Comparison of Sotorasib Plus Combination Therapy Versus Pembrolizumab Plus Combination Therapy in PD-L1 Negative KRAS p.G12C Positive Advanced Non-Squamous NSCLC

The primary objective of this study is to compare progression-free survival between subjects receiving a combination of sotorasib and chemotherapy versus pembrolizumab and chemotherapy in patients with advanced or stage IV nonsquamous non-small cell lung cancer that is PD-L1 negative and KRAS p.G12C positive. The study also aims to evaluate overall survival as a key clinical outcome. Secondary objectives include the comparison of the objective response rate between the two treatment arms. 5, 6

This clinical trial involves 354 participants diagnosed with nonsquamous non-small cell lung cancer. The study population includes both male and female individuals aged 18 years or older. Eligible participants possess Stage IV or advanced Stage IIIB/C disease characterized by a KRAS p.G12C mutation and negative PD-L1 expression. Selection requires a histologically or cytologically confirmed diagnosis and an ECOG performance status of 0 or 1. Individuals must have no prior history of systemic anticancer therapy in metastatic or non-curable settings. The primary objectives are:

• To compare progression-free survival between participants receiving sotorasib with chemotherapy and those receiving pembrolizumab with chemotherapy.
• To compare overall survival between these treatment groups.

This is a phase 3, multicenter, randomized, open-label study designed to evaluate the efficacy of a combination therapy in subjects with nonsquamous non-small cell lung cancer. The study compares the use of sotorasib with platinum doublet chemotherapy against pembrolizumab with chemotherapy as a frontline therapy. Eligible participants include adults with stage IV or advanced stage IIIB/C disease that is PD-L1 negative and positive for the KRAS p.G12C mutation, with an ECOG performance status of 0 or 1 and no prior systemic anticancer therapy in a metastatic setting. The primary endpoint is progression-free survival, determined by RECIST v1.1 via blinded independent central review. Secondary endpoints include overall survival and objective response. The estimated trial duration spans from November 2023 to June 2031.

Sotorasib is the investigational medicinal product administered via the oral route at a dosage of 9999 mg.

Pembrolizumab is used as a comparator treatment and is administered through intravenous infusion at a concentration of 9999 mg/ml.

The study includes several auxiliary medications. Pemetrexed is administered via intravenous injection at a dose of 9999 mg/m2. Carboplatin is also administered via intravenous injection at a dose of 9999 mg. Folic acid, provided as calcium folinate, is administered orally at a dosage of 9999 µg. Hydroxocobalamin is administered via intramuscular injection at a dose of 9999 µg. Dexamethasone, provided as betamethasone sodium phosphate, is administered orally at a dosage of 9999 mg. An unspecified antiemetic is also administered orally at a dosage of 9999 mg.

The assessment of efficacy in this study focuses on several key endpoints in subjects with nonsquamous non-small cell lung cancer that is PD-L1 negative and KRAS p.G12C positive. The primary endpoint is progression-free survival, which is defined as the time from randomization until disease progression or death from any cause. Progression is determined through an independent assessment of disease response using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by blinded reviewers.

Secondary efficacy parameters include:

• Overall survival, defined as the duration from randomization until death from any cause.
• Objective response, which is characterized by the best overall response, categorized as either complete response or partial response according to RECIST v1.1 and evaluated by blinded independent central review (BICR). A confirmatory scan is required 4 weeks after the initial response is observed for both complete and partial responses.