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Molecular Determinants of Sotorasib Clinical Efficacy in KRAS G12C–Mutated Non–Small-Cell Lung Cancer

ABSTRACT: This study describes transcriptional subtypes of non-squamous non–small cell lung cancer (NSCLC). Baseline tissue samples (fresh/archival) were analyzed using a whole-transcriptome RNA assay (Tempus RS.v2; Tempus Labs, Inc., Chicago, IL, USA). Objectives included expression characterization of the KRAS G12C subject population with respect to genetic mutation (ATM, SMARCA4, KEAP1, STK11) and transcriptional signatures: KPCL (Skoulidis, Cancer Discov (2015) 5 (8): 860–877) & NRF2 activation (Singh, Clin Cancer Res (2021) 27 (3): 877–888).

ORGANISM(S): Homo sapiens

PROVIDER: GSE295032 | GEO | 2025/06/02

REPOSITORIES: GEO

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Project description:BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

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Molecular Determinants of Sotorasib Clinical Efficacy in KRAS G12C–Mutated Non–Small-Cell Lung Cancer

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