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

Background

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.

Methods

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.

Results

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.

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 whose tumors harbored KRAS G12C mutations. Study is ongoing; updated data will be presented.

Clinical trial identification

NCT05067283.

Editorial acknowledgement

Medical writing support was provided by Kathleen Estes, PhD, of ICON plc (Blue Bell, PA, USA), and 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. Rojas: Financial Interests, Personal, Invited Speaker: AstraZeneca, BMS, Knight, MSD, Pfizer; Financial Interests, Personal, Advisory Board: BMS, MSD, Pfizer, Roche, Sanofi; Financial Interests, Personal, Member of Board of Directors: Bradford Hill. I. Lugowska: Financial Interests, Personal, Writing Engagement: Roche, ESMO; Financial Interests, Institutional, Other, Research grants: Roche; Financial Interests, Institutional, Other, Research grant: Agenus; Financial Interests, Personal and Institutional, Coordinating PI: MSD, Roche, BMS, Janssen, Astra, Amgen, RyVu, Incyte, Siropa, Mennarini, Celon, Pfizer, Agenus, Rhizen; Non-Financial Interests, Project Lead: MSCI; Non-Financial Interests, Other, Board Member: OECI; Other, Robert Lugowski (my husband) co-ownership: Clininote. R. Juergens: Financial Interests, Personal, Other, served in a consultancy or advisory role: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Merck, Novartis, Pfizer, F. Hoffmann-La Roche, Sanofi, and Takeda; Financial Interests, Personal, Other, received honoraria: AbbVie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, EMD Serono, Fusion Pharmaceuticals, Merck, Novartis, Pfizer, F. Hoffmann-La Roche, Sanofi, and Takeda; Financial Interests, Personal, Research Funding: AstraZeneca, Bristol Myers Squibb, and Merck. A. Sacher: Financial Interests, Institutional, Coordinating PI: Genentech-Roche, BMS, AstraZeneca; Financial Interests, Institutional, Local PI: Amgen, Iovance, CRISPR Therapeutics, Merck, Pfizer, GSK, Spectrum, Lilly. S. Weindler: Financial Interests, Institutional, Other, Consulting or Advisory role: Amgen; Financial Interests, Institutional, Other, Research funding (role as PI): Merck, BMS; Financial Interests, Institutional, Other, Travel, Accommodations, expenses: Vifor pharma, Eli Lilly. M.A.N. Sendur: Financial Interests, Personal, Other, Consulting or Advisory Role: BMS, Roche, Takeda, Pfizer, Astellas, Novartis, MSD; Financial Interests, Personal, Speaker’s Bureau: Roche, Takeda, Pfizer, Novartis, Astellas. R. Dziadziuszko: Financial Interests, Personal, Other, Advisory boards or consultancy, compensated: MSD, Roche, AstraZeneca, Pfizer, Novartis, Bristol Myers Squibb, Amgen. E. Castanon Alvarez: Financial Interests, Personal, Advisory Board: MSD, Roche, BMS; Financial Interests, Personal, Invited Speaker: GSK; Non-Financial Interests, Principal Investigator: AZ, BMS, Roche, MSD, GSK, ARC. E.S. Ahern: Financial Interests, Institutional, Research Funding: 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, Local PI: 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, Samumed, Tizona Therapeutics, Gilead, Repare Therapeutics, Alkermes, InhibRx, Janssen, cytomX, KSQ Therapeutics, Repare Therapeutics; Financial Interests, Institutional, Coordinating PI: Servier. L. Chen, T. Jemielita, Y.S. Choi: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks or ownership: Merck & Co., Inc., Rahway, NJ, USA. A. Stathis: Financial Interests, Institutional, Other, Travel grant: AstraZeneca, Incyte; Financial Interests, Institutional, Expert Testimony: Bayer, Eli Lilly; Financial Interests, Institutional, Advisory Board: Janssen, Roche; Financial Interests, Institutional, Local PI: AbbVie, ADC Therapeutics, Amgen, Bayer, Cellestia, Loxo Oncology, MSD, Novartis, Pfizer, Philogen, Roche; Financial Interests, Institutional, Trial Chair: AstraZeneca, Incyte. All other authors have declared no conflicts of interest.