A Phase II Study of Atezolizumab in Combination With Bevacizumab, Carboplatin or Cisplatin, and Pemetrexed for EGFR-mutant Metastatic Non-small Cell Lung Cancer Patients After Failure of EGFR Tyrosine Kinase Inhibitors.

Prior treatment

• Previous exposure to platinum-based palliative chemotherapy. The treatment-free interval of neoadjuvant or adjuvant platinum-based chemotherapy should be more than 6 months before study enrollment is allowed
• Previous exposure to VEGF inhibitor for anti-cancer treatment
• Prior treatment with any other anti-programmed cell death protein-1 (anti-PD-1), or PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms
• Currently participating or has participated in a study of an investigational agent or using an investigational device within 4 weeks of administration of atezolizumab.
• Expected to require any other form of antineoplastic therapy while on study
• Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for \> 2 weeks prior to study enrollment.
• 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 study enrollment.
• Malignancies other than NSCLC within 5 years prior to study enrollment, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS \> 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
• On chronic systemic steroid therapy or on any other form of immunosuppressive medication
• Has received a live-virus vaccination within 30 days of planned treatment start
• Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
• Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 3 weeks of the first dose of study medication
• Hepatitis B carrier: Patients with HBV infection were required to be receiving effective antiviral therapy and have a viral load less than 100 IU/mL at screening
• History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 1 month prior to study enrollment

Other illness

• Patients with untreated symptomatic brain metastases. Patients with treated brain metastases will be allowed if brain imaging obtained greater than 7 days from trial enrollment reveals stable disease. Patients with small (\< 3mm) asymptomatic brain metastasis are allowed to enroll. Patients on steroids doses higher than 10 mg of prednisone (or its equivalent) are excluded
• Leptomeningeal disease
• Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
• Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed) (see Appendix V)
• Active infection requiring therapy
• History of Human Immunodeficiency Virus (HIV) unless recent serology test is negative.
• Active Hepatitis C
• Interstitial lung disease or pneumonitis requiring oral or IV glucocorticoids
• Inadequately controlled hypertension (defined as systolic blood pressure \> 150 mmHg and/or diastolic blood pressure \> 100 mmHg). Anti-hypertensive therapy to achieve these parameters is allowable.
• Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)

Lab values

• Patients carries EGFR genotype T790M or exon20 insertion should be excluded.

Other

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters (e.g., PleurX®) are allowed.
• Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study

• Stage IIIB\~IV NSCLC with known EGFR activating mutation not amenable to curative surgery or radiotherapy. EGFR activating mutations include exon19 deletion, L858R, G719X, L861Q, or S768I.
• Radiological documentation of disease progression following one or more lines of EGFR TKI treatment but have not received palliative chemotherapy.
• Patients must receive tumor EGFR genotyping in re-biopsied FFPE tumor samples.
• At least 20 years of age.
• World Health Organisation (WHO) performance status 0-2 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks
• At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥ 15mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements.
• Normal bone marrow and organ function as defined below:
  • Marrow: Hemoglobin ≥10gm/dL, absolute granulocyte count (AGC) ≥1500/mm3 platelets ≥100,000/mm3, absolute lymphocyte count ≥1000/mm3.
  • Hepatic: Serum/plasma total bilirubin ≤1.5 x upper limit of normal (ULN) with the exception of \<2.9 mg/dL for patients with Gilbert's disease, ALT (SGPT) and AST (SGOT) ≤2.5 x ULN.
  • Renal: Serum/plasma creatinine (sCr) ≤1.5 x upper limit of normal, or creatinine clearance (Ccr) ≥45 mL/min.
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (\< 1% per year) when used consistently and correctly, and to continue its use for 5 months after the last dose of atezolizumab and/or 6 months after the last dose of bevacizumab. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.