Inclusion Criteria:
1. Histologically confirmed diagnosis of stage IV non-squamous NSCLC with no evidence of
EGFR sensitizing mutations or ALK or ROS1 rearrangements.
2. Availability of tumor tissue.
3. Evidence of PD-L1 expression evaluated with immunohistochemistry (≥1%).
4. No previous chemotherapy. Patients who have received prior neo-adjuvant, adjuvant
chemotherapy, radiotherapy or chemoradiotherapy with curative intent for
non-metastatic disease must have experienced a treatment-free interval of at least 6
months from randomization since the last dose of chemotherapy and/or radiotherapy.
5. ECOG performance status 0-1.
6. Life expectancy > 3 months
7. Age ≥18 years.
8. Measurable disease, as defined by RECIST v1.1.
9. Adequate hematologic and organ function, defined by the following laboratory results
obtained within 28 days prior to randomization:
- ANC ≥ 1500 cells/μL without granulocyte colony-stimulating factor support
- Platelet count ≥ 100,000/μL without transfusion
- Hemoglobin ≥ 9.0 g/dL Patients may be transfused to meet this criterion
- AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:
- Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN
- Patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 ×
ULN.
- Serum bilirubin ≤ 1.25 × ULN
- Patients with known Gilbert disease who have serum bilirubin level ≤ 3 mg/dL may
be enrolled
- Calculated creatinine clearance (CRCL) ≥ 45 mL/min or calculated CRCL must be ≥
60 mL/min
10. Patient compliance to trial procedures.
11. Written informed consent.
Exclusion Criteria:
1. No tumor tissue available.
2. PD-L1 expression < 1 % or PD-L1 expression unknown or not assessable
3. Patient positive for EGFR mutations or ALK or ROS1 rearrangements.
4. Patients with squamous histology or with specific contraindication to bevacizumab
therapy.
5. Previous chemotherapy. Adjuvant or neoadjuvant chemotherapy is considered a line of
therapy if completed less than 6 months before evidence of disease relapse.
6. Concomitant radiotherapy or chemotherapy.
7. Previous therapy with any checkpoint inhibitor.
8. Pregnancy or lactating women who are pregnant, lactating, or intending to become
pregnant during the study.
9. Symptomatic brain metastases; asymptomatic brain metastases are accepted if no steroid
therapy is required and if pretreated.
10. 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.
11. Leptomeningeal disease.
12. 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.
13. 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
on study.
14. 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)
15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
16. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster
ovary cells or any component of the Atezolizumab formulation
17. History of autoimmune disease, including but not limited to myasthenia gravis,
myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis,
psoriatic arthritis, inflammatory bowel disease, vascular thrombosis associated with
antiphospholipid syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré
syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with: 1)
history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement
hormone, 2) controlled Type I diabetes mellitus who are receiving a stable dose of
insulin regimen and 3) eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only in less than 10% of body surface area, well
controlled at baseline and only requiring low potency topical steroids are eligible
for this study.
18. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
pneumonitis on screening chest CT scan. History of radiation pneumonitis in the
radiation field (fibrosis) is permitted.
19. Positive test for HIV
20. Patients with active hepatitis B (chronic or acute; defined as having a positive
hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with
past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the
presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV
DNA must be obtained in these patients prior to randomization. Patients positive for
hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.
21. Active tuberculosis
22. Severe infections within 4 weeks prior to randomization, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
received therapeutic oral or IV antibiotics within 2 weeks prior to randomization.
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or to prevent chronic obstructive pulmonary disease exacerbation) are
eligible.
23. Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or greater), myocardial infarction within 3 months prior to randomization,
unstable arrhythmias, or unstable angina. Patients with known coronary artery disease,
congestive heart failure not meeting the above criteria, or left ventricular ejection
fraction < 50% must be on a stable medical regimen that is optimized in the opinion of
the treating physician, in consultation with a cardiologist if appropriate.
24. Major surgical procedure other than for diagnosis within 28 days prior to
randomization or anticipation of need for a major surgical procedure during the course
of the study
25. Prior allogeneic bone marrow transplantation or solid organ transplant
26. Administration of a live, attenuated vaccine within 4 weeks before randomization or
anticipation that such a live attenuated vaccine will be required during the study
27. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications
28. Any approved anti-cancer therapy, including chemotherapy, or hormonal therapy within 3
weeks prior to initiation of study treatment; the following exceptions are allowed:
Hormone-replacement therapy or oral contraceptives, TKIs approved for treatment of
NSCLC discontinued > 7 days prior to randomization; the baseline scan must be obtained
after discontinuation of prior TKIs.
29. Treatment with any other investigational agent or participation in another clinical
trial with therapeutic intent within 28 days prior to randomization
30. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
anti-PD-1, and anti-PD-L1 therapeutic antibodies. Patients who have had prior
anti-CTLA-4 treatment may be enrolled, provided the following requirements are met:
Minimum of 6 weeks from the last dose of anti-CTLA-4; No history of severe
immune-mediated adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 and 4)
31. Treatment with systemic immunostimulatory agents (including but not limited to IFNs,
IL-2) within 6 weeks or five half-lives of the drug, wichever is shorter, prior to
randomization. Prior treatment with cancer vaccines is allowed.
32. Treatment with systemic immunosuppressive medications (including but not limited to
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor
necrosis factor [anti-TNF] agents) within 2 weeks prior to randomization.
33. Patients who have received acute, low-dose, systemic immunosuppressant medications
(e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after
discussion with and approval by the Medical Monitor.
34. Patients with history of allergic reaction to IV contrast requiring steroid
pre-treatment should have baseline and subsequent tumor assessments done by MRI. The
use of inhaled corticosteroids for chronic obstructive pulmonary disease,
mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension,
and low-dose supplemental corticosteroids for adrenocortical insufficiency are
allowed.
35. 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.
36. Prior history of hypertensive crisis or hypertensive encephalopathy
37. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recentperipheral arterial thrombosis) within 6 months prior to randomization
38. 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).
39. Current or recent (within 10 days of randomization) use of aspirin (> 325 mg/day) or
treatment with dipyramidole, ticlopidine, clopidogrel, and clostazol
40. 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.
41. 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.
42. Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is
permitted.
43. Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to the first dose of bevacizumab
44. 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.
45. Serious, non-healing wound, active ulcer, or untreated bone fracture
46. 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.
47. Known sensitivity to any component of bevacizumab
