This study will assess the safety and efficacy of avutometinib (VS-6766) monotherapy or VS-6766 in combination with defactinib in subjects with recurrent Non-small cell lung cancer.

This is a multicenter, open-label Phase 2 study designed to evaluate safety and tolerability and efficacy of avutometinib (VS-6766) versus avutometinib (VS-6766) in combination with defactinib in subjects with KRAS and BRAF mutant NSCLC following treatment with an appropriate platinum-based regimen and an approved immune checkpoint inhibitor (CPI).

Inclusion Criteria:

• Male or female subjects ≥ 18 years of age
• Histologic or cytologic evidence of NSCLC
• Known KRAS or BRAF mutation
• The subject must have received appropriate prior therapy
• 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 (excluding placement of vascular access)
• History of treatment with a direct and specific inhibitor of MEK, KRAS or BRAF except for treatment of BRAF V-600E mutant NSCLC
• Exposure to strong CYP2C9 and CYP3A4 inhibitors or inducers within 7 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
• Active skin disorder that has required systemic therapy within the past 1 year
• History of rhabdomyolysis
• Concurrent ocular disorders
• Concurrent heart disease or severe obstructive pulmonary disease
• Subjects with the inability to swallow oral medications