Sotorasib and Combination Therapy Versus Standard Chemotherapy in Treatment-Naïve Patients with KRAS p.G12C-Mutated Metastatic Colorectal Cancer

The primary objective of this study is to compare progression-free survival (PFS) between an experimental regimen and a control regimen in treatment-naïve subjects with metastatic colorectal cancer harboring a KRAS p.G12C mutation. The secondary objectives include:

• Comparison of overall survival (OS) between the two study arms.
• Evaluation of additional efficacy measures.
• Assessment of objective response rate (ORR).
• Evaluation of safety and tolerability profiles.
• Characterization of the pharmacokinetics of sotorasib.

This clinical trial involves 200 participants diagnosed with metastatic colorectal cancer. The study population includes both male and female individuals who are treatment-naïve and possess a confirmed KRAS p.G12C mutation. Eligible subjects must be at least 18 years of age, or the legal age of majority within their respective country. Participants are required to have an Eastern Cooperative Oncology Group Performance Status of ≤ 1 and a life expectancy exceeding six months. Inclusion necessitates pathologically documented adenocarcinoma with measurable disease according to RECIST v1.1 criteria. Furthermore, subjects must demonstrate adequate hematologic and end-organ function, alongside the ability to maintain oral medication adherence.

This Phase 3, multicenter, randomized, open-label, active-controlled study is designed to evaluate the efficacy of sotorasib, panitumumab, and FOLFIRI compared to FOLFIRI with or without bevacizumab in treatment-naïve subjects diagnosed with metastatic colorectal cancer harboring a KRAS p.G12C mutation. The primary objective is to compare progression-free survival between the experimental and control arms. The study includes a screening visit to confirm the presence of the specific mutation and assess measurable disease via RECIST v1.1 criteria. Following randomization, subjects receive their assigned therapeutic regimen. The study is estimated to conclude by August 31, 2031. Secondary endpoints include overall survival, objective response rate, duration of response, and disease control rate. Clinical assessments are conducted to monitor treatment-emergent adverse events and pharmacokinetics.

The experimental regimen consists of Sotorasib administered via oral use at a dose of 960 mg.

Panitumumab is administered via intravenous use at a dosage of 6 mg/kg.

The treatment includes fluorouracil, which is provided through intravenous use at a dose of 2800 mg/m².

Irinotecan hydrochloride trihydrate is administered via intravenous use at a dose of 180 mg/m².

Calcium folinate is administered via intravenous use at a dose of 400 mg/m².

The comparator treatment consists of bevacizumab, which is administered via intravenous use at a dose of 5 mg/kg.

The primary efficacy endpoint is progression-free survival, defined as the interval from randomization until disease progression or death from any cause. Disease progression is determined through blinded independent central review utilizing Response Evaluation Criteria in Solid Tumors version 1.1.

Secondary efficacy parameters include:

• Overall survival, measured as the time from randomization until death from any cause.
• Objective response rate, representing the proportion of complete response and partial response. Confirmatory repeat assessments are required at least 4 weeks after initial response detection.
• Duration of response, defined as the time from the first documentation of an objective response until disease progression or death.
• Disease control rate, calculated as the proportion of complete response, partial response, and stable disease. A minimum interval of 7 weeks from randomization is required to determine stable disease.
• Time to response, measured from randomization to the first documentation of an objective response.
• Depth of response, assessed as the best percentage change from baseline in the sum of lesion diameters.
• Early tumor shrinkage, defined as achieving at least a 30% reduction in tumor size at the first post-baseline assessment, occurring at least 7 weeks from randomization.
• Investigator-assessed parameters for progression-free survival, objective response rate, duration of response, disease control rate, time to response, depth of response, and early tumor shrinkage.
• Pharmacokinetic parameters of sotorasib, including maximum plasma concentration and pre-dose concentrations.