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 beincluded 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 ofvascular 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 firstdose 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 isactive

• 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