KRAS G12C mutations occur in approximately 3–5% of CRC cases, representing a key therapeutic target. MK-1084 is an investigational, potent, and selective KRAS G12C covalent inhibitor being evaluated in the Phase I KANDLELIT-001 trial (NCT05067283). This open-label, multicenter study is assessing MK-1084 as monotherapy and in combination therapies in patients with advanced KRAS G12C-mutated solid tumors. Primary endpoints focus on safety and tolerability, while secondary endpoints include objective response rate and duration of response.

In the KANDLELIT-001 trial, MK-1084 demonstrated promising efficacy and manageable safety in patients with advanced KRAS G12C-mutant CRC. 

1. As monotherapy, MK-1084 achieved a confirmed ORR of 38% and a DCR of 83%, with a median time to response (TTR) of 1.5 months and a median duration of response (DOR) of 7.1 months. 

2. When MK-1084 combined with cetuximab, the ORR increased to 46% and DCR to 92%, with a median DOR of 10.8 months.

3. In the triplet arm (MK-1084 + cetuximab + chemotherapy), the ORR was 38% and DCR was 93%, though median DOR was not reached. 

Across all arms, treatment-related adverse events were manageable, with no TRAE-related deaths. Most patients remained on treatment at the cutoff, especially in the combination arms, supporting the continued development of MK-1084-based regimens.

KOL insights

Data support further evaluation of MK-1084-based combinations for the treatment of KRAS G12C–mutant colorectal cancer. – Expert Opinion

Conclusion

According to the DelveInsight estimates, there were approximately 4,700 cases of KRAS G12C–mutated CRC in the United States in 2024. Apart from Merck, several other companies also presented clinical data of their KRAS inhibitors in CRC (KANDLELIT-001, CodeBreaK 101, LOXO-RAS-20001). MK-1084 demonstrated promising efficacy in advanced KRAS G12C-mutant colorectal cancer, showing meaningful response rates both as monotherapy and in combination regimens. The competition is fierce in this setting, with latest ASCO 2025 data suggesting that Amgen’s triplet therapy could make strong strides in KRAS-mCRC. The updated phase Ib codebreak 101 data supports expansion of KRAS G12C-directed therapy beyond dual blockade, reinforcing the role of triplet therapy.