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
C.I. Rojas, Iwona Ługowska, Rosalyn A. Juergens, Adrian G. Sacher, Susanne Weindler, Mehmet Alı Nahıt Şendur, Rafał Dziadziuszko, Abhijit Pal, Eduardo Castañón Álvarez, E.S. Ahern, Nehal J. Lakhani, Li‐Chia Chen, Thomas Jemielita, Song‐Yi Choi, Anastasios Stathis
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.