Sotorasib Plus Panitumumab for Patients With KRAS G12C-Mutated Chemorefractory Metastatic Colorectal Cancer

Filippo Pietrantonio, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, discusses results from the CodeBreaK 300 study which assessed sotorasib plus panitumumab in patients with KRAS G12C-mutated chemorefractory metastatic colorectal cancer. 

Transcript: 

Hello, my name is Filippo Pietrantonio, I'm a GI medical oncologist at the National Cancer Institute of Milan, in Italy, and today I will discuss with you the 2025 Journal of Clinical Oncology publication on the final analysis, overall survival analysis of the CodeBreaK300 study. 

As a reminder, CodeBreaK 300 was a randomized, phase 3 study conducted in patients with KRAS G12C-mutated and chemorefractory metastatic colorectal cancer. Patients were randomized to either 2 experimental arms with sotorasib 960 mg, which is the standard dose associated with panitumumab, or sotorasib at a lower dose, 240 mg, plus panitumumab or investigator’s choice arm with regorafenib or trifluridine plus tipiracil. The primary study end point was progression-free survival, and it was met at the initial analysis with a median progression-free survival of 5.6 months. And the overall survival data were immature at the time of the primary analysis, with only about 1/3 of deaths registered. 

In the final analysis, the median follow-up was nearly doubled, almost 14 months compared to 7.8 months at the initial analysis, and the hazard ratio in the comparison between sotorasib at the standard dose plus panitumumab versus investigator’s choice arm was 0.7, it was not statistically significant, but it was suggestive of an overall survival benefit and 30% risk-reduction of death. Of course, the median overall survival in the investigator’s choice arm was 10.3 months and 11.9 months in the investigator’s choice versus sotorasib at the lower dose plus panitumumab, and it was even not reached in the sotorasib 960 mg plus panitumumab arm, which is the standard dose and approved dose by the FDA. Basically, this life expectancy in this patient population with chemorefractory metastatic colorectal cancer is longer than expected with regorafenib or trifluridine plus tipiracil and therefore it mirrors the benefit of the use of this targeted option in this patient population.

Of course, one of the reasons why the results were not statistically significant is that CodeBreaK 300 was a relatively small phase 3 study, and it was not powered to detect a statistically significant overall survival difference. Also, one of the reasons explaining the lack of statistically significant results may be the crossover, since about 31% of patients initially randomized to the control arm subsequently received a KRAS G12C inhibitor, mostly in association with an anti-EGFR agent. In this publication we also performed the rank preserving structural failure time model, which is able to take into account the crossover in the control arm and actually the hazard ratio was improved to 0.65 in favor of sotorasib standard dose plus panitumumab versus investigator’s choice arm. 

Basically, even though there is a lack of statistically significant result, this study highlights that the benefit of the targeted agent and the targeted combination in this patient population with KRAS G12C-mutated metastatic colorectal cancer and is also enforcing the future use of this combination in association with chemotherapy, especially in earlier lines of the treatment.

The CodeBreaK 301 study is ongoing to compare FOLFIRI plus sotorasib and panitumumab versus FOLFIRI plus or minus bevacizumab in the first line setting. And I believe that this is the way to demonstrate any dramatic improvement in the outcomes of this patient population when we give targeted options in combination with chemotherapy. Thank you very much.

Source: 

Pietrantonio F, Salvatore L, Esaki T, et al. Overall survival analysis of the phase III CodeBreaK 300 study of sotorasib Plus panitumumab versus investigator's choice in chemorefractory KRAS G12C colorectal cancer. J Clin Oncol. Published online: April 11, 2025. doi: 10.1200/JCO-24-02026