The KRAS G12C inhibitor MK-1084 for <i>KRAS</i> G12C–mutated advanced colorectal cancer (CRC): Results from KANDLELIT-001.

3508 Background: Preliminary data from the phase 1 KANDLELIT-001 trial (NCT05067283) showed a manageable safety profile and preliminary antitumor activity for MK-1084, a next-generation, selective KRAS G12C-GDP covalent inhibitor, in participants (pts) with previously treated, KRAS G12C-mutant solid tumors, including non–small-cell lung cancer and CRC. Here, we report data for MK-1084 monotherapy, MK-1084 + cetuximab, and MK-1084 + cetuximab + mFOLFOX6 in pts with advanced KRAS G12C-mutant CRC. Methods: KANDLELIT-001 enrolled pts with confirmed KRAS G12C mutation, RECIST-measurable disease, and ECOG PS 0-1. Pts with any advanced solid tumor and ≥1 prior systemic therapy received MK-1084 monotherapy PO QD or BID (total daily dose, 25-800 mg) in arms 1 and 3. Pts with advanced CRC and 1-2 prior systemic therapies received MK-1084 QD (total daily dose, 25-200 mg) plus cetuximab 500 mg/m 2 IV Q2W in arm 5. Pts with advanced CRC and 0-1 prior systemic therapies received MK-1084 QD (total daily dose, 25-100 mg) plus cetuximab 500 mg/m 2 Q2W and mFOLFOX6 in arm 6. The primary endpoints were dose-limiting toxicities (DLTs), AEs, and AEs leading to discontinuation. Secondary endpoints included ORR per RECIST v1.1 by investigator review. ORR was assessed in all pts who received their first MK-1084 dose ≥5 wk before the data cutoff date of August 12, 2024, for arms 1 and 3 and November 6, 2024, for arms 5 and 6. Results: In arms 1+3, 99 pts, including 53 (54%) with CRC, received MK-1084 alone. In arm 5, 34 pts, including 23 (68%) who had ≥2 prior lines of therapy, received MK-1084 + cetuximab. In arm 6, 20 pts, including 10 (50%) who had no prior therapy, received MK-1084 + cetuximab + mFOLFOX6. Median (range) study follow-up was 14.8 mo (0.2-30.8) in arms 1+3, 5.3 mo (2.6-11.5) in arm 5, and 1.9 mo (0.1-5.4) in arm 6. One pt in arm 6 experienced a DLT (grade 3 febrile neutropenia); there were no DLTs in arms 1, 3, or 5. Treatment-related AEs occurred in 62% of pts in arms 1+3, 97% of pts in arm 5, and 90% of pts in arm 6, were grade ≥3 in 9%, 18%, and 25%, respectively, and led to discontinuation of any drug in 1%, 3%, and 15%, respectively. There were no treatment-related deaths. The two most common treatment-related AEs in each arm were increased AST (17%) and nausea (17%) in arms 1+3, dermatitis acneiform (47%) and rash (24%) in arm 5, and nausea (55%) and rash (50%) in arm 6. ORR (95% CI) was 36% (23-50) in pts with CRC in arms 1+3 (n = 53), 50% (32-68) in arm 5 (n = 34), and 14% (2-43) in arm 6 (n = 14); all responses were partial responses. Conclusions: Preliminary data suggest that MK-1084 monotherapy, MK-1084 + cetuximab, and MK-1084 + cetuximab + mFOLFOX6 have manageable safety profiles and show evidence of antitumor activity in pts with advanced, KRAS G12C-mutated CRC. Pts continue to be followed, and enrollment continues. Clinical trial information: NCT05067283 .