459MO Phase Ia study to evaluate GDC-6036 monotherapy in patients with solid tumors with a KRAS G12C mutation

Advanced-stage tumors harboring a KRAS G12C mutation have limited treatment options. GDC-6036, a highly potent and selective KRAS G12C inhibitor, has shown robust tumor growth inhibition in multiple preclinical models of a variety of tumor types. As part of an ongoing phase I dose-escalation/expansion study (NCT04449874), patients (pts) with KRAS G12C mutant other solid tumors (oST), exclusive of non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) (NSCLC and CRC reported elsewhere), were administered GDC-6036 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). As of 28 Jan 2022, 14 pts with pretreated oST (4 cholangiocarcinoma, 3 pancreatic adenocarcinoma, and 1 each: anus, appendix, breast, duodenum, endometrial, lung neuroendocrine, and stomach cancers) had received GDC-6036 monotherapy at 400 mg. Median (range) number of prior cancer therapies was 2 (1-8). No dose-limiting toxicities were reported across NSCLC, CRC and oST. Median (range) time on study treatment was 63.5 (8-151) days among oST pts, and median GDC-6036 dose intensity was 99%. Five (36%) pts had discontinued study treatment (4 radiographic progression and 1 death due to disease progression). The most frequent GDC-6036-related AEs reported in ≥ 2 pts were nausea, vomiting, diarrhea, alanine aminotransferase increased, and aspartate aminotransferase increased. Two (14%) pts required a dose modification (interruption, 1 pt; reduction, 1 pt; no withdrawal) for GDC-6036-related AEs. Across NSCLC, CRC and oST pts, 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 the oST pts was 21% (3/14 pts; anus, lung neuroendocrine and stomach cancers), while the confirmed ORR was 14% (2/14 pts). GDC-6036 demonstrated an acceptable safety profile, a PK profile compatible with once-daily dosing, and encouraging efficacy in pts with pretreated oST with a KRAS G12C mutation. Data from additional pts will be presented.