Atezolizumab in Combination With Bevacizumab, Carboplatin and Pemetrexed for EGFR-mutant Metastatic NSCLC Patients After Failure of EGFR Tyrosine Kinase Inhibitors

Inclusion Criteria:

* Stage IIIB or IV NSCLC with known EGFR activating mutation not amenable to curative surgery or radiotherapy.
* Radiological documentation of disease progression following one or more lines of EGFR TKI treatment but have not received palliative chemotherapy. For tumors with uncommon EGFR mutation, including exon 20 insertions, exon 18 point mutations and or complex mutations, patients should have received one or more lines of EGFR TKI treatment.
* Patients must receive tumor EGFR genotyping by peripheral blood circulating tumor-DNA (ctDNA)
* Measurable disease as defined by RECIST 1.1 Criteria.
* At least 18 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 computerised 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 ≥10.0 gm/dL, absolute granulocyte count (AGC) ≥1,000/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) ≥50 mL/min.
* Serum/plasma albumin \> 3.0 gm/dL
* 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.
* Ability to understand and willingness to sign an IRB approved written informed consent document.

Exclusion Criteria:

* Previous exposure to platinum-based palliative chemotherapy. The use of neoadjuvant or adjuvant platinum-based chemotherapy 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 (PDL2) agent or an antibody targeting other immuno-regulatory receptors or mechanisms
* Patients carries EGFR genotype T790M but have not received 3rd generation EGFR TKI Osimertinib
* 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
* 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
* 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 randomization
* Leptomeningeal disease
* Uncontrolled tumor-related pain
* Patients 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.
* 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. Uncontrolled or symptomatic hypercalcemia (\> 1.5 mmol/L ionized calcium or 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.
* Malignancies other than NSCLC within 5 years prior to randomization, 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
* Clinically active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, or abdominal carcinomatosis (known risks factors for bowel perforation)
* Severe hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
* Active autoimmune disease that has required systemic treatment in the past 2 years (replacement therapies for hormone deficiencies are allowed)
* Systemic cytotoxic chemotherapy, antineoplastic biologic therapy, or major surgery within 3 weeks of the first dose of study medication
* Active infection requiring therapy
* History of Human Immunodeficiency Virus (HIV)
* 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
* Active Hepatitis C
* Interstitial lung disease or pneumonitis requiring oral or IV glucocorticoids
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study
* Psychiatric disorders and substance (drug/alcohol) abuse

Exclusion Criteria Related to Bevacizumab

* 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.
* 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
* History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 1 month prior to randomization
* Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation)
* Current or recent (within 10 days of randomization) use of aspirin (\> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol
* Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes that has not been stable for \> 2 weeks prior to randomization
* The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least 2 weeks prior to randomization.
* Prophylactic anticoagulation for the patency of venous access devices is allowed, provided the activity of the agent results in an INR \< 1.5 × ULN and aPTT is within normal limits within 14 days prior to randomization.
* Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is permitted.
* Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to the first dose of bevacizumab
* 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
* Proteinuria, as demonstrated by urine dipstick or \> 1.0 g of protein in a 24-hour urine collection
* 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.
* Known sensitivity to any component of bevacizumab
* Clear tumor infiltration into the thoracic great vessels is seen on imaging
* Clear cavitation of pulmonary lesions is seen on imaging