UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation

Sacher, Adrian; LoRusso, Patricia; Patel, Manish R; Miller, Wilson H; Garralda, Elena; Forster, Martin D; Santoro, Armando; ... GO42144 Investigator and Study Group; + view all (2023) Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation. New England Journal of Medicine , 389 (8) pp. 710-721. 10.1056/NEJMoa2303810. Green open access

[thumbnail of nejmoa2303810.pdf]
Preview
Text
nejmoa2303810.pdf - Published Version

Download (670kB) | Preview

Abstract

BACKGROUND: Divarasib (GDC-6036) is a covalent KRAS G12C inhibitor that was designed to have high potency and selectivity. METHODS: In a phase 1 study, we evaluated divarasib administered orally once daily (at doses ranging from 50 to 400 mg) in patients who had advanced or metastatic solid tumors that harbor a KRAS G12C mutation. The primary objective was an assessment of safety; pharmacokinetics, investigator-evaluated antitumor activity, and biomarkers of response and resistance were also assessed. RESULTS: A total of 137 patients (60 with non-small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received divarasib. No dose-limiting toxic effects or treatment-related deaths were reported. Treatment-related adverse events occurred in 127 patients (93%); grade 3 events occurred in 15 patients (11%) and a grade 4 event in 1 patient (1%). Treatment-related adverse events resulted in a dose reduction in 19 patients (14%) and discontinuation of treatment in 4 patients (3%). Among patients with NSCLC, a confirmed response was observed in 53.4% of patients (95% confidence interval [CI], 39.9 to 66.7), and the median progression-free survival was 13.1 months (95% CI, 8.8 to could not be estimated). Among patients with colorectal cancer, a confirmed response was observed in 29.1% of patients (95% CI, 17.6 to 42.9), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.2). Responses were also observed in patients with other solid tumors. Serial assessment of circulating tumor DNA showed declines in KRAS G12C variant allele frequency associated with response and identified genomic alterations that may confer resistance to divarasib. CONCLUSIONS: Treatment with divarasib resulted in durable clinical responses across KRAS G12C-positive tumors, with mostly low-grade adverse events. (Funded by Genentech; ClinicalTrials.gov number, NCT04449874.).

Type: Article
Title: Single-Agent Divarasib (GDC-6036) in Solid Tumors with a KRAS G12C Mutation
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1056/NEJMoa2303810
Publisher version: http://doi.org/10.1056/NEJMoa2303810
Language: English
Additional information: This version is the version of record. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Humans, Proto-Oncogene Proteins p21(ras), Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Antineoplastic Agents, Colorectal Neoplasms, Mutation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10176284
Downloads since deposit
5Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item