663P Safety and preliminary efficacy of the KRAS G12C Inhibitor MK-1084 in solid tumors and in combination with pembrolizumab in NSCLC

We present preliminary results from a phase 1, open-label, global, dose-escalation study (NCT05067283) of MK-1084, a selective KRAS G12C inhibitor, as monotherapy in advanced solid tumors and in combination with pembrolizumab (pembro) for first-line metastatic NSCLC. Eligible pts aged ≥18 y had locally advanced unresectable or 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 or blood-based confirmation of KRAS G12C mutation, measurable disease per RECIST v1.1 and ECOG PS of 0 or 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 Apr 5, 2023, 43 pts received MK-1084 in Arm 1 and 15 received MK-1084 plus pembro in Arm 2. Median (range) follow-up was 6.0 (0.03–14.47) mo in Arm 1 and 4.4 (0.07–10.17) mo in Arm 2. Arm 1 included 28 pts (65%) with CRC and 9 (21%) with NSCLC; 31 pts (72%) had ≥2 lines of prior therapy. No DLTs have been reported to date. AEs of any cause occurred in 36 pts (84%) in Arm 1 and 13 (87%) in Arm 2; none led to discontinuation. Treatment-related AEs occurred in 22 pts (51%) in Arm 1 (all grade 1 or 2 except 1 pt [2%] with grade 3 increased blood alkaline phosphatase) and 11 (73%) in Arm 2 (all grade 1 or 2 except 2 pts [13%] with grade 3 pruritus, rash, and papular rash); none were grade 4 or 5. There were no grade ≥3 transaminases elevations. ORR was 19% (8/42 pts, all PR; 4 in CRC, 4 in NSCLC) in Arm 1 and 47% (7/15 pts, all PR) in Arm 2; 7 and 3 pts not yet assessed, respectively. 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 whose tumors harbored KRAS G12C mutations. Study is ongoing; updated data will be presented.