Background
Phase 1–2 open-label non-randomized trial. Heavily pretreated patients with KRAS G12C-mutated metastatic colorectal cancer. KRAS G12C occurs in ∼3% of mCRC. Two cohorts: monotherapy (adagrasib 600 mg bid, n=44) and combination (adagrasib + cetuximab, n=32). Rationale for combination: preclinical data showing KRAS G12C inhibition triggers adaptive feedback via EGFR reactivation, which can be blocked by anti-EGFR therapy. Median prior lines of therapy: 3.
Interventions and follow up
Arm A (monotherapy): Adagrasib 600 mg PO bid continuously until disease progression or unacceptable toxicity (n=44; 43 evaluable)
Arm B (combination): Adagrasib 600 mg PO bid + cetuximab 400 mg/m² IV loading then 250 mg/m² IV weekly (or 500 mg/m² q2wk), until disease progression or unacceptable toxicity (n=32; 28 evaluable; non-randomized)
Primary endpoint: Objective response (CR+PR) per RECIST 1.1 and safety for each cohort
mFollow up: 20.1 months (monotherapy), 17.5 months (combination)
Arm B (combination): Adagrasib 600 mg PO bid + cetuximab 400 mg/m² IV loading then 250 mg/m² IV weekly (or 500 mg/m² q2wk), until disease progression or unacceptable toxicity (n=32; 28 evaluable; non-randomized)
Primary endpoint: Objective response (CR+PR) per RECIST 1.1 and safety for each cohort
mFollow up: 20.1 months (monotherapy), 17.5 months (combination)
Results
ORR (monotherapy): 19% (8/43, 95% CI 8–33%)
mPFS (monotherapy): 5.6 months (95% CI 4.1–8.3)
mDoR (monotherapy): 4.3 months
ORR (combination): 46% (13/28, 95% CI 28–66%)
mPFS (combination): 6.9 months (95% CI 5.4–8.1)
mDoR (combination): 7.6 months
mPFS (monotherapy): 5.6 months (95% CI 4.1–8.3)
mDoR (monotherapy): 4.3 months
ORR (combination): 46% (13/28, 95% CI 28–66%)
mPFS (combination): 6.9 months (95% CI 5.4–8.1)
mDoR (combination): 7.6 months
Adverse events
Overall: Grade 3–4 treatment-related AEs 34% (monotherapy) vs 16% (combination); no grade 5 AEs in either cohort
GI (monotherapy): Most common grade ≥3 nausea, vomiting, diarrhea
Dermatologic/electrolyte (combination): Most common any grade skin toxicity (acne, rash, paronychia), hypomagnesemia, diarrhea
GI (monotherapy): Most common grade ≥3 nausea, vomiting, diarrhea
Dermatologic/electrolyte (combination): Most common any grade skin toxicity (acne, rash, paronychia), hypomagnesemia, diarrhea
Conclusions
Adagrasib monotherapy produced an ORR of 19% in KRAS G12C mCRC — modest but the first prospective signal of activity for a KRAS inhibitor in CRC. The adagrasib + cetuximab combination produced an ORR of 46%, roughly doubling response rate and extending mPFS to 6.9 months, validating the adaptive feedback hypothesis and establishing combination therapy as the preferred approach in this population.
Key Limitations
Non-randomized, uncontrolled design — efficacy cannot be formally compared between cohorts or against historical controls. Small sample sizes (43 and 28 evaluable patients). ORR for monotherapy (19%) is significantly lower than for adagrasib in NSCLC (43%), reflecting greater adaptive resistance in CRC. KRAS G12C affects only ∼3% of mCRC. Long-term OS not yet mature. RAS wild-type status of the cetuximab-combination cohort limits generalizability (RAS-mutant patients and those with prior anti-EGFR were excluded from the combination cohort).
Clinical Context
KRYSTAL-1 CRC data led to FDA accelerated approval of adagrasib + cetuximab for KRAS G12C mCRC in August 2023. The combination (not monotherapy) is now the standard approach for KRAS G12C mCRC. The parallel CodeBreaK 300 trial (sotorasib + panitumumab) similarly established KRAS G12C inhibition + anti-EGFR as the standard of care in this biomarker-selected setting. First-line trials (KRYSTAL-10) are ongoing.