KEYMAKER-U01J: Calderasib plus pembrolizumab with or without cetuximab as first-line treatment for advanced or metastatic nonsquamous non–small-cell lung cancer (NSCLC) with <i>KRAS</i> G12C mutations.

Abstract

TPS8679 Background: The anti–PD-1 pembrolizumab (pembro) + chemotherapy (chemo) is a standard of care first-line therapy for metastatic NSCLC with no EGFR or ALK alterations. Despite these advances, here remains an unmet need for patients with tumors that have certain mutations, including those in the KRAS gene. KRAS mutations are associated with poor OS in NSCLC. Calderasib (MK-1084), a next-generation, selective KRAS G12C-GDP covalent inhibitor, has previously demonstrated preliminary antitumor activity in combination with pembro ± chemo in KRAS G12C–mutant metastatic NSCLC in the phase 1 KANDLELIT-001 study. The anti-EGFR cetuximab has shown promising efficacy in combination therapies in NSCLC with KRAS G12C mutations. The phase 2 KEYMAKER-U01J study (NCT07252739) is evaluating the addition of investigational agents to pembro in advanced or metastatic nonsquamous NSCLC with KRAS G12C mutations; the treatment arms presented here include pembro + calderasib ± cetuximab. Methods: This phase 2, randomized, open-label study is enrolling participants (pts) aged ≥18 years with previously untreated histologically or cytologically confirmed stage IIIB, IIIC, or IV (M1a, M1b, or M1c) nonsquamous NSCLC (AJCC v9), with a KRAS G12C mutation that is ineligible for curative resection or chemoradiation. Pts must also have measurable disease per RECIST v1.1, an ECOG PS of 0 or 1, and provide a tumor sample for biomarker analysis. Following a safety lead-in of ~10 pts in arm 3, 1:1:1 randomization of ~120 pts will occur. In arm 1 (control arm), pts will receive up to 18 cycles of pembro 400 mg Q6W intravenously (IV) plus carboplatin AUC 5 mg/mL/min up to 2 cycles and pemetrexed 500 mg/m 2 Q3W until discontinuation criteria are met. Pts in arm 2 (reference arm) will receive up to 18 cycles of pembro 400 mg IV Q6W plus calderasib orally until discontinuation criteria are met. Pts in arm 3 will receive up to 18 cycles of pembro 400 mg IV Q6W plus calderasib with cetuximab 500 mg/m 2 IV Q2W until discontinuation criteria are met. Discontinuation criteria include unacceptable AEs, PD, occurrence/progression of another malignancy, or pt/physician withdrawal. Randomization will be stratified by PD-L1 tumor proportion score (&lt; 50% vs ≥50%). Dual primary endpoints are safety (dose-limiting toxicities, AEs, and AEs leading to study discontinuations) and objective response (CR or PR) per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints are duration of response and PFS per RECIST v1.1 by BICR, OS, and pharmacokinetic characterization. On-study tumor imaging will occur Q6W until week 24, Q9W until week 51, then Q12W, or more frequently if clinically indicated. AEs will be graded per NCI CTCAE v5.0. Enrollment began in December 2025, with 80–105 sites scheduled to enroll globally. Clinical trial information: NCT07252739 .