On January 16, the U.S. Food and Drug Administration (FDA) approved the KRAS G12C inhibitor sotorasib (Lumakras) with the monoclonal antibody panitumumab (Vectibix) for adult patients with KRAS G12C–mutated metastatic colorectal cancer, as determined by an FDA-approved test, who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
The FDA also approved the therascreen KRAS RGQ PCR Kit (QIAGEN GmbH) as a companion diagnostic device to aid in identifying patients with colorectal cancer whose tumors harbor KRAS G12C mutations and who may be eligible for the newly approved combination.
CodeBreaK 300
Efficacy was evaluated in CodeBreaK 300 (ClinicalTrials.gov identifier NCT05198934), a randomized, open-label, controlled trial in patients with KRAS G12C–mutated metastatic colorectal cancer who previously received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Mutations were prospectively identified in tumor tissue samples using the QIAGEN therascreen KRAS RGQ PCR kit. A total of 160 patients were randomly assigned 1:1:1 to receive either sotorasib at 960 mg orally once daily and panitumumab 6 at mg/kg intravenously every 2 weeks, sotorasib 2at 40 mg orally once daily and panitumumab at 6 mg/kg intravenously every 2 weeks, or investigator’s choice of standard of care trifluridine/tipiracil or regorafenib.
The major efficacy outcome measure was progression-free survival as evaluated by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1. Additional efficacy outcome measures included overall survival, overall response rate, and duration of response. The study was not statistically powered for overall survival. Median progression-free survival was 5.6 months (95% confidence interval [CI] = 4.2–6.3 months) in the sotorasib 960 mg/panitumumab arm and 2 months (95% CI = 1.9–3.9 months) in the standard-of-care arm (hazard ratio = 0.48, 95% CI = 0.3, 0.78, 2-sided P = .005). The final analysis of overall survival was not statistically significant. The overall response rate was 26% (95% CI = 15%–40%) in the sotorasib at 960 mg/panitumumab arm and 0% (95% CI: 0%–7%) in the standard-of-care arm. Median duration of response was 4.4 months (range = 1.9+–6+ months) in the sotorasib at 960 mg/panitumumab arm.
The final analysis of progression-free survival for patients assigned to the sotorasib at 240 mg/panitumumab arm compared to the standard-of-care arm was not statistically significant.
The most common adverse reactions (occurring in ≥ 20% of patients) for sotorasib at 960 mg/panitumumab were rash, dry skin, diarrhea, stomatitis, fatigue, and musculoskeletal pain. The most common grade 3 or 4 laboratory abnormalities occurring in two or more patients were decreased magnesium, decreased potassium, decreased corrected calcium, and increased potassium.
The recommended sotorasib dose is 960 mg orally once daily. The recommended panitumumab dose is 6 mg/kg administered as an intravenous infusion every 14 days until disease progression, unacceptable toxicity, or until sotorasib is withheld or discontinued. Administer the first dose of sotorasib before the first panitumumab infusion.
This review used the Real-Time Oncology Review pilot program, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
This application was granted Orphan Drug designation.
