Inclusion Criteria:

• Male or female patients ≥ 18 years of age with a life expectancy of at least 3 months.
• Histologic or cytologic evidence of NSCLC, without histological evidence of a small cell or neuroendocrine components, that are either metastatic (Stage 4) or locally advanced (Stage 3B-C) and unresectable (IASLC 8th edition).
• Patients must have a known somatic KRAS G12C mutation determined using a validated next-generation sequencing (NGS) test (tumor tissue or circulating tumor DNA [ctDNA]) prior to enrollment. Adequate material (as defined in the lab manual) must be available prior to study therapy to be used for central confirmation of KRAS mutation status. Central confirmation does not need to be completed prior to enrollment.
• The patient must have received prior therapy with a KRAS G12C inhibitor and experienced progressive disease.
• The patient must have received anti-programmed cell death protein 1 or anti-programmed death-ligand 1 immunotherapy (unless contraindicated) AND/OR platinum-based combination chemotherapy AND targeted therapy if actionable oncogenic driver mutations were identified (i.e., EGFR, ALK, and ROS1).
• The patient must have received appropriate treatment with at least 1 prior systemic regimen, but no more than 3 prior regimens, for Stage 3B-C or 4 NSCLC.
• The patient may have previously received adjuvant/neoadjuvant chemotherapy for earlier-stage disease. Adjuvant/neoadjuvant chemotherapy in early stages will not count as a prior regimen unless disease progression occurred during or within 6 months following adjuvant/neoadjuvant therapy.
• Measurable disease according to RECIST 1.1 with at least 1 measurable disease lesion.
• An Eastern Cooperative Group (ECOG) performance status ≤ 1.
• Must have adequate organ function defined by the following laboratory parameters:
  • Adequate hematologic function including: hemoglobin (Hb) ≥ 9.0 g/dL; platelets ≥ 100,000/mm^3; and absolute neutrophil count (ANC) ≥ 1500/mm^3. If a red blood cell transfusion has been administered the Hb must remain stable and ≥ 9 g/dL for at least 1 week prior to first dose of study therapy;
  • Adequate hepatic function: (i) total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 μmol/L) upon discussion with Medical Monitor; (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (or < 5 x ULN in patients with liver metastases);
  • Adequate renal function with creatinine clearance rate of ≥ 50 mL/min as calculated by the Cockcroft-Gault formula, or serum creatinine ≤ 1.5 x ULN;
  • International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation;
  • Albumin ≥3.0 g/dL (451 μmol/L);
  • Creatine phosphokinase (CPK) ≤ 2.5 x ULN;
  • Adequate cardiac function with left ventricular ejection fraction ≥ 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
• Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v5.0. Exceptions include alopecia and peripheral neuropathy Grade ≤ 2. Patients with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor.
• Male and female patients with reproductive potential agree to use a highly effective method of contraceptive during the trial and for at least 6 months following the last dose of study interventions.

Exclusion Criteria:

• Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy, or treatment with an investigational agent within 14 days of first receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 (C1D1) for chest radiation > 30Gy).
  • Note: palliative radiation, other than to target lesions, is permitted during the study except during the DLT assessment period. Patients receiving palliative radiation during the DLT assessment period will be replaced. Prior G12C therapy must be discontinued at least 6 days prior to Day 1 of study therapy for PK lead-in.
• Presence of other malignancy that could be mistaken for the malignancy under study during disease assessments.
• History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
• Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study therapy.
• Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants.
• Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy, or treatment with an investigational agent within 14 days of first receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 (C1D1) for chest radiation > 30Gy).
  • Note: palliative radiation, other than to target lesions, is permitted during the study except during the DLT assessment period. Patients receiving palliative radiation during the DLT assessment period will be replaced. Prior G12C therapy must be discontinued at least 6 days prior to Day 1 of study therapy for PK lead-in.
• Presence of other malignancy that could be mistaken for the malignancy under study during disease assessments.
• History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
• Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study therapy.
• Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants.
• Exposure to QT-prolonging medications within 14 days prior to the first dose and during the course of therapy. 
• Use of proton pump inhibitors (PPI) within 3 days and H2 receptor antagonists within 1 day prior to study Day 1.
• exposure to strong CYP3A4 inhibitors, inducers, or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy.
• Exposure to P-glycoprotein (P-gp) inhibitors or inducers or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy.
• Exposure to strong inhibitors or inducers of breast cancer resistance protein (BCRP) within 14 days prior to the first dose and during the course of therapy. 
• Exposure to CYP2C9 and CYP2D6 sensitive substrates with narrow therapeutic index during the course of therapy.
• Part A: Leptomeningeal metastases or any central nervous system (CNS) metastases. Part B: Leptomeningeal metastases or active CNS metastases 480 msec using Fridericia’s formula.
• Weight loss > 10% within 4 weeks prior to first dose of study therapy.
• Known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (clinical symptoms) ≤ 28 days prior to first dose of study therapy.
• Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy.
• Active skin disorder that has required systemic therapy within the past 1 year.
• History of rhabdomyolysis.
• History of interstitial lung disease (ILD) or pneumonitis.
• Concurrent ocular disorders:
  • Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes;
  • Patient 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.
  • Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA], myocardial infarction, cerebrovascular stroke or transient ischemic attack within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease. 22. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
  • Patients with a history of hypersensitivity to any of the active (avutometinib, adagrasib) or inactive (croscarmellose sodium, hydroxypropylmethylcellulose, lactose monohydrate, mannitol, magnesium stearate, microcrystalline cellulose) ingredients of the investigational products.
  • Female patients who are pregnant or breastfeeding.
  • Any other medical condition (e.g., cardiac, gastrointestinal, pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the investigator would place the patient at unacceptably high risk for toxicity.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 9/18/23 Questions regarding updates should be directed to the study team contact.