Overview

While cigarette smoking remains the primary cause of most lung cancer cases, lung carcinoma in never smokers account for nearly 20 percent of cases. Never smokers with lung cancer typically present with different molecular profiles from that of smokers, which results in prognostic and therapeutic implications. Molecular changes in NSCLC that have therapeutic significance include mutations in the epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene. These driver mutations typically are present in lung tumors found in never or light smokers.

The addition of bevacizumab to carboplatin and paclitaxel in first-line treatment of non-squamous NSCLC showed improved survival compared to carboplatin and paclitaxel alone, 12.3 vs. 10.3 months respectively. Results from the POINTBREAK trial demonstrated that carboplatin + pemetrexed + bevacizumab is an alternative option to carboplatin + paclitaxel + bevacizumab, with comparable survival but less toxicity. In recent years, immunotherapy has emerged as a form of treatment that can lead to robust responses in a subset of patients. The PD-1 inhibitor nivolumab and the PD-L1 inhibitor atezolizumab have shown prolonged survival in comparison to docetaxel in patients who previously progressed with chemotherapy, irrespective of PD-L1 expression. Thus, this study combines immunotherapeutic agent atezolozumab with an ant-angiogenic agent, bevacizumab, and double platinum therapy (carboplatin and pemetrexed).

Eligibility

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.