Sotorasib and panitumumab demonstrate clinically meaningful benefit in KRAS G12C-mutated metastatic colorectal cancer

Dr Filippo Pietrantonio - ‎The National Cancer Institute of Milan, Milan, Italy

We know that KRAS G12C mutations are found in approximately 3% of patients with metastatic colorectal cancer. In the CodeBreaK 100 study monotherapy with sotorasib, which is an irreversible and selective KRAS G12C inhibitor, achieved an overall response rate of 10%. However, preclinical data showed that KRAS G12C inhibition is associated with feedback reactivation of the EGFR/Ras/MAP kinase pathway and so there is a strong biological rationale to combine a KRAS G12C inhibitor with anti-EGFR therapy. So, for example, preliminary activity data of the CodeBreaK 101 study showed an overall response rate of 30% which is quite promising with the combination of sotorasib plus panitumumab.

This was the reason why the CodeBreaK 300 study was designed as a global randomised and active control phase III study. This study enrolled patients with chemo-refractory metastatic colorectal cancer and centrally confirmed KRAS G12C mutation. 160 patients were randomised to either panitumumab plus sotorasib at the standard dose of 960mg daily or panitumumab plus sotorasib at a lower dose of 240mg daily or investigator’s choice therapy with trifluridine/tipiracil or regorafenib.

The primary study endpoint was progression free survival and the trial met its primary endpoint for superior PFS with both sotorasib doses, the 960mg and 240mg, plus panitumumab versus investigator’s choice. Also, the overall response rate and the disease control rate were higher in the sotorasib plus panitumumab combinations versus investigator’s choice. The safety profile of these combinations was quite tolerable with no new safety concerns, no treatment related deaths.

The most frequent grade 3 or more treatment related adverse events with sotorasib plus panitumumab combinations were skin rash, hypermagnesemia, dermatitis acneiform and diarrhoea but they were consistent with the safety profiles of panitumumab and sotorasib.

Of course, at the time of the primary analysis, the overall survival data were immature so continued follow-up of the trial is ongoing and updated results will be provided in the future. But, based on these results, sotorasib at the dose of 960mg daily plus panitumumab may represent a potential new standard of care therapy for patients with chemo-refractory KRAS G12C mutated metastatic colorectal cancer. This is a small molecular subgroup with a high unmet need so it’s important to have as soon as possible this treatment option for our patients. Thank you very much.