KRAS mutations are among the most common genetic alterations in Colorectal cancer (CRC), with the KRAS G12C mutation present in approximately 3-5% of CRC cases. The US Food and Drug Administration (FDA) has approved LUMAKRAS (sotorasib) + VECTIBIX (panitumumab) for KRAS G12C-mutated mCRC after prior fluoropyrimidine-, oxaliplatin-, irinotecan-based chemotherapy, based on findings from the Phase III CodeBreaK 300 trial. 

At ASCO 2025, Amgen presented findings from the CodeBreaK 101 Phase Ib trial (subprotocol H). The objective of this study (NCT05198934) was to investigate whether triplet therapy could enhance efficacy in patients who had received at least one prior systemic therapy but had not been exposed to KRAS G12C inhibitors. In the trial by November 2024, 40 patients were enrolled (female: 47.5%; median age: 56.0 years; median [range] prior lines of systemic therapy: 2 [1-6]).  The updated objective response rate (ORR) was 57.5% (40.9, 73.0) and the disease control rate (DCR) was 92.5% (79.6, 98.4). The median time to respond was 1.6 months and the duration of response was 6.6 months. After a median follow-up of 29.2 months, the median PFS was 8.2 (7.0, 10.8) months and the median OS was 17.9 (12.9, 25.1) months. 

At the time of analysis, a total of seven patients are continuing the study, of whom five are off treatment and under follow-up. Grade 3 treatment-related adverse events (TRAEs) occurred in 50.0% patients (n=20) with no new safety signals. Discontinuation of sotorasib, panitumumab, or FOLFIRI (5-FU, irinotecan, or leucovorin/ levoleucovorin) due to adverse events (AEs) was observed in 1 (2.5%), 1 (2.5%), and 16 (40.0%) patients, respectively. 

KOL insights

“I am anticipating the long-term safety and efficacy results from the Phase Ib CodeBreaK 101 trial [NCT04185883] in patients with previously treated KRAS G12C–mutated metastatic CRC receiving sotorasib [LUMAKRAS] plus panitumumab [VECTIBIX] and FOLFIRI. We saw in the Phase III CodeBreaK 300 trial [NCT05198934] that the combination of sotorasib and panitumumab improved clinical outcomes, resulting in the FDA approval of this regimen in the chemotherapy-refractory setting. However, CodeBreaK 101 was the first study to evaluate the combination with FOLFIRI. If these data remain promising, then the ongoing Phase III CodeBreaK 301 study [NCT06252649] evaluating this combination vs SOC in the first-line setting may be practice changing.” – 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. In terms of the treatment landscape, approvals remains limited. Two targeted combination therapies have been approved for KRAS G12C-mutated mCRC [KRAZATI (adagrasib) + ERBITUX (cetuximab), and  LUMAKRAS (sotorasib) + VECTIBIX (panitumumab). Competition in the KRAS-mutant CRC treatment space is intensifying, with multiple companies actively developing targeted therapies. Revolution Medicines, Eli Lilly and Company, Cardiff Oncology, InventisBio, Tyligand Pharmaceuticals (Suzhou), and D3 BIO are among the key players advancing novel approaches for KRAS-mutant CRC. The growing interest in this KRAS- biomarker in CRC underscores unmet medical needs and the potential to expand beyond the currently approved KRAS G12C inhibitors. 

Findings from  Phase Ib CodeBreaK 101 trial is the first long-term outcome for a KRAS G12C-targeted triplet in mCRC. These results signify significant advances for a mutation that has long been considered “undruggable,” with remarkable ORR and OS established in heavily pretreated populations. However, toxicity remains a challenge, with Grade ≥3 TRAEs occurring in 50% of patients—the most common being acneiform rash, neutropenia, and stomatitis. Additionally, 40% of patients discontinued FOLFIRI due to adverse events, which raises concerns about long-term tolerability.

Building on these findings, the ongoing Phase III CodeBreaK 301 trial is evaluating this combination against FOLFIRI with or without bevacizumab as a first-line treatment option for patients with KRAS G12C–mutated mCRC.