Tarloxotinib and Sotorasib for the Treatment of KRAS G12C-Mutated Unresectable or Metastatic Non-small Cell Lung Cancer

Inclusion Criteria

• Histologically confirmed diagnosis of squamous or non-squamous NSCLC with KRAS G12C mutation
• Unresectable or metastatic disease
• No available treatment with curative intent
• Must have previously received treatment with at a platinum-containing chemotherapy regimen. Additional prior therapies for metastatic KRAS G12C mutated NSCLC are also permitted
• Must have previously received at least one month trial of sotorasib or a therapy targeting KRAS G12C mutation with documented progression. If sotorasib dose from prior therapy was reduced for toxicity, patients that meet the above criteria are expected to receive study treatment at the reduced dose
• Must have measurable or evaluable disease as defined by RECIST 1.1
• Age > 18 years
• Life expectancy of at least 3 months
• Recovery from adverse effect of prior therapy at the time of enrollment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Absolute neutrophile count > 1000/mm^3
• Platelet count > 100,000 /mm^3
• Hemoglobin > 8 in the absence of transfusions for at least 2 weeks
• Total bilirubin < 1.5 x upper limit of normal (or < 3 x upper limit of normal [ULN] if associated with liver metastases or Gilbert’s disease)
• Aspartate transaminase (AST) or alanine transaminase (ALT) < 3 x ULN (or < 5x ULN if associated with liver metastases
• Creatinine clearance (CrCl) > 60 mL/min calculated by Chronic Kidney Disease Epidemiology Collaboration Formula (CKD-EPI) or Modification of Diet in Renal Disease (MDRD)
• Women of child-bearing potential agrees to use contraception while participating in the study and for a period of 6 months following termination of study treatment
• Completed informed consent process
• Willing to comply with clinical trial instructions and requirements

Exclusion Criteria

• Active, untreated brain metastases. Patients are eligible if brain metastases are previously treated and asymptomatic. Patients must be neurologically stable and on a stable or tapering dose of corticosteroids for at least 2 weeks prior to C1D1
• History of intestinal disease or major gastric surgery likely to alter absorption of study treatment or inability to swallow pills
• Congestive heart failure > New York Heart Association (NYHA) Class 3
• Corrected QT (QTc) > 480 milliseconds or family history of long QT syndrome
• Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be switched to alternative treatment prior to study entry
• Pregnancy or breast feeding
• Has known activating non-KRAS G12C oncogene-driver mutations, including but not limited to: ALK, ROS1, RET, BRAF, NTRK1/2/3, MET, EGFR
• Previously have received anti-EGFR or anti-human epidermal growth factor receptor 2(HER2) TKIs
• Previously have received anti-EGFR or anti-HER2 monoclonal antibodies
• Clinically active or symptomatic interstitial lung disease
• Known concurrently malignancy that is expected to require active treatment within 2 years or may interfere with the interpretation of the efficacy and safety outcomes of this study
• Infection requiring systemic treatment within 7 days prior to cycle 1 day 1
• Patients with known hypersensitivity to either tarloxotinib, sotorasib, or any of the ingredients.