Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Criteria:

- Documentation of Disease

- 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 FDA-approved assay done within a laboratory with CLIA, ISO/IEC,
CAP, or similar certification.

- Definition of Disease

- 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 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: 1) 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
2) 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.

- Prior Treatment

- No prior angiogenesis inhibitor therapy (i.e. bevacizumab or ramucirumab)

- Patients can have received prior MET inhibitor therapy

- Patients can have received prior 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

- 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

- Required Organ Function

- Adequate hematologic function defined as follows:

- Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3

- Platelets ≥ 100,000 cells/mm3

- Hemoglobin ≥ 9 g/d

- Adequate renal function defined as follows:

- 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 BSA is not required for eGFR)

- Urine protein < 2+ or 24-hour urine protein < 1.0g

- Adequate hepatic function defined as follows:

- 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)

- AST and ALT ≤2.5x institutional ULN. For patients with liver metastases,
AST and ALT ≤ 5 x ULN.

- Coagulation: PT or INR ≤ 1.5 ULN, and PTT or aPTT ≤ 1.5 x ULN (unless
abnormalities are unrelated to coagulopathy or prophylactic anticoagulation)

- Comorbid Conditions No history of interstitial lung disease requiring steroid
treatment

- Prior history of Grade ≥3 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, MI, CHF (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 GI bleeding within
6 months of therapy

- Must not have a history of arterial thromboembolic event, venous thromboembolic
event grade ≥ 3, CVA/TIA, 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, HBV, and/or 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 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 RNA levels above the lower limit of detection) are
excluded.

- Allergies o 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).