Phase 1/2 Study of Avutometinib (VS-6766) + Sotorasib With or Without Defactinib in KRAS G12C NSCLC Patients

Inclusion Criteria: * Male or female patients ≥ 18 years of age * Histologic or cytologic evidence of NSCLC * Known KRAS G12C mutation * Either exposed or not exposed to a KRAS inhibitor to be included in Part A (avutometinib + sotorasib + defactinib) and not exposed to KRAS inhibitor to be included in Part B (avutometinib + sotorasib + defactinib), Cohort 1 * Received at least 1 dose of a G12C inhibitor to be included in Part B, Cohort 2 (avutometinib + sotorasib + defactinib) * Must have received appropriate treatment with at least one prior systemic regimen, but no more than 2 prior regimens, for Stage 3B-C or 4 NSCLC * Measurable disease according to RECIST 1.1 * An Eastern Cooperative Group (ECOG) performance status ≤ 1 * Adequate organ function * Adequate recovery from toxicities related to prior treatments * Agreement to use highly effective method of contraceptive Exclusion Criteria: * Systemic anti-cancer therapy within 4 weeks of the first dose of study therapy * History of prior malignancy, with the exception of curatively treated malignancies * Major surgery within 4 weeks, minor surgery within 2 weeks (excluding placement of vascular access) * History of treatment with a direct and specific inhibitor of MEK * Exposure to strong CYP3A4 inhibitors or inducers within 14 days prior to the first dose and during the course of therapy * Symptomatic brain metastases requiring steroids or other local interventions. * Known SARS-Cov2 infection ≤28 days prior to first dose of study therapy * Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active * Active skin disorder that has required systemic therapy within the past year * History of rhabdomyolysis * Concurrent ocular disorders * Concurrent heart disease or severe obstructive pulmonary disease * Inability to swallow oral medications * Female patients that are pregnant or breastfeeding * Previously treated with sotorasib and were dose reduced due to toxicity