The FDA has granted approval to sotorasib (Lumakras), combined with panitumumab (Vectibix), for the treatment of adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC) who have previously undergone fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This decision marks a significant advancement in targeted therapy for a subset of mCRC patients with limited treatment options.
The approval is based on data from the Phase 3 CodeBreaK 300 trial (NCT05198934), a randomized, open-label, active-controlled study. The trial evaluated the efficacy and safety of sotorasib in combination with panitumumab compared to standard of care (SOC) in patients with chemorefractory KRAS G12C-mutated mCRC.
CodeBreaK 300 Trial Results
The CodeBreaK 300 trial randomized 160 patients 1:1:1 to receive either:
- Sotorasib 960 mg orally once daily plus panitumumab 6 mg/kg intravenously every 2 weeks (n=53)
- Sotorasib 240 mg orally once daily plus panitumumab 6 mg/kg intravenously every 2 weeks (n=53)
- Investigator's choice of trifluridine/tipiracil or regorafenib (standard care; n=54)
The primary endpoint of the study was progression-free survival (PFS), assessed by blinded independent central review according to RECIST 1.1 criteria. Key secondary endpoints included overall survival (OS), objective response rate (ORR), and duration of response (DOR).
At a median follow-up of 7.8 months, patients receiving 960 mg of sotorasib with panitumumab achieved a median PFS of 5.6 months (95% CI, 4.2 to 6.3) compared to 2.0 months (95% CI, 1.9 to 3.9) in the standard care arm (HR, 0.48; 95% CI, 0.3 to 0.78; 2-sided P = .005). The ORR was 26% (95% CI, 15% to 40%) in the sotorasib 960 mg arm and 0% (95% CI, 0% to 7%) in the standard care arm. Median DOR in the combination arm was 4.4 months (range, 1.9+ to 6+).
While the study was not statistically powered for OS, there was a trend towards improved overall survival in the sotorasib plus panitumumab arm. The final analysis of PFS for the sotorasib 240 mg plus panitumumab arm compared to the SOC arm was not statistically significant.
Safety Profile
Grade 3 or higher treatment-related adverse events were reported in 35.8% of patients in the 960 mg sotorasib arm, 30.2% in the 240 mg sotorasib arm, and 43.1% in the standard care arm. The most common adverse events in the sotorasib/panitumumab arms were skin-related toxicities and hypomagnesemia.
Companion Diagnostic
Alongside the approval of the drug combination, the FDA also approved the therascreen KRAS RGQ PCR Kit (QIAGEN GmbH) as a companion diagnostic device. This kit will assist in identifying patients with CRC whose tumors harbor KRAS G12C mutations and who may be candidates for treatment with sotorasib and panitumumab.
Clinical Implications
"In metastatic colorectal cancer, KRAS mutations are historically associated with worse mortality rates and inferior outcomes compared to non-mutated tumors, and standard treatment options have shown minimal benefit," said Marwan G. Fakih, MD, a primary investigator in the CodeBreaK 300 study and co-director of the Gastrointestinal Cancer Program at City of Hope. "The CodeBreaK 300 study showed superior progression-free survival compared to the investigated standard of care and represents a clinically meaningful benefit for patients with KRAS G12C-mutated metastatic colorectal cancer."
