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Sotorasib + Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

Compared with standard care in 160 patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C, sotorasib plus panitumumab increased progression-free survival, researchers report, with only expected toxic effects and few treatment discontinuations.

In the phase 3 CodeBreaK 300 trial, patients were randomized to the KRAS G12C inhibitor sotorasib 240 mg or 960 mg once daily plus the epidermal growth factor receptor (EGFR) inhibitor panitumumab or to the investigators’ choice of trifluridine–tipiracil or regorafenib (standard care). Based on a primary endpoint of progression-free survival, the study showed the following: “After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib–panitumumab and 240-mg sotorasib–panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib–panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P=0.006), and the hazard ratio in the 240-mg sotorasib–panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P=0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib–panitumumab, 240-mg sotorasib–panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib–panitumumab.”

Editorial: “It will be important to see the final overall survival results in this population of patients with refractory metastatic colorectal cancer,” writes an editorialist. “Mature data from this trial and data from KRYSTAL-10 will provide much-needed insight. KRYSTAL-10 is a phase 3 randomized trial in which second-line treatment with the KRAS G12C inhibitor adagrasib in combination with the EGFR antibody cetuximab is being compared with standard chemotherapy in the assessment of overall survival and progression-free survival (primary end points) among patients with advanced solid tumors with KRAS G12C mutation (NCT04793958). The CodeBreaK 300 trial is an exciting first step for targeting KRAS in colorectal cancer, and we look forward to continuing to refine the therapeutic approach against KRAS-mutated colorectal cancers with KRAS G12C inhibitors, new RAS inhibitors, and a growing understanding of therapy resistance.”

Source: New England Journal of Medicine