Background
Phase III RCT (CodeBreaK 300) of 160 patients with chemorefractory metastatic colorectal cancer harboring the KRAS G12C mutation, previously treated with chemotherapy.
Interventions and follow up
Arm A: Sotorasib 960 mg PO daily + panitumumab
Arm B: Sotorasib 240 mg PO daily + panitumumab
Arm C (control): Investigator-choice trifluridine-tipiracil or regorafenib (standard care)
Primary endpoint: Progression-free survival (PFS, blinded independent review)
mFollow up: 7.8 mo
Arm B: Sotorasib 240 mg PO daily + panitumumab
Arm C (control): Investigator-choice trifluridine-tipiracil or regorafenib (standard care)
Primary endpoint: Progression-free survival (PFS, blinded independent review)
mFollow up: 7.8 mo
Results
mPFS: 5.6 mo (Arm A) vs 3.9 mo (Arm B) vs 2.2 mo (Arm C)
Arm A vs C: HR 0.49, 95% CI 0.30–0.80; P=.006
Arm B vs C: HR 0.58, 95% CI 0.36–0.93; P=.03
ORR: 26.4% (Arm A) vs 5.7% (Arm B) vs 0% (Arm C)
Arm A vs C: HR 0.49, 95% CI 0.30–0.80; P=.006
Arm B vs C: HR 0.58, 95% CI 0.36–0.93; P=.03
ORR: 26.4% (Arm A) vs 5.7% (Arm B) vs 0% (Arm C)
Adverse events
Grade ≥3 events (A vs B vs C): 35.8% vs 30.2% vs 43.1%
Notable toxicities (sotorasib-panitumumab): Skin-related toxic effects and hypomagnesemia were common, consistent with anti-EGFR therapy
Notable toxicities (sotorasib-panitumumab): Skin-related toxic effects and hypomagnesemia were common, consistent with anti-EGFR therapy
Conclusions
Sotorasib plus panitumumab significantly improved PFS versus standard care in chemorefractory KRAS G12C-mutated metastatic colorectal cancer, with the 960 mg dose showing the greatest activity.
Key Limitations
Modest sample size; short follow-up with immature OS; control arm of single-agent later-line standards; benefit confined to the small KRAS G12C subset (~3-4% of mCRC).
Clinical Context
CodeBreaK 300 supported FDA (2025) approval of sotorasib plus panitumumab for previously treated KRAS G12C-mutated mCRC and validated combined KRAS-G12C/EGFR blockade to overcome adaptive resistance. ESMO recognizes this combination as a later-line option in this subset, reinforcing the value of broad molecular profiling (including KRAS G12C) in mCRC.
References