, PDS, and AMGEN; participating on a Data Safety Monitoring Board or Advisory Board for Jounce and Beigene; having a leadership or fiduciary role for Cancergrace; and having stock/stock options for Nektar, Vesselon, Achilles, Nuvalent, Lyell, En Fuego, and Vertex. Dr. Dowell reports receiving consulting fees from Takeda, Catalyst, Beigene, and Janssen. Dr. Villaruz reports receiving consulting fees from Sanofi, Gilead, Johnson & Johnson, EMD Serono, Daiichi Sankyo, AstraZeneca, and Janssen. Dr. Cass reports receiving honoraria from OncLive, Medscape, and PharmacyTimes; and participating on the Data Safety Monitoring Board/Advisory Board for G1 Therapeutics, Takeda, and Regeneron. Dr. Iams reports receiving consulting fees from OncLive, Clinical Care Options, Chardan, Cello Health, and Curio Science; and participating on the Data Safety Monitoring Board/Advisory Board for Genentech, Mirati, Outcomes Insights, Jazz Pharmaceuticals, G1 Therapeutics, Takeda, AstraZeneca, Sanofi, Janssen, Amgen, Bristol Myers Squibb, and NovoCure. Dr. Aisner reports receiving consulting fees from Merus, Genentech, Bayer, AbbVie, and AstraZeneca; receiving support for attending meetings from AstraZeneca; and serving as Chair of Board for Genomics Organization for Academic Laboratories. Dr. Aggarwal reportsreceiving consulting fees from Genentech, Lilly, Merck, AstraZeneca, Daiichi Sankyo, Sanofi/Regeneron, Pfizer, Janssen, Boehringer-Ingelheim, Takeda, Arcus Biosciences, Mirati Therapeutics, Gilead Sciences, Novocure, AbbVie, and Jazz Pharmaceuticals; receiving speaking fees from AstraZeneca and Roche/Genentech; and receiving research funding from 10.13039/100004334Merck Sharp & Dohme, AstraZeneca/10.13039/501100004628MedImmune, 10.13039/501100022274Daiichi Sankyo, Loxo@Lilly, and Candel Therapeutics. Dr. Camidge reports receiving honoraria for consulting from AbbVie, Anheart, Beigene, Eli Lilly, Immunocore, Janssen, Prelude, Seattle Genetics, Valence, Appolomics, AstraZeneca/Daiichi, Dizal, EMD Serono, Elevation, Hengrui, Hummingbird, Medtronic, Mersana, Mirati, Nalo Therapeutics, Onkure, Regeneron, Roche, Sanofi, Takeda, Theseus, and Xcovery. Dr. Marmarelis reports receiving research funding from Eli Lilly, AstraZeneca, and Merck; receiving consulting fees from AstraZeneca, Novocure, Boehringer Ingelheim, Janssen, Takeda, Blueprint Pharmaceuticals, Bayer, Bristol Myers Squibb, Ikena, and Regeneron; receiving honoraria from Thermo Fisher; and having stock in Merck and Johnson & Johnson. Dr. Sun reports receiving honoraria from Bayer and participating on the Data Safety Monitoring Board/Advisory Board for Seagen, Sanofi Genzyme, and Regeneron. The remaining authors declare no conflict of interest., (Crown Copyright © 2024 Published by Elsevier Inc. on behalf of the AGA Institute.)