The New England Journal of MedicineSotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C

The inhibitor sotorasib shows promise in combination therapy for metastatic CRC.

A recent phase 3 trial has investigated the potential of combining the KRAS G12C inhibitor, sotorasib, with the EGFR inhibitor, panitumumab, for treating patients with chemorefractory metastatic colorectal cancer. The study focused on patients with the KRAS G12C mutation, a mutation found in approximately 3 to 4% of patients with this type of cancer.

Study Design

• Phase 3, multicenter, open-label, randomized trial.
• Participants:
  • Patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor.
• Treatment groups:
  • 53 patients received sotorasib at a dose of 960 mg once daily plus panitumumab.
  • 53 patients received sotorasib at a dose of 240 mg once daily plus panitumumab.
  • 54 patients received the investigator’s choice of trifluridine–tipiracil or regorafenib (standard care).

Key Findings

• Median progression-free survival was 5.6 months (95% 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.
• 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).
• 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.

HCN Medical Memo
The trial found that both doses of sotorasib (960 mg and 240 mg) in conjunction with panitumumab led to a significant increase in PFS and response rate compared to standard care. The adverse events associated with the sotorasib–panitumumab combination were in line with expectations, with no new safety concerns emerging. Furthermore, there were only a few instances of treatment discontinuation due to adverse events.

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