Filippo Pietrantonio, MD, Instituto Nazionale dei Tumori, Milan, Italy, presented primary results from the phase 3 CodeBreaK 300 study, evaluating sotorasib plus panitumumab for the treatment of KRAS G12C-mutated metastatic colorectal cancer.

This study found that the combination of sotorasib plus panitumumab significantly improved progression-free survival among patients in this population, compared to the standard of care. Dr Pietrantonio concluded, “sotorasib at the standard dose of 960 mg plus panitumumab could be regarded as a potential new standard-of-care therapy" for this patient population.

These results were first presented at the 2023 European Society for Medical Oncology Annual Congress in Madrid, Spain.

Transcript:

Hello, everyone. My name is Filippo Pietrantonio. I am a GI medical oncologist at the National Cancer Institute of Milan in Italy. At ESMO 2023, I presented the results of the CodeBreaK 300 study. This study investigated sotorasib plus panitumumab in patients with KRAS G12C-mutated metastatic colorectal cancer. A little bit of background, KRAS^G12C mutations are found in approximately 3% of patients with metastatic colorectal cancer, so it's a quite uncommon molecular subgroup of patients. In previous studies, monotherapy with the KRASG12C-inhibitors achieved a modest overall response rate of approximately 10% percent in the CodeBreaK 100 study with sotorasib, which is an irreversible and selective KRASG12C-inhibitor.

Preclinical data showed that KRAS^G12C-inhibition causes a feedback reactivation of the RAS-MAP kinase pathway with accumulation of activated EGFR. There is a strong biological rationale to combine KRAS^G12C-inhibitors with anti-EGFR therapy in this molecular subgroup of patients to improve outcomes over monotherapy. And so, for example, in the CodeBreaK 101 Phase 1b study, the combination of sotorasib plus panitumumab achieved an overall response rate of 30%, which is promising in this patient population.

Based on these promising results, the CodeBreaK 300 study was designed as a global Phase 3 randomized, open-label and active-controlled trial. Main key eligibility criteria were chemorefractory in previous treatment with at least 2 lines of therapy and centrally-confirmed KRAS^G12C mutation. 160 patients were enrolled in this trial and randomized to either panitumumab plus sotorasib at the standard dose, 960mg daily, or panitumumab at a lower dose, 240 mg daily, or investigator's choice of therapy in the control arm with trifluridine-tipiracil or regorafenib.

The primary study end point was progression-free survival by blinded independent central review, and this end point was met with both sotorasib doses plus panitumumab significantly improved progression-free survival over investigator's choice of therapy. Also, overall response rate and disease control rate were increased with sotorasib, both a standard and lower dose, plus panitumumab versus investigator's choice. However, overall survival data were still immature at the time of the data cutoff, so follow-up of this study is ongoing.

Regarding the safety profile, the most common grade 3 or more treatment-related adverse events with sotorasib plus panitumumab combination were dermatitis acneiform and skin rash, hypomagnesemia, and diarrhea. And these adverse events were consistent with the safety profiles of both sotorasib and panitumumab. In the investigator's choice arm, the frequency of grade 3 or more treatment-related adverse events was 43%. While in the experimental arms, this frequency was 36% in the 960mg arm and 30% in the 240mg arm.

Based on these results, sotorasib at the standard dose of 960mg plus panitumumab could be regarded as a potential new standard-of-care therapy in patients with chemorefractory and KRAS G12C-mutated metastatic colorectal cancer. KRAS^G12C mutations are a positive predictive biomarker-validated therapeutic target, and hopefully this combination will be available soon for the treatment of our patients. Thank you very much.

Source:

Pietrantonio F, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mmutated metastatic colorectal cancer (mCRC): CodeBreaK 300 phase III study. Presented at ESMO Annual Congress; October 20-24, 2023; Madrid, Spain. LBA10