Sotorasib Plus Panitumumab May Improve Survival Outcomes for Chemorefractory Patients With KRAS G12C-Mutated Metastatic Colorectal Cancer

Results From the CodeBreaK 300 Trial

Marwan Fakih, MD, City of Hope Comprehensive Cancer Center, Duarte, California, shares insights on the latest results from the phase 3 CodeBreaK 300 trial, evaluating sotorasib plus panitumumab for patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer.

Dr Fakih concluded based on the overall survival trends in this study “that the combination of sotorasib 960 mg per day in combination with panitumumab should be a standard of care in the treatment of patients with metastatic colorectal cancer with KRAS G12C that have progressed on first-line and second-line therapies.”

Transcript:

Hi, my name is Marwan Fakih. I'm a professor of oncology at City of Hope in California. Today I would like to discuss a little bit the CodeBreaK 300 trial, which is a phase 3 clinical trial evaluating sotorasib plus panitumumab in patients with KRAS G12C mutations with colorectal cancer with metastatic disease that had progressed on prior therapy.

KRAS G12C occurs in approximately 4% of patients with metastatic colorectal cancer. This is a population with unmet need after failing oxaliplatin, fluoropyrimidine, irinotecan, and bevacizumab. The effective treatments in this patient population are typically limited to trifluridine-tipiracil, with or without bevacizumab, fruquintinib, or regorafenib. These agents do improve the overall survival, but the clinical benefits are somewhat still limited.

We know from prior studies that the inhibition of KRAS G12C with sotorasib is associated with clinical activity. However, monotherapy treatment with sotorasib is associated with approximately 10% overall response rate and a limited progression-free survival. The resistance to monotherapy with sotorasib is really related to the activation of EGFR, through phosphorylation of EGFR. And we know from prior phase 2 clinical data that the combination of sotorasib plus panitumumab is associated with a higher response rate, with very favorable median progression-free survival that exceeds 5 months based on the phase 2 data that showed promising activity of the combination of sotorasib and panitumumab.

The CodeBreaK 300 trial was conducted to see and prove that the combination of sotorasib plus panitumumab could be superior to the standard of care available for patients with KRAS G12C who have progressed on prior fluoropyrimidine, irinotecan, oxaliplatin, and also following bevacizumab in those patients. And this study was also conducted to evaluate 2 different doses of sotorasib, namely 960 mg dose level and 240 mg dose level. And this is really for dose optimization and given the fact that both dose levels had been associated with some activity in prior studies of sotorasib.

The study was a randomized phase 3 clinical trial of 160 patients. And what we have seen in this study is that the higher dose of sotorasib of 960 mg in combination with panitumumab had the most promising clinical activity on the study. The study was randomized 1-to-1-to-1, 53 patients with sotorasib-panitumumab at the higher dose, 53 at the lower dose of sotorasib, 240 [mg], with panitumumab, and 54 patients received investigator choice of treatment, which was trifluridine or regorafenib.

Now the overall response rate that had been reported previously on this study has been confirmed on further follow-up and slightly increased: 30.2% of patients receiving sotorasib at the 960 mg dose level plus panitumumab had an objective response and the median duration of that response was 10 months, which is very promising. When we look at the lower dose of 240 mg of sotorasib, the response rate was diminished at 7.5% and the response rate for the investigator arm was 1.9%, which is really consistent with the historic data of trifluridine and regorafenib.

The primary end point of this study was progression-free survival and that had been previously reported in the New England Journal of Medicine. And again, on further follow up, reconfirmed the same findings with a median progression-free survival of 5.7 months for the higher dose sotorasib 960 mg plus panitumumab versus 4.01 months for sotorasib at the lower dose level plus panitumumab. And again, in the control arm, we see similar data as we have seen historically of approximately 2 months median progression-free survival.

Now what we have reported recently in the Journal of Clinical Oncology is the median overall survival data and the overall survival analysis. The study was designed to report on the overall survival when 50% of the events have occurred, meaning 50% of patients had an event of death on the study. And what we have seen here is a very strong trend favoring the higher dose of 960 mg sotorasib plus panitumumab.  

At the time of the cut point, the median overall survival with the higher dose of sotorasib 960 mg plus panitumumab was not met, at the 240 mg dose level plus panitumumab was 11.9 months. And the overall survival for the investigator choice was 10.3 months. The hazard ratio was 0.7 for the higher dose of 960 mg [sotorasib] plus panitumumab, meaning that we have seen a trend towards a 30% prolongation in overall survival.

Now, the study was not powered to detect an overall survival benefit, and these results are not considered statistically significant, largely because the study is underpowered. However, I think the strong trend that we are seeing in overall survival is a testament that the improvements in PFS are meaningful in this patient population and confirms further, along with the overall response rate that we have seen, that the combination of sotorasib 960 mg per day in combination with panitumumab should be a standard of care in the treatment of patients with metastatic colorectal cancer with KRAS G12C that have progressed on first-line and second-line therapies, i.e. patients who have progressed on oxaliplatin, fluoropyrimidines, and irinotecans. Based on that, we see the approval by the FDA for this combination.

Thank you for your attention.

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