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

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

NCT05067283.

Editorial acknowledgement

Medical writing assistance was provided by Susan Tyree, PhD, CMPP, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

C.I. Rojas: Financial Interests, Personal, Advisory Board: BMS, Roche, MSD, Pfizer, Sanofi; Financial Interests, Personal, Invited Speaker: BMS, MSD, AstraZeneca, Knight, Pfizer; Financial Interests, Personal, Member of Board of Directors: Bradford Hill. I. Lugowska: Financial Interests, Personal, Invited Speaker: Roche, ESMO; Financial Interests, Institutional, Other, Research grants: Roche; Financial Interests, Institutional, Other, Research grant: Agenus; Financial Interests, Personal and Institutional, Invited Speaker: MSD, Roche, BMS, Janssen, Astra, Amgen, RyVu, Incyte, Siropa, Menarini, Celon, Pfizer, Agenus, Rhizen; Non-Financial Interests, Personal, Project Lead: MSCI; Non-Financial Interests, Personal, Other, Board Member: OECI; Other, Personal, Other, Robert Lugowski (my husband) co-ownership: Clininote. R. Juergens: Financial Interests, Institutional, Advisory Role: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Merck, Novartis, Pfizer, Hoffmann-La Roche, Sanofi, Takeda; Financial Interests, Institutional, Other, Honoraria: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Fusion Pharmaceuticals, Merck, Novartis, Pfizer, Hoffmann-La Roche, Sanofi, Takeda; Financial Interests, Institutional, Research Grant: AstraZeneca, Bristol Myers Squibb, Merck. A. Sacher: Financial Interests, Institutional, Invited Speaker: Genentech-Roche, BMS, AstraZeneca, Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly, BridgeBio, Hotspot Therapeutics. S. Weindler: Financial Interests, Institutional, Advisory Role: Amgen; Financial Interests, Institutional, Principal Investigator, Research funding, role as PI: Merck, BMS; Financial Interests, Institutional, Other, Travel, Accommodations, expenses: Vifor pharma, Eli Lilly. M.A.N. Sendur: Financial Interests, Institutional, Advisory Role: BMS, Roche, Takeda, Pfizer, Astellas, Novartis, MSD; Financial Interests, Institutional, Speaker’s Bureau: Roche, Takeda, Pfizer, Novartis, Astellas . R. Dziadziuszko: Financial Interests, Institutional, Advisory Role, Advisory boards or consultancy, compensated: MSD, Roche, AstraZeneca, Pfizer, Novartis, Bristol Myers Squibb, Amgen . E. Castanon Alvarez: Financial Interests, Personal, Expert Testimony: MSD, Roche, BMS; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Personal, Principal Investigator: AZ, BMS, Roche, MSD, GSK, ARC. E.S. Ahern: Financial Interests, Institutional, Research Grant: Amgen. N. Lakhani: Financial Interests, Personal, Advisory Board: Innovent Biologics; Financial Interests, Personal, Advisory Board, Participation in Ad Board: Ikena, SK Life Sciences; Financial Interests, Institutional, Invited Speaker: ALX Therapeutics, Ascentage, Constellation Pharma, Alpine Biosciences, Forty Seven, Merck, Pfizer, Regeneron, Symphogen, InhibRx, Seagen, Sapience Therapeutics, Jounce, Northern Biologics, Odonate, Loxo/Lilly, Ikena, Mersana Therapeutics, Astellas, Celgene, Helsinn, Shattuck Labs, Samumed, GSK, Alkermes, Servier, Samumed, Tizona Therapeutics, Gilead, Repare Therapeutics, Alkermes, InhibRx, Janssen, CytomX, KSQ Therapeutics, Repare Therapeutics. L. Chen, T. Jemielita, S.Y. Choi: Financial Interests, Institutional, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. A. Stathis: Financial Interests, Institutional, Expert Testimony: Bayer, Eli Lilly; Financial Interests, Institutional, Advisory Board: Janssen, Roche; Financial Interests, Institutional, Principal Investigator, Local PI: AbbVie, ADC Therapeutics, Amgen, Bayer, Cellestia, Loxo Oncology, MSD, Novartis, Pfizer, Philogen, Roche; Financial Interests, Institutional, Other, Travel: Incyte; Financial Interests, Institutional, Other, Trial chair: AstraZeneca, Incyte. All other authors have declared no conflicts of interest.