Tepotinib and Ivonescimab for the Treatment of Advanced or Recurrent METex14 Skipping Positive Non-small Cell Lung Cancer

Inclusion Criteria

• Patients must have pathologically confirmed non-small cell lung cancer. This includes, but is not limited, to histologies such as adenocarcinoma, squamous cell carcinoma, sarcomatoid carcinoma, and poorly differentiated carcinoma
• Patients must have documentation of MET exon 14 skipping present in their cancer using an Food and Drug Administration (FDA)-approved assay done within a laboratory with Clinical Laboratory Improvement Act (CLIA), International Organization for Standardization (ISO)/International Electrotechnical Commission (IEC), College of American Pathologists (CAP), or similar certification
• Patients must have advanced or recurrent disease * Advanced disease is defined as stage IV disease or stage IIIB/C disease not amenable to local therapy such as radiation or surgery
• Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• Must not have other known actionable oncogenic alterations, such as (but not limited to) EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, ROS1 gene rearrangement, RET gene rearrangement, NTRK rearrangement, HER2 mutation, KRAS activating mutations, and BRAF V600E mutation
• Must not have leptomeningeal disease or brain metastases unless: * Metastases have been locally treated and have remained clinically controlled and asymptomatic for at least 3 days following the stereotactic radiation and/or 14 days following whole brain radiation, and prior to sub-study randomization, AND * Participant has no residual neurological dysfunction and has been off corticosteroids for at least 24 hours prior to start of study therapy ** Small/asymptomatic brain metastasis for which stereotactic radiation is indicated must be treated
• No prior angiogenesis inhibitor therapy (i.e. bevacizumab or ramucirumab)
• Patients can have received prior MET inhibitor therapy
• Patients can have received prior immune checkpoint inhibitor (ICI) therapy
• If applicable, patients must have progressed on their most recent line of therapy * Must have not had prior systemic therapy within 21 days of the start of protocol therapy * Must not have received radiation therapy within 7 days of starting protocol therapy
• Age ≥ 18
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Not pregnant and not nursing
• Female patients of childbearing age must have negative serum pregnancy test results before randomization
• Female patient of childbearing potential having sex with an unsterilized male partner must agree to use a highly effective method of contraception from the beginning of screening until 90 days after the last dose of ivonescimab or until 1 week after last dose of tepotinib (whichever is longer)
• Unsterilized male patient having sex with a female partner of childbearing potential must agree to use an effective method of contraception from the beginning of screening until Day 90 after the last dose of ivonescimab
• Absolute neutrophil count (ANC) ≥ 1,500 cells/mm^3
• Platelets ≥ 100,000 cells/mm^3
• Hemoglobin ≥ 9 g/dl
• Creatinine clearance (CrCL) of ≥ 50 mL/min by the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥ 50 mL/min using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (adjustment by body surface area [BSA] is not required for eGFR)
• Urine protein < 2+ or 24-hour urine protein < 1.0g
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (patients with known Gilbert's disease who have bilirubin level ≤ 3 x ULN may be enrolled)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x institutional ULN. For patients with liver metastases, AST and ALT ≤ 5 x ULN
• Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5 ULN (unless abnormalities are unrelated to coagulopathy or prophylactic anticoagulation)
• Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN (unless abnormalities are unrelated to coagulopathy or prophylactic anticoagulation)
• No history of interstitial lung disease requiring steroid treatment
• Prior history of grade ≥ 3 immune-related adverse event (irAE)
• Must not have evidence of major blood vessel invasion or tumor invading into organs or risk of esophagotracheal or esophagopleural fistula
• Must not have active autoimmune or lung disease requiring systemic therapy (prednisone ≤ 10mg allowed) within 2 years of treatment
• Poorly controlled hypertension with repeated systolic blood pressure ≤ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy
• Severe infection within 4 weeks prior to randomization, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection (as determined by the investigator) requiring systemic anti-infective therapy within 2 weeks prior to randomization (excluding antiviral therapy for hepatitis B or C)
• Active or prior history of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, or chronic diarrhea)
• Must not have a history of unstable angina, myocardial infarction (MI), congestive heart failure (CHF) (New York Heart Association [NYHA] grade ≥ 2) requiring hospitalization in the preceding 6 months
• Must not have a history of gastric or esophageal varices, severe ulcers, or wounds that do not heal, or fistulas, or abscesses, or acute gastrointestinal (GI) bleeding within 6 months of therapy
• Must not have a history of arterial thromboembolic event, venous thromboembolic event grade ≥ 3, cerebrovascular accident (CVA)/transient ischemic attack (TIA), hypertension (HTN) crisis or HTN encephalopathy within 6 months of therapy
• Must not have a history of bleeding tendencies or coagulopathy or clinically significant bleeding symptoms or risk within 4 weeks of therapy * Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots) * Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed * Nasal bleeding/epistaxis (bloody nasal discharge is allowed) * Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to randomization is not allowed. The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• For patients with known HIV, hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infection: * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * Patients with active hepatitis B are required to have stable or declining levels of hepatitis B deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR) on appropriate anti-viral therapy with acceptable tolerability for one month prior to randomization * All patients with active hepatitis C (hepatitis C virus [HCV] antibody positive with HCV ribonucleic acid [RNA] levels above the lower limit of detection) are excluded
• No history of allergic reaction to the study agent(s), compounds of similar chemical or biologic composition to the study agent (s) (or any of its excipients)