Sitravatinib Plus Pembrolizumab in Patients With Advanced Treatment-Naïve PD-L1+ Non-Squamous NSCLC

Inclusion Criteria: In order to be to be eligible to participate in this study, an individual must meet all of the following criteria: * Histologically or cytologically confirmed non-squamous NSCLC that is metastatic (Stage IV), recurrent, or unresectable locally advanced (Stage IIIB/IIIC) disease, not amenable to treatment with curative intent. * No prior systemic therapy for advanced disease. Prior chemotherapy for local or locally advanced disease is allowed if completed \>6 months prior to trial enrollment. Prior immunotherapy is not allowed. * PD-L1 ≥ 1% using the 22c3 PD-L1 IHC assay or a local assay performed in a CLIA facility * Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. * Life expectancy of at least 3 months. * Measurable disease as per RECIST v1.1 * Adequate bone marrow and organ function demonstrated by: * Absolute neutrophil count \>1,500/mm3 (1.5 × 10\^9/L). * Hemoglobin ≥ 8.0 g/dL not dependent on transfusion support. * Platelet count ≥ 75 × 10\^9/L (≥ 75,000 per mm3). * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5 × ULN without liver metastases; \< 5.0 x ULN if documented liver metastases * Serum total bilirubin ≤ ULN, or for patients with potential Gilbert's, direct bilirubin ≤ ULN * Calculated creatinine clearance ≥ 40 mL/min, using the Cockcroft-Gault formula. * Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment. * Completed informed consent process, including signing IRB approved informed consent form. * Willing to comply with clinical trial instructions and requirements. * Willing to undergo an on-treatment biopsy with an appropriate biopsy site identified prior to treatment initiation Exclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: * Symptomatic or untreated brain metastases ≥ 2cm in diameter. Patients with brain lesions that are adequately treated with local therapy (i.e. radiation therapy) and neurologically stable without the need for corticosteroids for at least 2 weeks prior to enrollment are allowed. Patients with brain lesions that are asymptomatic, smaller than 2cm, in non-critical regions of the brain and not requiring corticosteroids for at least 2 weeks prior to enrollment may be eligible after review with the Sponsor Investigator. * Leptomeningeal disease * Known mutations/alterations in EGFR, ROS1, ALK, or BRAF * Any prior treatment with checkpoint inhibitor therapy or other immunotherapy agents * Any prior treatment with therapy having the same mechanism of action as sitravatinib (e.g., tyrosine kinase inhibitor with a similar target profile or bevacizumab/ramucirumab) * Active or prior documented autoimmune disease within the past 2 years (note: patients with type 1 diabetes, vitiligo, Graves' disease, hypothyroidism due to an autoimmune condition only requiring hormone replacement, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded). * Active or prior immunocompromising conditions, including use of immunosuppressive medication within 2 weeks of enrollment. This does not include topical, intranasal or inhaled steroids with minimal systemic absorption or systemic corticosteroids at physiologic doses not to exceed 10mg/day of prednisone or equivalent. Use of higher dose corticosteroids for short/defined course (ie prophylaxis in patients with contrast dye allergy) is also allowed if indicated. * Uncontrolled HIV. Patients with HIV may be eligible if they meet the following criteria: * CD4+ T cell count\>350 cell/uL * No history of AIDS-defining opportunistic infection within the past 12 months * Currently tolerating treatment with ART for at least 4 weeks prior to enrollment, with HIV viral load \<400 copies/mL * Patients on specific ART drugs with possibility for drug-drug interaction with sitravatinib may be excluded (see appendix 5). * Active hepatitis C (HCV) infection. Patients with a history of HCV may be eligible if they have completed curative antiviral treatment with undetectable HCV viral load and liver function tests are otherwise within acceptable limits (as described in Section 4.5.2). Patients with chronic Hepatitis B (HBV) infection are not excluded if liver function is within acceptable limits, but should be evaluated for reactivation risk and started on suppressive antiviral therapy prior to enrollment if appropriate. * History of stroke or transient ischemic attack within the previous 6 months. * History of life threatening venous thromboembolic event (such as hemodynamically significant pulmonary embolism) or any arterial thrombotic event within the previous 6 months. Patients with non-life threatening venous thromboembolic events are not excluded and should be managed with anti-coagulation as per standard institutional practice. * Any of the following cardiac abnormalities: * Unstable angina pectoris within the past 6 months. * Congestive heart failure ≥ NYHA Class 3 within the past 6 months. * Prolonged QTc on electrocardiogram \>500 milliseconds. * Left ventricular ejection fraction (LVEF) \< 40%. * Uncontrolled hypertension (\>150mm Hg or \>100mm Hg diastolic) on multiple observations despite standard of care treatment * Major surgery within 4 weeks of the date of randomization. * History of significant hemoptysis or hemorrhage within 4 weeks of the date of randomization. * Known or suspected presence of another malignancy that could be mistaken for the malignancy under study during disease assessments. * Has received a live vaccine within 30 days prior to the first dose of trial treatment. * Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior to the date of randomization. * Breast-feeding or planning to breast-feed during the study or within 30 days following the last dose of sitravatinib and within 5 months following the last dose of pembrolizumab. * Any serious illness, uncontrolled inter-current illness, psychiatric illness, active or uncontrolled infection, or other medical history, including laboratory results, which, in the Investigator's opinion, would be likely to interfere with the patient's participation in the study, or with the interpretation of the results.