Adagrasib with or without Nivolumab before Surgery for the Treatment of KRAS G12C Mutated Stage IB-IIIA Resectable Non-small Cell Lung Cancer

Inclusion Criteria

• Age ≥ 18 years.
• Histologically confirmed diagnosis of NSCLC (squamous or nonsquamous) with KRAS G12C mutation. * Diagnostic core biopsy specimens must be reviewed by a faculty pathologist at the enrolling/treating institution, and biopsy tissue must be available for further biomarker evaluation. If no archived tissue is available, patients will require a repeat biopsy prior to initiation of study treatment. * KRAS G12C mutation determined by any Clinical Laboratory Improvement Act (CLIA)-certified testing platform on patient tumor tissue or plasma sample.
• Stage IB-IIIA NSCLC * T2aN0, T3N0, T1-2N1, T3-4N1, T1-2N2. This includes T2aN0 tumors ≥ 3 cm. Subjects with N3 nodal involvement are not included.
• Primary resection option for potential cure as assessed by a faculty surgeon at treating institution.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Leukocytes ≥ 2,000/mm^3 (within the screening period).
• Absolute neutrophil count (ANC) ≥ 1000/mm^3 (within the screening period).
• Platelet count ≥ 100,000/mm^3 (within the screening period).
• Hemoglobin ≥ 9 g/dL (within the screening period).
• Creatinine ≤ 1.5 x institutional upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 60 mL/min (within the screening period).
• Total bilirubin ≤ 1.5 x institutional ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL) (within the screening period).
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]), and alkaline phosphatase ≤ 3 x institutional ULN (within the screening period).
• Pulmonary Function Testing to include diffusion capacity of the lung for carbon monoxide (DLCO) must be performed to determine feasibility of surgical resection.
• Women of child-bearing potential (WOCBP): * Agree to use contraception while participating in this study, and for a period of 6 months following last dose of adagrasib or nivolumab, as effects of these agents on the developing human fetus are unknown. Men whose partner is a WOCBP must also agree to use contraception during this period. * Negative pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within two weeks of registration. * Women must not be breastfeeding or plan to breastfeed for the duration of therapy or 6 months after.
• Completed informed consent process, including signing institutional review board (IRB)/ethics committee (EC)-approved informed consent form.
• Willing and able to comply with clinical trial instructions and requirements. Subjects must be competent to report adverse events (AEs), understand the drug dosing schedule, and use of medications to control AEs.

Exclusion Criteria

• NSCLC not amenable to curative intent resection based on evaluation by faculty surgeon at treating institution. * This includes any patient with pathologically confirmed N3 disease.
• Prior systemic treatment for lung cancer including chemotherapy, immune checkpoint inhibitor therapy, or a therapy targeting KRAS G12C mutation.
• Prior thoracic radiation.
• Any concurrent malignancies for which active therapy is being received. * Exceptions: non-melanoma skin cancers; in situ dysplasia of the bladder, gastric, breast, colon, or cervix.
• Brain metastases at time of screening. * All patients must have brain imaging prior to enrollment (MRI brain or CT brain with contrast preferred).
• Active or prior documented autoimmune or inflammatory disease as follows (Cohort B only): * Medically relevant autoimmune disease requiring systemic treatment within 2 years prior to the first dose of study treatment.
• Systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration (Cohort B only). Inhaled or topical steroids are permitted. * Adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Major surgery within 4 weeks prior to first dose of study treatment.
• History of allogeneic transplant or primary immunodeficiency.
• Uncontrolled human immunodeficiency virus (HIV) infection or acute or chronic hepatitis B or C infection. * Patients treated for hepatitis C with no detectable viral load and patients treated for HIV with no detectable viral load for at least 1 month while on a stable regimen of agents that are not strong inhibitors of CYP3A4 are permitted. * HIV testing is not required in absence of clinical suspicion of HIV.
• Any of the following cardiac abnormalities: * Unstable angina pectoris or myocardial infarction within the past 6 months. * Symptomatic or uncontrolled atrial fibrillation within the past 6 months. * Congestive heart failure ≥ New York Heart Association (NYHA) Class 3 within the past 6 months. * Corrected QT interval (QTc) ≥ 480 msec in screening electrocardiogram (ECG) measured using standard institutional method or history of familial long QT syndrome.
• Ongoing need for a medication with any of the following characteristics that cannot be switched to alternative treatment prior to study entry: Known risk of Torsades de Pointes; substrate of CYP3A with narrow therapeutic index; strong inducer or inhibitor of CYP3A and/or P-gp; strong inhibitor of BCRP; and proton pump inhibitors.
• History of stroke or transient ischemic attack within 6 months prior to first dose of study treatment.
• History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow oral medications.
• Underlying medical conditions that, in the Investigator’s opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.
• Women who are pregnant or nursing.
• Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.
• Receipt of a live vaccine within 30 days prior to first dose of study treatment.