Carboplatin Plus Pemetrexed Plus Atezolizumab Plus Bevacizumab in Chemotherapy and Immunotherapy-naïve Patients With Stage IV Non-squamous Non-small Cell Lung Cancer

This is a multicenter single arm phase II clinical trial. All eligible patients will receive:

Carboplatin (AUC 5) i.v. day 1 plus pemetrexed (500 mg/m2) i.v. day 1 plus atezolizumab 1200 mg i.v. day 1 plus bevacizumab 15 mg/kg i.v. day 1 every 3 weeks for up to 4 cycles.

Patients with non-PD after 4 cycles will be permitted to continue with maintenance therapy with pemetrexed plus atezolizumab plus bevacizumab every 3 weeks until the time of disease progression or intolerable toxicities.

The hypothesis of this study is that the addition of Atezolizumab (an anti-PD-L1 antibody), to the combination of Carboplatin plus Pemetrexed plus Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, for the treatment of patients with stage IV non-squamous, non-small cell lung cancer (NSCLC) will improve progression free survival (PFS) compared with a historical control of carboplatin plus pemetrexed plus bevacizumab.

Eligibility Criteria:
Inclusion Criteria:

* Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
* Age ≥ 18 years at the time of consent.
* ECOG Performance Status of 0-1 within 28 days prior to registration.
* Must have life expectancy of \> 3 months at time of consent
* Histological or cytological confirmation of non-squamous NSCLC.
* Must have known PD-L1 status using the Dako 22C3 antibody (+ vs. -) OR must have at least 5 unstained slides to perform PD-L1 testing (results not required for eligibility). PD-L1 positive is defined as a tumor proportion score (TPS) ≥ 1%. PD-L1 negative is defined as a TPS \<1%.
* Patients with known targetable mutations in EGFR or BRAF or known translocations in ALK or ROS1 are eligible if they have received FDA approved targeted therapy first. A 1-week washout prior to enrollment is strongly encouraged (3 weeks preferred).
* Stage IV disease or recurrent disease
* Measurable disease according to RECIST v1.1 criteria within 28 days prior to registration with either PET/CT scan, CT scan of chest and abdomen, or CT chest including upper abdomen and adrenal glands which define stage IV disease.
* Patients who had disease progression greater than 1 year after completing prior adjuvant therapy for stage I - III are eligible as long as no systemic therapy was given for recurrence.
* No prior immunotherapy or antiangiogenic therapy.
* Prior platinum therapy or pemetrexed are permissible if previously given in the adjuvant setting for stage I-III disease and disease recurrence is \> 1 year from completion of therapy.
* If subject received major surgery or radiation therapy of \> 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
* Demonstrate adequate organ function as defined below, with all screening labs to be obtained within 28 days prior to registration

  * Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm3
  * Hemoglobin (Hgb) ≥ 9 g/dL
  * Platelets ≥ 100 K/mm3
  * Serum creatinine: ≤1.5 X upper limit of normal (ULN) OR Calculated Creatinine Clearance: ≥ 40 cc/min using the Cockcroft-Gault formula
  * Bilirubin ≤ 1.5 × upper limit of normal (ULN)
  * Aspartate aminotransferase (AST) ≤ 1.5 × ULN or \< 5x ULN if the transferase elevation was due to liver metastases
  * Alanine aminotransferase (ALT) ≤ 1.5 × ULN or \<5x ULN if the transferase elevation was due to liver metastases
  * International Normalized Ratio (INR) or Prothrombin Time (PT) \& aPTT ≤ 1.5 × ULN (unless subjects is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants)
* Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to registration. NOTE: A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (\> 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
* For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use two non-hormonal methods of contraception, including at least one method with a failure rate of \< 1% per year, during the treatment period and for 5 months after the last dose of atezolizumab or 120 days after the last dose of any study drug, whichever is later;

  * examples of non-hormonal contraceptive methods with a failure rate of \< 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. Must use "estrogen-free" hormonal method if this is chosen contraception method.
  * A barrier method may be used as the second contraceptive method. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
* Contraception method must begin starting from the time of informed consent until 120 days after treatment discontinuation.
* For men: Agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
* With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 120 days after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
* The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
* As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria:

* Active infection requiring systemic therapy
* Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
* Active secondary cancers.
* Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Brain imaging with either MRI or CT with contrast must be performed on all subjects at screening to evaluate for the presence of brain metastases. Patients with a history of treated CNS lesions are eligible, provided that all of the following criteria are met:

  * Measurable disease, per RECIST v1.1, must be present outside the CNS.
  * The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.
  * Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).
  * The patient has not received stereotactic radiotherapy within 14 days prior to initiation of study treatment or whole-brain radiotherapy within 21 days prior to initiation of study treatment
  * The patient has no ongoing requirement for corticosteroids as therapy for CNS disease and off steroid therapy for at least 14 days. Anticonvulsant therapy at a stable dose is permitted.
  * Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.
* Major surgery within 3 weeks of the first dose of trial treatment.
* Completed palliative radiotherapy within 7 days of the first dose of trial treatment.
* The patient had a history of uncontrolled hereditary or acquired thrombotic disorder.
* Patients with a history of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon) within 2 months prior to enrollment.
* The patient had clinically relevant congestive heart failure (CHF; NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
* The patient had experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to enrollment.
* The patient had uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard medical management.
* The patient has had a serious or non-healing wound, ulcer, or bone fracture within 28 days prior to enrollment.
* Patients with ≥ 2 + protein on dipstick urinalysis. All patients with ≥ 2 + protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours to be eligible.
* Clear cavitation of pulmonary lesions seen on imaging.
* The patient had significant bleeding disorders, vasculitis, or experienced Grade 3-4 gastrointestinal (GI) bleeding within 3 months prior to enrollment.
* History of GI perforation and/or fistulae within 6 months prior to enrollment.
* Evidence of tumor invading or abutting major blood vessels.
* The patient had a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
* Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted.
* Previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb).
* Has active autoimmune disease that has required systemic treatments in the past 2 years, including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents; chronic or occasional use of low-dose steroid therapy can be still be considered eligible as long as no greater than the daily equivalent of 5mg oral prednisone.
* Exceptions to excluding patients with active autoimmune disease include the following:

  * Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
  * Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
  * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations are eligible for the study provided all of following conditions are met:

    * Rash must cover \< 10% of body surface area
    * Disease is well controlled at baseline and requires only low-potency topical corticosteroids
    * No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months
* Subjects with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study. Subjects on chronic systemic steroids would be excluded from the study.
* Had prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
* Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment
* Treatment with systemic immunosuppressive medication (including, but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions:

  * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study.
  * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
* Treatment with denosumab (a RANKL inhibitor) within 4 weeks prior to initiation of study treatment. Patients receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate during atezolizumab treatment.
* History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
* Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
* Has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* Has known active Hepatitis B or C. Active Hepatitis B is defined as a known positive HBsAg result. Active Hepatitis C is defined by a known positive Hep C Ab result and known quantitative HCV RNA results greater than the lower limits of detection of the assay. For patients with past HBV infection or resolved HBV infection (defined as the presence of hepatitis B core antibody \[HBcAb\] and absence of HBsAg), the patient is only eligible if they are negative for HBV DNA.
* Active tuberculosis
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator.
* Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
* Has known interstitial lung disease or history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan; history of radiation pneumonitis in the radiation field (fibrosis) is permitted. Lymphangitic spread of the NSCLC is not exclusionary.