362P Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation

Abstract

Background The oncogenic KRAS G12C mutation is found in ∼4% CRC patients (pts). GDC-6036 is an oral, highly potent and selective KRAS G12C inhibitor, with robust tumor growth inhibition in multiple preclinical models. Methods As part of an ongoing phase I dose-escalation/expansion study (NCT04449874), pts with advanced and metastatic KRAS G12C mutant CRC were administered GDC-6036 50-400 mg orally once a day in 21-day cycles until intolerable toxicity or disease progression. Endpoints included safety (NCI-CTCAE v5), pharmacokinetics (PK), and preliminary anti-tumor activity (RECIST v1.1). Serial circulating tumor DNA (ctDNA) levels were assessed using the PredicineBEACON MRD assay. Results As of 28 Jan 2022, 43 pts with CRC were enrolled (n, 50 mg: 2; 100 mg: 7; 200 mg: 4; 400 mg: 30). Median (range) number of prior cancer therapies was 3 (1-7). No dose-limiting toxicities were reported across all solid tumors. Median (range) time on study treatment was 2.8 (0.1-11.2) months among pts with CRC and median GDC-6036 dose intensity was 100%. Sixteen (37%) pts discontinued study treatment (13 due to RECIST progression, 2 due to symptomatic deterioration, 1 patient withdrawal). The most frequent GDC-6036-related AEs (≥ 10% pts) were nausea, diarrhea, vomiting, dyspepsia, fatigue, and decreased appetite; the only Grade ≥3 AE was diarrhea (3 pts, 7%; all Grade 3). AEs were manageable with supportive measures. Five (12%) pts required a dose modification (interruption [4 pts] or reduction [1 pt]; no withdrawal) for GDC-6036-related AEs. Across all solid tumor patients, the mean half-life for GDC-6036 ranged from 13-17 hours at doses of 50-400 mg. The unconfirmed overall response rate (ORR) in pts with CRC was 29% (12/41 pts with measurable disease; 1 complete response), while the confirmed ORR was 20% (8/41 pts) across dose levels in this ongoing study. Among responders, a decrease in ctDNA levels was observed as early as C1D15. Conclusions In patients with KRAS G12C mutant CRC, GDC-6036 demonstrated encouraging antitumor activity and early reduction in ctDNA along with acceptable and manageable safety, and PK profile compatible with once daily dosing. Data from additional pts will be presented.