44O Updated results from a phase I study evaluating the KRAS G12C inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC

Abstract

We present updated results from a phase 1 dose-escalation study (NCT05067283) of selective KRAS G12C inhibitor MK-1084 as monotherapy in advanced solid tumors and in combination with pembrolizumab (pembro) for first-line metastatic NSCLC. Eligible pts had locally advanced unresectable/metastatic solid tumors and ≥1 line of prior therapy (Arm 1), or previously untreated metastatic NSCLC with PD-L1 TPS ≥1% (Arm 2), with histologic/blood-based confirmation of KRAS G12C mutation, measurable disease per RECIST v1.1 and ECOG PS ≤1. Pts received MK-1084 PO QD or BID (25–800 mg) as monotherapy (Arm 1) or with pembro 200 mg Q3W (Arm 2) using a modified toxicity probability dose-escalation design. Treatment continued until PD, unacceptable toxicity, withdrawal, or maximum permitted cycles (≤35 cycles for pembro; no limit for MK-1084). Primary endpoints were dose-limiting toxicities (DLTs), AEs and discontinuations due to AEs. AEs were graded per NCI CTCAE v5.0. ORR per RECIST v1.1 by investigator review was a secondary endpoint. As of Aug 4, 2023, 54 pts received MK-1084 in Arm 1 and 24 received MK-1084 plus pembro in Arm 2. Median (range) follow-up was 8.1 (1.5–18.4) mo in Arm 1 and 5.2 (0.2–14.1) mo in Arm 2. Arm 1 included 37 pts (69%) with CRC and 11 (20%) with NSCLC; 39 pts (72%) had ≥2 lines of prior therapy. No DLTs occurred in Arm 1. One pt in Arm 2 receiving MK-1084 400 mg QD + pembro experienced DLTs (grade 3 increased alanine aminotransferase [ALT] and grade 3 increased aspartate aminotransferase [AST]). AEs of any cause occurred in 96% of pts in Arm 1 and 96% in Arm 2. Treatment-related AEs (TRAEs) occurred in 57% of pts in Arm 1 and 79% in Arm 2. 9% and 42% experienced grade 3-4 TRAEs (no grade 5). The most common TRAEs across all dose levels were increased ALT (Arm 1, 15%; Arm 2, 42%), increased AST (17%; 33%), and diarrhea (13%; 17%). ORR was 22% (12/54 pts, all confirmed PR; 6 in CRC, 5 in NSCLC, and 1 pt with cervical adenocarcinoma) in Arm 1 and 71% (15/21 pts, all confirmed PR) in Arm 2. MK-1084 as monotherapy and in combination with pembro showed manageable safety and preliminary antitumor activity in pts with previously treated solid malignancies and previously untreated NSCLC with KRAS G12C mutations.