Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial
- PMID: 40774040
- DOI: 10.1016/j.lungcan.2025.108683
Intracranial activity of sotorasib vs docetaxel in pretreated KRAS G12C-mutated advanced non-small cell lung cancer from a global, phase 3, randomized controlled trial
Abstract
Objectives: To assess the efficacy and safety of sotorasib in patients with brain metastases using data from the phase 3 CodeBreaK 200 study, which evaluated sotorasib in adults with pretreated advanced or metastatic KRAS G12C-mutated non-small cell lung cancer (NSCLC).
Materials and methods: Patients with KRAS G12C-mutated NSCLC who progressed after platinum-based chemotherapy and checkpoint inhibitor therapy were randomized 1:1 to sotorasib or docetaxel. An exploratory post-hoc analysis evaluated central nervous system (CNS) progression-free survival (PFS) and time to CNS progression in patients with treated and stable brain metastases at baseline. Measures were assessed by blinded independent central review per study-modified Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria.
Results: Of the patients randomly assigned to receive sotorasib (n=171) or docetaxel (n=174), baseline CNS metastases were present in 40 (23%) and 29 (17%) patients, respectively. With a median follow-up of 20.0 months for this patient subgroup, median CNS PFS was longer with sotorasib compared with docetaxel (9.6 vs 4.5 months; hazard ratio, 0.43 [95% CI, 0.20-0.92]; P=0.02). Among patients with baseline treated CNS lesions of ≥10 mm, the percentage of patients who achieved CNS tumor shrinkage of ≥30% was two-fold higher with sotorasib than docetaxel (33.3% vs 15.4%). Treatment-related adverse events among patients with CNS lesions at baseline were consistent with those of the overall study population.
Conclusions: These results suggest intracranial activity with sotorasib complements the overall PFS benefit observed with sotorasib vs docetaxel, with safety outcomes similar to those in the general CodeBreaK 200 population.
Clinical trials registration number: NCT04303780.
Keywords: Brain metastases; KRAS G12C-mutated; NSCLC; Non-small cell lung cancer; Randomized controlled trial; Sotorasib; Survival.
Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.
Conflict of interest statement
Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anne-Marie C. Dingemans reports grants or contracts from Amgen, Dutch Cancer Society, HANART; consulting fees from Amgen, Bayer, Boehringer Ingelheim, Sanofi, Roche, Johnson & Johnson, AstraZeneca, Pfizer, Mirati; payment or honoraria from Janssen, Pfizer, AstraZeneca, Lilly, Amgen; participation on a data safety monitoring board or advisory board for Takeda, Roche, Lilly; and leadership role for EORTIC LCG. Konstantinos Syrigos reports consulting fees from Merck Sharp & Dohme, AstraZeneca, Bristol-Myers Squibb, and Amgen. Yuanbin Chen reports research grants from Amgen, AstraZeneca, Merck, AbbVie, Daiichi Sankyo, Shanghai Junshi; and speakers bureau for Amgen, AstraZeneca, Pfizer, Jazz, Takeda, Bristol Myers Squibb. Enriqueta Felip reports participating in advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Roche, Genmab, Gilead, GlaxoSmithKline, ITeos Therapeutics, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Regeneron, Turning Point; speakers’ bureau for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, F. Hoffman-La Roche, Genentech, Gilead, Janssen, Johnson & Johnson, Medical Trends, Medscape, Merck Serono, Merck Sharp & Dohme, Novartis, Peer Voice, Pfizer, Pierre Fabre, Regeneron; travel support from AstraZeneca, Janssen, Roche; and board member for Grifols. Frank Griesinger reports scientific support from CRISP; grants from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Novartis, Pfizer, Regeneron, Roche, Takeda; speaker for ASTRA, Boehringer, Bristol-Myers Squibb, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, AbbVie, Siemens, Tesaro/GlaxoSmithKline, Amgen, Sanofi, Daiichi-Sankyo, BeiGene, Gilead; and advisory board for ASTRA, Boehringer, Bristol-Myers Squibb, Celgene, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, Ariad, AbbVie, Tesaro/GlaxoSmithKline, Siemens, Tesaro, Amgen, Sanofi, Daiichi-Sankyo, BeiGene, Gilead. Kadoaki Ohashi reports consulting fees from Amgen. Gerard Zalcman reports funding from Amgen for ESMO meeting 2024, travel and attendance. Jens Benn Sørensen reports consulting fees from Bristol-Myers Squibb, Roche, AstraZeneca, Novartis, Pfizer, Takeda, and Janssen. Normand Blais reports consulting fees from Amgen. Carlos G. M. Ferreira reports grants from Bristol-Myers Squibb, MSD; nonremunerative positions of influence for IASLC, ASCO; speakers bureau for BeiGene; stock from Oncoclinicas; employment at Oncoclinicas. Colin R. Lindsay reports financial interests in Amgen; invited speaker for Amgen, Qiagen; advisory board for Amgen; investigator for Apollomics, Mirati Therapeutics, Revolution Medicines, Roche, Boehringer Ingelheim; and travel funding from Amgen. Rafal Dziadziuszko reports speaker bureau for Pfizer; consultant for Amgen, AstraZeneca, Bristol Myers Squibb, F. Hoffman-La Roche, Merck, Sharp & Dohme, Pfizer, Takeda; and drug samples from Novartis. Patrick J. Ward reports advisory board for Amgen, Fresenius Kabi, Astra Zeneca, AZ/DSI, Neuvogen, MD Outlook. Cynthia Chinedu Obiozor and Yang Wang are employees of Amgen and report owning stock in Amgen. Solange Peters reports grants, attending advisory board, delivering talks (all fees to institution) for AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, BioNTech, BerGenBio, Bicycle Therapeutics, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Foundation Medicine, Genmab, Genzyme, Gilead, GlaxoSmithKline, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Qlucore, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Nuvation Bio, Nykode Therapeutics, Novartis, Novocure, Pharma Mar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, Takeda, Zymeworks; speaker for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Foundation Medicine, GlaxoSmithKline, Illumina, Ipsen, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Takeda; and investigator for Amgen, Arcus, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, iTeos, Merck Sharp and Dohme, Mirati, Pharma Mar, Pfizer, Promontory Therapeutics, Roche/Genentech, Seattle Genetics. Lorenzo Livi, Astrid Paulus, Sang-We Kim, Brett G. M. Hughes report no conflicts of interest.
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