KANDLELIT-014: A phase 2 study of MK-1084 as monotherapy and in combination with cetuximab in <i>KRAS</i> G12C-mutant advanced solid tumors.

Abstract

TPS3185 Background: KRAS is one of the most frequently mutated oncogenes in human cancers, with the G12C mutant isoform accounting for ~15% of all KRAS mutations. Despite their promising antitumor activity and manageable safety profile in advanced solid tumors, first-generation KRAS G12C inhibitors are often limited by acquired resistance in the monotherapy setting. MK-1084 is a next-generation, highly potent and selective KRAS G12C–GDP covalent inhibitor that exerts downstream regulation of the MAPK pathway. EGFR-mediated reactivation of RAS-MAPK signaling is proposed as a key driver of resistance to KRAS G12C inhibitors, particularly in colorectal cancer (CRC). The combination of KRAS G12C inhibitors and EGFR-targeted monoclonal antibodies has demonstrated clinical benefit in KRAS G12C-mutated CRC and non-small cell lung cancer (NSCLC), supporting the potential of this mutation as a clinically-relevant target across tumor types. KANDLELIT-014 (NCT07209111) is a phase 2, randomized, open-label, multicenter, tumor-agnostic study of MK-1084 as monotherapy and in combination with EGFR inhibitor cetuximab in participants with previously treated advanced solid tumors harboring a KRAS G12C mutation. Methods: Eligible participants are aged ≥18 years with histological or blood-based KRAS G12C-mutated locally advanced unresectable or metastatic solid tumors (other than CRC) that have progressed on or following standard-of-care systemic treatment, or for whom no satisfactory alternative treatment options are available. Additional eligibility criteria include an ECOG PS score of 0 or 1 and measurable disease per RECIST v1.1. Participants were excluded if they had uncontrolled, significant cardiovascular or cerebrovascular diseases; an additional progressive active malignancy that required treatment within the past 3 years; or active CNS metastases, carcinomatous meningitis, or primary brain tumors. Participants will be randomly assigned 1:1 to receive MK-1084 100 mg orally once daily as monotherapy (Arm 1) or in combination with cetuximab 500 mg/m 2 intravenously every 2 weeks (Arm 2) until discontinuation criteria are met. Randomization will be stratified according to the following tumor groups: NSCLC, pancreatic ductal adenocarcinoma, endometrial cancer, biliary tract cancer, and other solid tumors. The primary end points are ORR per RECIST v1.1 as assessed by blinded independent central review (BICR), safety, and tolerability. Key secondary end points include OS, DOR per RECIST v1.1 by BICR, and PFS per RECIST v1.1 by BICR. Imaging will be performed every 6 weeks until Week 18, every 8 weeks until Week 50, and every 12 weeks thereafter until disease progression or discontinuation. AEs will be evaluated from randomization to 30 days after the last dose of study treatment per NCI CTCAE v5.0. This global study is actively enrolling. Clinical trial information: NCT07209111 .