KRAS G12C inhibition has so far mostly been focused on KRAS G12C-mutant non-small cell lung cancer (NSCLC), but there has also been regulatory action in relapsed KRAS G12C colorectal cancer. In January 2025, the United States Food and Drug Administration (FDA) approved a LUMAKRAS/VECTIBIX combination after giving regulatory nod to KRAZATI/ERBITUX last year. In mCRC, LUMAKRAS and KRAZATI regimens showed objective response rates (ORRs) of 26% and 34%, respectively. In the first-line setting for KRAS-mCRC, treatment options remain limited, and there is still a significant unmet need for more effective and well-tolerated therapies. 

Lilly’s Olomorasib (LY3537982) is an investigational oral therapy designed to selectively and potently inhibit the KRAS G12C protein. As a second-generation covalent inhibitor, it demonstrates potential for over 90% target occupancy, which may enable safer and more tolerable combination regimens due to its enhanced selectivity and reduced off-target toxicity. 

At ASCO 2025, Lilly presented findings from phase I/II LOXO-RAS-20001 trial (NCT04956640). This study explores olomorasib/cetuximab combo in advanced KRAS G12C-mutant CRC. Patients previously treated with oxaliplatin or irinotecan were enrolled in dose escalation/expansion (100 or 150 mg BID). The mTPI-2 method guided dose escalation. Key goals were to assess safety, determine the optimal dose, and evaluate antitumor activity per RECIST v1.1.

As of data cutoff of Jan 2025, Olomorasib (100 or 150 mg BID) in combination with cetuximab demonstrated favorable safety and promising efficacy at both dose levels in patients with KRAS G12C-mutant CRC. This combination showed 43.0% ORR, 92.5% DCR, and mPFS of 7.4 months.  The 100 mg BID dose had better efficacy (ORR: 45.3% and 6-month PFS rate: 65.1%) than 150 mg BID  (ORR: 37.9% and 6-month PFS rate: 55.6%). Both doses showed strong disease control rates (DCR > 92%). Progression and adverse event rates were low. TRAEs aligned with the known safety profiles of olomorasib and cetuximab with infrequent grade ≥3 events. Olomorasib dose reductions due to TRAEs were rare (2%), and no discontinuations of the combination. In conclusion, the 100 mg BID dose is preferred due to its balance of efficacy and tolerability.

KOL insights

These data confirm the relevance of combination approaches to circumvent resistance in KRAS G12C-mutated cancers; they pave the way for new personalized treatment strategies in situations where options have until now been extremely limited. – Expert Opinion

Although the monotherapy response rates remain low in CRC patients, combination therapies are more promising. Another option recently explored are the pan-KRAS and pan-RAS inhibitors which inhibit RAS regardless of the mutated allele, or in the latter case, also independent of the RAS isozyme, which may compensate for the effects of mutant-specific KRAS inhibitors. – Expert Opinion

Conclusion

KRAS is one of the most promising areas of small molecule-based therapeutic research at the moment. According to the DelveInsight estimates, there were approximately 4,700 cases of KRAS G12C–mutated CRC in the United States in 2024. Regarding the treatment landscape, approvals are still limited. For mCRC with KRAS G12C mutations, two combination therapies have received approval: KRAZATI (adagrasib) + ERBITUX (cetuximab) and LUMAKRAS (sotorasib) + VECTIBIX (panitumumab). The competition for KRAS-mutant CRC treatments is heating up, as numerous firms are working on targeted therapies. The key players advancing novel approaches for KRAS-mutant CRC include Revolution Medicines, Amgen, BMS, Merck, Cardiff Oncology, InventisBio, Tyligand Pharmaceuticals (Suzhou), and D3 BIO. In KRAS-mCRC, Merck & Co also presented findings from their phase I KANDLELIT-001 trial at ASCO 2025, where MK-1084 ((+/- Erbitux +/- chemo) is currently being investigated. Data presented at ASCO 2025 reported that at a median follow-up of 23.2 months, the confirmed ORR in patients receiving MK-1084 monotherapy was 38%, and the disease control rate was 83%.