Episode 11: Sotorasib plus panitumumab increases PFS in metastatic KRAS G12C mutated colorectal cancer patients: CodeBreak 300

Prof Eric Van Cutsem from University Hospitals Leuven and Prof Marc Van den Eynde from Cliniques Universitaires Saint Luc will discuss the efficacy and toxicity of the combined treatment of the KRAS G12C inhibitor sotorasib in 2 different doses with the EGFR inhibitor panitumumab.

The CodeBreak 300 is the first phase 3 trial including chemorefractory patients with KRAS G12C mutation, randomized into two treatment arms: sotorasib dosed at 960 mg or 240 mg once daily, combined with panitumumab IV every two weeks. At the design of the study, the control arm consisted of the investigator’s choice of trifluridine/tipiracil or regorafenib in monotherapy.

The primary endpoint was PFS, with key secondary endpoints including ORR and OS. At a median follow-up of 7.8 months, the trial demonstrated clear positivity, with a median PFS increase of 5.6 months and 3.9 months for the 960 mg and 240 mg sotorasib-panitumumab combinations, respectively, compared to 2.2 months in the control arm, in line with historical data expectations.

These patients typically exhibit very low tumour responses to standard treatments, a fact confirmed by the CodeBreak 300 ORR, where the control arm’s ORR hovered around 0%. Interestingly, the high dose of sotorasib-panitumumab achieved an ORR of over 25%, with the Kaplan-Meier curve already showing separation for PFS and OS data.

The adverse events included skin toxicity and digestive toxicity, with a less pronounced difference between the doses of sotorasib than expected.

The experts debate that this phase 3 study included only a limited number of chemorefractory participants, utilizing PFS as a primary endpoint contrasts with the typical OS endpoint. They question whether further studies are necessary or if the data are robust enough to justify implementing the drug in treatment. Given the small patient niche and the considerable effort required to include 150 patients, obtaining OS difference data will be challenging.

The KRAS G12C mutation serves as a negative prognostic factor, occurring in approximately 3 to 4% of patients with metastatic colorectal cancer. As other KRAS G12C inhibitors undergo testing, experts are convinced that these patients are no longer undruggable.