Selection Criteria:
* Patients must have pathologically confirmed Extensive Stage Small Cell Lung Cancer (ES-SCLC).
* No prior systemic therapy for the disease under study (ES-SCLC).
* Patients must have measurable disease according to Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.
* Patient must be ≥ 18 years of age.
* Patient must have an ECOG performance status of 0-1.
* Patient must have the ability to understand and willingness to sign a written informed consent document.
* Willing to provide archived tumor tissue (if sufficient tumor tissue available) and blood samples for research.
* Patient must have adequate organ function and marrow function as defined below, obtained ≤ 14 days prior to registration/randomization. No blood transfusions or growth factor therapy allowed within 7 days of screening labs.
* Absolute Neutrophil Count (ANC) ≥ 1500/microliter (mcL)
* Platelets ˃100,000/mcL
* Hemoglobin \>9.0 gram/deciliter (g/dL)
* Prothrombin time (PT) or international normalized ratio (INR) ≤ 1.5x Upper Limit Normal (ULN), and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5x ULN
* Serum Creatinine ≤ 2x ULN
* Creatinine clearance (CrCl) ≥ 50 milliliter/minute (mL/min)
* Urine Protein \<2+
* Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 2.5x ULN or ≤ 5x ULN for patients with liver metastasis
* Total Bilirubin ≤ 1.5x ULN or ≤ 3x ULN for patients with liver metastasis or suspected/documented Gilbert's disease
* Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used.
* Patient must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study, and for 120 days after the last dose of study drug(s).
* Patients must not have symptomatic central nervous system (CNS) metastases, CNS metastasis ≥ 1.5 cm, CNS radiation within 7 days prior to randomization, potential need for CNS radiation within the first cycle, or leptomeningeal disease.
* Patients must not have imaging during the screening period that shows:
1. Radiologically documented evidence of major blood vessel invasion (central pulmonary artery, central pulmonary veins, aorta, brachiocephalic artery, common carotid artery, subclavian artery, superior vena cava) or tumor invading organs (heart, trachea, esophagus, central bronchi \[not including segmental bronchi\]) or if there is a risk of esophagotracheal or esophagopleural fistula .
2. Radiographic evidence of major blood vessel encasement with narrowing of the vessel or intratumor lung cavitation or necrosis that the investigator determines will pose a significantly increased risk of bleeding.
* 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.
* Patients must not have major surgical procedures or serious trauma within 28 days prior to randomization or plans for major surgical procedures within 28 days after the first dose.
* Patients must not have history of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to randomization, including but not limited to:
1. Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots). Transient hemoptysis associated with diagnostic bronchoscopy is allowed.
2. Nasal bleeding/epistaxis (bloody nasal discharge is allowed).
3. 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.
* Patients must not have history of major diseases before randomization, specifically:
1. Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association (NYHA) classification ≥ Grade 2) or unstable vascular disease (e.g., aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 12 months prior to randomization, or other cardiac impairment that may affect the safety evaluation of the study drug (e.g., poorly controlled arrhythmias, myocardial ischemia).
2. History of any grade arterial thromboembolic event, Grade 3 and above venous thromboembolic event, as specified in National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 12 months prior to randomization.
3. History of esophageal gastric varices, severe ulcers, wounds that do not heal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months prior to randomization.
4. History of perforation of the gastrointestinal tract and/or fistula, history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection) within 6 months prior to randomization.
* Patients must not have poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy.
* Patients must not have prolongation of QTc interval \>480 msec
* Patients must not have active autoimmune or lung disease requiring systemic therapy (e.g., with disease modifying drugs, prednisone \>10 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to randomization.
* Patients must not have severe infection within 4 weeks prior to randomization, including but not limited to comorbidities requiring hospitalization, sepsis, or severe pneumonia; active infection requiring systemic anti-infective therapy within 2 weeks prior to randomization (excluding antiviral therapy for hepatitis B or C).
* Patients must not have uncontrolled pleural effusions, pericardial effusions, or ascites that is clinically symptomatic.
* Patients must not have history of non-infectious pneumonia requiring systemic corticosteroids, or current interstitial lung disease.
* Patients must not have active or prior history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, or chronic diarrhea.
* Patients must not have pre-existing peripheral neuropathy ≥ Grade 2 by CTCAE V5.0.
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration/randomization are eligible for this trial.
* Patient must not have received any live vaccine within 28 days prior to registration/randomization.
* Patients with a known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent are not eligible.
* Patients with any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the treatment according to the protocol are not eligible.
* Patients may not participate in any other therapeutic clinical trials, including those with other investigational agents not included in this trial during treatment on this study without prior approval from PrECOG.
