1392TiP - Phase III study of pembrolizumab plus MK-1084 vs pembrolizumab plus placebo as first-line treatment for metastatic non-small cell lung cancer (NSCLC) with a KRAS G12C mutation and PD-L1 tumour proportion score (TPS) ≥50%: MK-1084-004

Background

KRAS is one of the most frequently mutated oncogenes in human cancers, and the KRAS G12C mutation occurs in approximately 12% of patients with NSCLC. Preliminary findings from a phase 1 trial of MK-1084 (doses 25–400 mg per day), a selective KRAS G12C inhibitor, plus pembrolizumab (anti–PD-1) demonstrated a manageable safety profile with preliminary antitumor activity (ORR, 70%; 95% CI, 50%–86%) in patients with previously untreated NSCLC with PD-L1 TPS ≥1%. We present the study design of a randomized, double-blind phase 3 trial (NCT06345729) evaluating pembrolizumab plus MK-1084 or placebo in patients with previously untreated, metastatic NSCLC with a KRAS G12C mutation and PD-L1 TPS ≥50%.

Trial design

Eligible patients aged ≥18 years with histologically or cytologically confirmed stage IV NSCLC (by AJCC v8) with a confirmed KRAS G12C mutation and PD-L1 TPS ≥50%, measurable disease per RECIST version 1.1, and ECOG PS 0 or 1 will be enrolled. Patients will be randomized 1:1 to receive pembrolizumab 200 mg IV Q3W plus MK-1084 100 mg or placebo by mouth QD. Treatment will continue until progressive disease, unacceptable toxicity, withdrawal, or maximum permitted cycles (up to 35 cycles for pembrolizumab; no limit for MK-1084). Randomization will be stratified by ECOG PS (0 vs 1), presence of brain metastases (yes vs no), and prior immunotherapy in the neoadjuvant/adjuvant setting (yes vs no). Primary objectives are PFS per RECIST version 1.1 by blinded independent central review (BICR) and OS. Key secondary endpoints include ORR and duration of response per RECIST version 1.1 by BICR and safety. Imaging will be performed at baseline, every 6 weeks until week 48, and then every 12 weeks. AEs will be evaluated from baseline through 30 days after cessation of study treatment (90 days for serious AEs) using NCI CTCAE v5.0. Efficacy analyses will be evaluated in all randomized patients and safety analyses in patients who receive ≥1 dose of study treatment. The study is actively enrolling patients.

Clinical trial identification

NCT06345729.

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

P.W. Cobb: Financial Interests, Institutional, Research Funding: Clinipace Tolmar, AstraZeneca, Spectrum, Pfizer, Novartis, Exelexis, Veloxis, BeiGene, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD), Inhibrix, Genentech, Lilly, Syros, Viracta, Celgene, AbbVie, Hengenix, Summit, Regene. M. Hochmair: Financial Interests, Institutional, Advisory Board: Roche, Bristol Myers Squibb, MSD, Lilly, AMGEN, Takeda; Financial Interests, Institutional, Speaker, Consultant, Advisor: Roche, Bristol Myers Squibb, MSD, Lilly, Amgen, Takeda; Financial Interests, Institutional, Speaker’s Bureau: Roche, Bristol Myers Squibb, MSD, Lilly, Amgen, Takeda. M.H.H. Schuler: Financial Interests, Personal, Invited Speaker: Amgen, Bristol Myers Squibb, Janssen, Roche, GSK, MSD; Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, GSK, Janssen, Novartis, Roche, Sanofi, Takeda, Tacalyx, MSD; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, AstraZeneca, Janssen; Non-Financial Interests, Principal Investigator, Member, Study Steering Board: Janssen; Non-Financial Interests, Principal Investigator, Member, Study Steering Committee: Amgen. G.J. Riely: Financial Interests, Institutional, Research Funding: Lilly, MSD, Mirati Therapeutics, Novartis, Pfizer, Roche/Genentech, Takeda; Financial Interests, Institutional, Other, Patents, Royalties, Other Intellectual Property: Patent application submitted covering pulsatile use of erlotinib to treat or prevent brain metastases; Financial Interests, Institutional, Other, Travel, Accommodations, Expenses: Bayer; Merck; Financial Interests, Institutional, Other Relationship: Mirati Therapeutics; Pfizer; Roche/Genentech; Takeda; Financial Interests, Institutional, Other, provided funding support for study conduct and medical writing.: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. 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. S.J. Kim, X. Chen: 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/Shares: Merck & Co., Inc., Rahway, NJ, USA. H. Lara-Guerra: 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/Shares: Merck & Co., Inc., Rahway, NJ, USA, Spyre Therapeutics, Inc., Austin, TX, USA. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer, Genmab; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, BeiGene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp, Merck KGAA, Mirati Therapeutics Inc., Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Financial Interests, Institutional, Local PI: Nuvalent; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientiffic Advisory Committee: CAC Hospital Universitari Parc Taulí.