Background
Phase III open-label RCT (CodeBreaK 200); N=345 randomized; advanced KRAS-G12C-mutated NSCLC progressing after platinum chemotherapy and a PD-1/PD-L1 inhibitor; untreated/symptomatic brain mets excluded; crossover to sotorasib permitted.
Interventions and follow up
Arm A: Sotorasib 960mg PO daily
Arm B: Docetaxel 75mg/m2 IV Q3W
Primary endpoint: Progression-free survival by blinded independent central review
mFollow up: 17.7mo
Arm B: Docetaxel 75mg/m2 IV Q3W
Primary endpoint: Progression-free survival by blinded independent central review
mFollow up: 17.7mo
Results
mPFS: 5.6mo vs 4.5mo (A vs B), HR 0.66, 95% CI 0.51-0.86, P=.0017
ORR: 28% vs 13%
OS: No significant difference (not powered for OS; confounded by crossover)
ORR: 28% vs 13%
OS: No significant difference (not powered for OS; confounded by crossover)
Adverse events
Overall: Grade ≥3 treatment-related events 33% vs 40% (A vs B)
Serious treatment-related AEs: 11% vs 23%
Sotorasib (notable): Diarrhea, hepatotoxicity (↑ALT/AST)
Docetaxel (notable): Neutropenia, fatigue
Serious treatment-related AEs: 11% vs 23%
Sotorasib (notable): Diarrhea, hepatotoxicity (↑ALT/AST)
Docetaxel (notable): Neutropenia, fatigue
Conclusions
In previously treated KRAS-G12C-mutated advanced NSCLC, sotorasib significantly prolonged PFS vs docetaxel with a more favorable safety profile, supporting it as a targeted second-line option.
Key Limitations
Modest absolute PFS gain (~1mo); open-label; no OS benefit and high crossover; FDA ODAC questioned reliability of PFS data; comparator did not include docetaxel + ramucirumab.
Clinical Context
Sotorasib holds FDA accelerated approval for previously treated KRAS-G12C NSCLC (May 2021, based on CodeBreaK 100); EMA conditional approval 2022. CodeBreaK 200 was the confirmatory trial but FDA declined full approval. ESMO lists sotorasib as a later-line option after chemoimmunotherapy.