RAS Blockers for KRAS G12C-Mutant Metastatic Colorectal Cancer
For patients with previously treated KRAS G12C-mutant metastatic colorectal cancer, use sotorasib or adagrasib in combination with cetuximab or panitumumab (EGFR inhibitors) rather than as monotherapy, as combination therapy achieves superior response rates (30-46% vs 10-19%) and improved progression-free survival. 1
Treatment Algorithm for KRAS G12C-Mutant mCRC
First-Line Setting
- KRAS G12C inhibitors are not recommended in the first-line setting 1
- Standard first-line therapy should be administered based on RAS mutation status and tumor sidedness 1
Non-First-Line Setting (After Prior Systemic Therapy)
Preferred Regimen:
- Adagrasib 600 mg twice daily + cetuximab (ORR 34-46%, median PFS 6.9 months, median OS 15.9 months) 1
- Sotorasib 960 mg once daily + panitumumab (ORR 30%, median PFS 5.7 months, median OS 15.2 months) 1
Alternative Monotherapy (if EGFR inhibitor toxicity is a concern):
- Adagrasib monotherapy (ORR 19%, median PFS 5.6 months) 1
- Sotorasib monotherapy (ORR 9.7%, median PFS not specified) 1
Key Clinical Evidence
Combination Therapy Superiority
The KRYSTAL-1 trial demonstrated that adagrasib combined with cetuximab achieved a 46% objective response rate compared to only 19% with adagrasib monotherapy in KRAS G12C-mutant mCRC 1. Updated 2024 data with 94 patients showed an ORR of 34%, disease control rate of 85.1%, and median OS of 15.9 months 1.
The CodeBreaK 101 trial showed sotorasib plus panitumumab achieved a 30% confirmed ORR versus only 7.1-9.7% with sotorasib monotherapy 1.
Mechanistic Rationale for Combination
EGFR activation is a primary resistance mechanism to KRAS G12C inhibition in colorectal cancer 2. In murine patient-derived CRC xenograft models, the combination of sotorasib and panitumumab demonstrated increased antitumor activity compared to either agent alone 2. This biological rationale explains why combination therapy is essential in CRC, unlike in NSCLC where monotherapy may be sufficient 2.
Important Exception to Standard RAS-Mutant Treatment
Patients with KRAS G12C-mutant tumors represent a critical exception to the general rule that RAS-mutant CRC should not receive EGFR inhibitors 1. While cetuximab and panitumumab are contraindicated in other RAS-mutant CRC due to lack of benefit and potential harm, these agents are specifically recommended in combination with KRAS G12C inhibitors for KRAS G12C-mutant disease 1.
Safety Profile
Adagrasib + cetuximab:
- Grade ≥3 treatment-related adverse events: 16% 1
- Lower toxicity than adagrasib monotherapy (34% grade ≥3 events) 1
Sotorasib + panitumumab:
- Grade ≥3 treatment-related adverse events: 27% 1
- Higher than sotorasib monotherapy (11.6% grade ≥3 events) 1
Resistance Mechanisms
Acquired resistance to KRAS G12C inhibitors has been well-characterized and includes both on-target KRAS mutations and bypass pathway activation 1, 3, 4. The addition of EGFR inhibitors specifically addresses EGFR-mediated resistance, which is the predominant mechanism in colorectal cancer 2.
Clinical Pearls
- KRAS G12C mutations occur in approximately 17% of KRAS-mutant mCRC cases 1
- Testing should be performed via NGS panel to identify this actionable mutation 1
- Repeat molecular testing may be considered after targeted therapy to assess for acquired resistance mutations that could guide subsequent treatment 1
- Sotorasib exhibits non-linear, time-dependent pharmacokinetics with steady state reached within 22 days 2
- Food increases sotorasib AUC by 25%; however, the approved dosing does not require fasting 2