Dr Boland on the Emergence of KRAS G12C Inhibitors in mCRC

Patrick Boland, MD, medical oncologist, Gastrointestinal Oncology team, Rutgers Cancer Institute of New Jersey, RWJBarnabas Health, discusses the development of therapeutic strategies targeting KRAS G12C mutations in colorectal cancer (CRC).

The emergence of KRAS G12C inhibitors have marked a significant development in the treatment of patients with varying tumor types, Boland begins. This novel drug class have already demonstrated efficacy in lung cancer and recently hasshown activity in CRC in the phase 3 CodeBreaK 300 trial (NCT05198934), he states.

The multicenter, open-label investigation evaluated the efficacy of the KRAS G12C inhibitor sotorasib (Lumakras) in combination with the EGFR inhibitor panitumumab (Vectibix) for patients with mCRC harboring KRAS G12C mutations who were chemorefractory. The study, which was presented at the 2023 ESMO Congress and concurrently published in the New England Journal of Medicine, demonstrated that the combination of panitumumab and sotorasib at both dose levels significantly improved progression-free survival (PFS) compared with investigator's choice of therapy: trifluridine/tipiracil (TAS-102) or regorafenib, Boland reports.

Patients randomly assigned to receive 960 mg of sotorasib/panitumumab achieved a median PFS of 5.6 months, while those receiving 240 mg had a median PFS of 3.9 months. In contrast, the investigator's choice arm had a median PFS of 2.2 months. The hazard ratios for disease progression or death were 0.49 (95% CI, 0.30-0.80; P = .006) for the 960-mg sotorasib/panitumumab arm and 0.58 (95% CI, 0.36-0.93; P = .03) for the 240-mg sotorasib/panitumumab arm, both favoring the combination therapies. Improvements in disease control rates were also observed. The median follow-up for the analysis was 7.8 months (range, 0.1-13.9) and the data cutoff date was June 19, 2023.

Although the study wasn't specifically powered for overall survival, the preliminary results appear promising and mature follow-up data is anticipated, Boland notes. Based on these data, panitumumab plus sotorasib could emerge as a new option for patients with KRAS G12C-mutated CRC in the future, Boland says. These encouraging results in CRC also underscore the potential of KRAS G12C inhibitors as a valuable addition to the therapeutic armamentarium in mCRC, he concludes.