Amgen's LUMAKRAS: Pioneering the Way for KRAS G12C Mutated CRC Treatment

CodeBreaK 101

Approximately 30-50% of CRC are known to have a mutated (abnormal) KRAS gene. KRAS G12C mutation found in approximately 3 to 7% of KRAS CRC cases. LUMAKRAS has received approval for the treatment of non-small cell lung cancer (NSCLC) with KRAS G12C mutations, and there is ongoing exploration of its potential in KRAS G12C mutated colorectal cancer (CRC).

According to Phase Ib data presented in ASCO 2023, out of the 31 evaluable patients, the confirmed objective response rate (ORR) was 58.1%, with all responses being partial responses. Interestingly, even patients who had previously received sotorasib showed positive responses, with one achieving a partial response and another achieving stable disease. The disease control rate (DCR) was 93.5%. However, as the follow-up period was relatively short, data regarding progression-free survival and overall survival are not yet mature. Treatment-related adverse events (TRAEs) were observed in 97% of patients, with one patient discontinuing the full regimen due to a grade 3 increase in ALT levels. Approximately 45.5% of patients experienced grade ≥ 3 TRAEs, but no fatal TRAEs were reported. The safety findings were consistent with the known profiles of sotorasib, panitumumab, and FOLFIRI. There were no clinically significant pharmacokinetic interactions between sotorasib and irinotecan. These findings provide valuable insights into the safety and efficacy of the combination therapy, highlighting the potential of this treatment approach for patients with KRAS G12C-mutated mCRC. Further research and longer-term follow-up are needed to fully understand the impact on survival outcomes. 

In the dose exploration phase of the study, none of the six patients experienced any dose-limiting toxicities (DLTs), thus establishing the dose for further investigation in the dose expansion phase. The combination of sotorasib, panitumumab, and FOLFIRI demonstrated a manageable safety profile, with adverse events (AEs) consistent with what was expected for the specific therapies being studied. The confirmed ORR was 55%, indicating a significant number of patients showed positive responses to the treatment. Additionally, the DCR was 93%, further highlighting the favorable outcomes. Notably, responses were observed in patients regardless of the number of prior lines of therapy and even in those who had previously progressed on irinotecan-based therapy. This suggests that the combination of sotorasib, panitumumab, and FOLFIRI holds promise for achieving favorable response rates in pre-treated patients with KRAS G12C-mutated mCRC, irrespective of prior exposure to irinotecan and 5-FU. These findings provide valuable insights into the potential effectiveness of this treatment regimen for this specific patient population.

Table 1: Efficacy of CodeBreaK 101

Response by investigator assessment*

Part 1

Sotorasib + Panitumumab + FOLFIRI


Part 2

Sotorasib + Panitumumab + FOLFIRI




Objective response rate (%)




Complete Response




Partial Response




Stable Disease (%)




Progressive Disease (%)




Disease Control Rate (%)




Note: * 42 patients enrolled at least 7 week before analysis cutoff were included for response summary

KOL insights

“Combination of sotorasib and panitumumab demonstrated favorable safety and tolerability in heavily pretreated patients with KRAS G12C-mutated metastatic colorectal cancer, showing a three-fold increase in response rates compared to Soto monotherapy” –Expert Opinion.

Conclusion: The initial data set for the combination of sotorasib, panitumumab, and FOLFIRI in previously treated patients with KRAS G12C-mutated mCRC demonstrates encouraging results in terms of both safety and efficacy. The confirmed ORR reached an impressive 58.1%. The adverse events experienced by patients were manageable and aligned with the anticipated safety profile of the drugs utilized. Additionally, no significant pharmacokinetic interaction was observed between Soto and irinotecan, a component of FOLFIRI. These findings provide conclusive evidence supporting the potential of this novel combination as an effective treatment option for patients with pretreated KRAS G12C-mutated mCRC