Defactinib, Avutometinib and Nivolumab for the Treatment of Anti-PD1 Refractory LKB1-Mutant Advanced Non-Small Cell Lung Cancer

Exclusion Criteria

• •Patients who have had systemic therapy within 3 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• •Patients who are receiving any other investigational agents
• •Patients with unstable or symptomatic brain metastasis or known leptomeningeal disease. Asymptomatic brain metastases are allowed if they meet the following criteria:
• •* Have been treated and have been stable for greater than or equal to 4 weeks as documented by radiologic imaging
• •* Have not required increasing doses of corticosteroids within 2 weeks prior to study treatment
• •Patients with history of pre-existing auto-immune conditions that would pose a higher risk for toxicity with nivolumab will be excluded
• •Patients who experienced serious auto-immune toxicity with prior immune checkpoint inhibitor therapy
• •History of allergic reactions attributed to compounds of similar chemical or biologic composition to avutometinib or defactinib
• •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• •Known hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection that is active and/or requires therapy
• •Active skin disorder that has required systemic therapy within the past 1 year. Surgically removed early stage skin cancers are allowed. Topical creams are allowed as well
• •History of rhabdomyolysis
• •Concurrent ocular disorders:
• •* Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes
• •* Patients with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure \> 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO
• •* Patients with active or chronic, visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions
• •Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease
• •Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism should be converted to low-molecular-weight heparin (LMWH) or direct oral anticoagulants (DOACs). Exposure to medications (with or without prescriptions), supplements, herbal remedies, or foods with potential for drug-drug interactions with defactinib within 14 days prior to the first dose of avutometinib or defactinib and during the course of therapy, including:
• •* Strong CYP3A4 inhibitors or inducers, strong CYP2C9 inhibitors or inducers, strong P-glycoprotein (P-gp) inhibitors or inducers
• •Patients with a known "treatable driver mutation" with FDA approved targeted therapy (such as EGFR, ALK, ROS1, NTRK, BRAF, RET, MET exon 14, HER2). The exception is KRAS as listed in the inclusion section
• •History of prior malignancy within past 2 years prior to study entry, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression
• •Female patients who are pregnant or breastfeeding