Phase II Randomized Trial of Carboplatin+Pemetrexed+Bevacizumab+/- Atezolizumab in Stage IV NSCLC

Inclusion Criteria:

   - Must have histologically or cytologically confirmed stage IV non-squamous non-small
   cell lung cancer

   - Must have either tumors that harbor an EGFR mutation in exon 19 or exon 21, or must be
   never smoker wild-types. Never smoker wild-types are defined as patients with tumors
   without an ALK or ROS1 rearrangement, and are not harboring any EGFR mutation (this
   includes exons 19 or 21, exon 20, and any other rare EGFR mutations). Never smoker
   wild-type patients must have smoked less than 100 cigarettes in a lifetime. Patients
   with an EGFR mutation in exon 19 or 21 may be included irrespective of their smoking
   history. If a patient whose tumor originally had an exon 19 or 21 mutation develops a
   secondary activating or sensitizing mutation in exon 18-21 as a result of resistance
   to EGFR TKI therapy, then that patient is eligible. If tissue-based testing for EGFR
   mutation status is not available, blood-based EGFR testing that confirms presence of a
   mutation in exon 19 or 21 is acceptable, and these patients may be included in the
   stud

   - Must have measurable disease by CT or MRI, defined as at least one lesion that can be
   accurately measured in at least one dimension in accordance with RECIST criteria v 1.1

   - Tumors that harbor an EGFR exon 19 or exon 21 mutation must have received prior
   treatments with one or more TKIs. A minimum washout period of 3 days is required to
   begin treatment in this trial. Patients who are never smoker wild-types must be
   treatment naïve

   - Must be chemotherapy, anti-VEGF therapy alone, and immunotherapy naive, with the
   exception of prior oral TKIs which are required for EGFR mutated patients. Patients
   who have received prior anti-VEGF therapy in combination with a TKI for advanced stage
   EGFR-mutated disease may be included. The number of prior oral TKIs and duration of
   use is neither specified nor limited.

   - History of treated asymptomatic CNS metastases are eligible, provided they meet all of
   the following criteria:

      - No ongoing requirement for corticosteroids as therapy for CNS disease

      - No stereotactic radiation within 7 days or whole-brain radiation within 14 days
      prior to randomization

      - No clinical evidence of interim progression between the completion of
      CNS-directed therapy and the screening radiographic study

      - New asymptomatic CNS metastases detected at the screening scan must be ≤1 cm in
      size with no prior radiation therapy. These patients may then be eligible without
      the need for an additional brain scan prior to randomization, if all other
      criteria are met

   - May have received curative intent therapy (adjuvant therapy or therapy for locally
   advanced NSCLC), if this therapy was completed greater than 1 year from entry into the
   trial

   - Age > 18 years

   - ECOG performance status of 0 or 1

   - Must have normal organ and marrow function as defined below. The use of G-CSF should
   follow standard recommendations and physician discretion. If blood transfusion is
   performed for achieving hemoglobin levels, the levels should stay at ≥ 9.0 mg/ml for
   at least a week after transfusion.

Absolute neutrophil count > 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets > 100,000/mcL Total
bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) < 3 times
institutional normal limits, or up to 5 times institutional normal limits if the patient
has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR > 40 Ml/min/1.73 m2
for patients with creatinine levels above institutional normal as per Cockcroft-Gault
formula International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range
of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) <1.5 X ULN
unless subject is receiving anticoagulant therapy as long as PT or PTT is within
therapeutic range of intended use of anticoagulants Thyroid stimulating hormone (TSH)
Within normal limits a

a: If TSH is not within normal limits at baseline, the subject will still be eligible if
total T3 or free T4 are within normal limits.

   - Full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral
   anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the
   patient must have an INR ≤3.0. For heparin and LMWH there should be no clinically
   significant active bleeding (with no bleeding within 14 days prior to first dose of
   protocol therapy) or pathological condition present that carries a high risk of
   bleeding (for example, tumor involving major vessels or known varices).

   - Ability to understand and willingness to sign a written informed consent and HIPAA
   consent document.

   - A biopsy, either core, cell block from FNA or cell block from surgical resection, must
   be available for the study. If the sample is not adequate, the patient must agree to
   provide a fresh biopsy specimen before the start of treatment. Any available archival
   tissue will also be collected. While a biopsy sample must be adequate and available
   for the study, an inadequate tissue sample would not be explicitly exclusionary and
   further discussion with the sponsor is allowed to assess the eligibility of the
   patient for the trial if, for clinical or other reasons, a new biopsy sample cannot be
   obtained.

   - Urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick
   or routine analysis is ≥2+, a 24 hour urine collection for protein must demonstrate
   <1000 mg of protein in 24 hours to allow participation in the protocol).

   - Females of child-bearing potential must be willing to use an effective method of
   contraception, for the course of the study through at least 6 months after the last
   dose of study medication.

   - Males who have Women of Child-bearing Potential (WOCBP) partners must agree to use
   effective method of contraception for the course of the study through 8 months after
   the last dose of study medication.

      - Note: Abstinence is acceptable if this is the usual lifestyle and preferred
      contraception for the subject.

Exclusion Criteria:

   - Patients currently receiving any other investigational agents, immunomodulatory
   agents, chemotherapy, or TKIs. EGFR mutation-positive patients must have received
   prior TKI treatment

   - Any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.

   - Untreated CNS metastases that are >1 cm in size are excluded, even if they are
   asymptomatic. Patients with treated brain metastases will be allowed if brain imaging
   obtained within 30 days of trial enrollment reveals stable disease.

   - Cirrhosis at a level of Child-Pugh B or worse, or cirrhosis of any degree and a
   history of hepatic encephalopathy, or clinically meaningful ascites resulting from
   cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis
   requiring diuretics or paracentesis.

   - Any arterial thromboembolic events, including but not limited to myocardial
   infarction, transient ischemic attack, cerebrovascular accident, or unstable angina,
   within 6 months prior to first dose of protocol therapy.

   - Uncontrolled or poorly-controlled hypertension (>150 mmHg systolic or > 100 mmHg
   diastolic for >4 weeks) despite standard medical management

   - Prior history of hypertensive crisis or hypertensive encephalopathy

   - Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
   recent peripheral arterial thrombosis) within 6 months prior to randomization

   - Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic
   anticoagulation)

   - History of abdominal or tracheosphageal fistula or gastrointestinal perforation within
   6 months prior to randomization

   - Clinical signs of gastrointestinal obstruction or requirement for routine parenteral
   hydration, parenteral nutrition, or tube feeding

   - Evidence of abdominal free air not explained by paracentesis or recent surgical
   procedure

   - Serious, non-healing wound, active ulcer, or untreated bone fracture within 28 days
   prior to first dose of protocol therapy

   - Subjects with a history of smoking greater than a 100 cigarettes in a lifetime, unless
   their tumor has an EGFR exon 19 or exon 21 mutation.

   - Patients with active, suspected, or known autoimmune disease that has required
   systemic treatment in the past one year (i.e., with use of disease modifying agents,
   corticosteroids or immunosuppressive drugs). Hormone replacement therapy (e.g.
   thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
   pituitary insufficiency, etc.) is not considered a form of systemic treatment.

   - Patients with a history of hemoptysis (defined as bright red blood or ≥1/2 teaspoons)
   within 1 month prior to first dose of protocol therapy or with radiographic evidence
   of major blood vessel invasion or encasement by cancer.

   - Undergone major surgery within 28 days prior to first dose of study treatment, or
   minor surgery/ subcutaneous venous access device placement within 7 days prior to
   first dose of protocol therapy. The patient has elective or planned major surgery to
   be performed during the course of the clinical trial.

   - Receiving chronic anti-platelet therapy other than aspirin, including non-steroidal
   anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others),
   dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose
   325 mg/day) is permitted. Occasional use of NSAIDs is allowed (for example daily use
   for less than a week; treating physician discretion is permitted to differentiate
   between occasional vs chronic use)

   - Have not recovered from adverse events due to agents administered earlier except
   neuropathy and alopecia. Physician's discretion is allowed to decide which unresolved
   adverse events from previous therapy (for NSCLC) prohibit patient participation in
   this study.

   - Requiring more than 10 mg prednisolone (or its equivalent) per day are excluded.

   - Any evidence of interstitial lung disease (ILD) or pneumonitis or a prior history of
   ILD or pneumonitis requiring oral or IV glucocorticoids. History of radiation
   pneumonitis in the radiation field (fibrosis) is permitted

   - Patients with known latent or active tuberculosis infection are excluded.

   - Have received a live vaccine within 30 days prior to cycle 1 Day 1.

   - Uncontrolled illness including, but not limited to, ongoing or active infection,
   symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
   (significant), cirrhosis, or psychiatric illness/ social situations that would limit
   compliance with the study requirements.

   - Known history of testing positive for immunodeficiency virus (HIV) or known acquired
   immunodeficiency syndrome (AIDS).

   - Known history of chronic hepatitis B virus infection or chronic hepatitis C virus
   indicating chronic infection that is not cured.

   - Subjects with previous malignancies (except non-melanoma skin cancers, and in situ
   cancers, such as, bladder, gastric, colon, cervical/ dysplasia, melanoma, or breast)
   are excluded unless a complete remission was achieved at least 2 years prior to study
   registration and no additional therapy is required or anticipated to be required
   during the study period.

   - Leptomeningeal disease

   - Uncontrolled tumor-related pain

      - Requiring pain medication must be on a stable regimen at study entry.

      - Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or
      metastases causing nerve impingement) should be treated prior to randomization.
      Patients should be recovered from the effects of radiation. There is no required
      minimum recovery period.

      - Asymptomatic metastatic lesions whose further growth would likely cause
      functional deficits or intractable pain (e.g., epidural metastasis that is not
      currently associated with spinal cord compression) should be considered for
      locoregional therapy, if appropriate, prior to randomization.

   - Ca > 12 mg/dl or corrected serum calcium > ULN

      - Patients who are receiving denosumab prior to randomization must be willing and
      eligible to receive a bisphosphonate instead while in the study

   - Pregnant or breast feeding

   - Known hypersensitivity to Chinese hamster ovary cell products or any of the study
   drugs.

   - Prior allogeneic bone marrow transplantation or solid organ transplant

   - Clear tumor infiltration into the thoracic great vessels is seen on imaging

   - Clear cavitation of pulmonary lesions is seen on imaging

   - Diagnosis of squamous cell carcinoma of the lung.

   - Lung tumor with a known ALK or ROS1 rearrangement or an EGFR mutation other than in
   exon 19 or exon 21.