Critères d'inclusion : Patient older than 18 years and no more than 75 year-old
Subject affiliated to an appropriate social security system
Signed informed consent before any trial related activities and according to local guidelines
ECOG performance status of 0 or 1
Histologically or cytologically confirmed, stage IIIB/IV non-squamous NSCLC (per the Union Internationale contre le Cancer/American Joint Committee on Cancer staging system, 7th edition). Patients with stage IIIB had to be not operable (that means not eligible for radiochemotherapy followed by a maintenance treatment by Durvalumab).
Patient with a sensitizing mutation in the EGFR gene must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more EGFR TKIs, such as erlotinib, gefitinib, or another EGFR TKI appropriate for the treatment of EGFR-mutant NSCLC
Patient with an ALK fusion oncogene (confirmed in local laboratory) must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more ALK inhibitors (i.e., crizotinib, alectinib, ceritinib) appropriate for the treatment of NSCLC in patients having an ALK fusion oncogene
Patient with a ROS1 fusion oncogene (confirmed in local laboratory) must have experienced disease progression (during or after treatment) or intolerance to treatment with one or more ROS inhibitors (i.e., crizotinib,) appropriate for the treatment of NSCLC in patients having an ROS1 fusion oncogene
No prior chemotherapy treatment for Stage IV non-squamous NSCLC except if less than 3 cycles, with treatment free-interval of at least 1 year from inclusion since last chemotherapy
Patient who has 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 inclusion since the last chemotherapy, radiotherapy, or chemoradiotherapy
Patient with a history of treated asymptomatic CNS metastases is eligible, provided he meets all of the following criteria:
Only supratentorial and cerebellar metastases allowed (i.e., no metastases to midbrain, pons, medulla, or spinal cord)
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 inclusion
No evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
Measurable disease, as defined by RECIST v1.1
Adequate hematologic and end-organ function, defined by the following laboratory
Adequate method of contraception during the treatment period and at least 5 months after the last dose of atezolizumab or 6 months after the last dose of chemotherapy
Critères de non-inclusion : Cancer-specific exclusions
Active or untreated CNS metastases as determined by CT or magnetic resonance imaging (MRI) evaluation during screening and prior radiographic assessments
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 inclusion
Uncontrolled tumour-related pain
Patients requiring pain medication must be receiving 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 inclusion. 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 loco-regional therapy, if appropriate, prior to inclusion.
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 calcium >12 mg/dL or corrected serum calcium > ULN)
Patients who are receiving denosumab prior to inclusion must be willing and eligible to discontinue its use and replace it with a bisphosphonate instead.
Malignancies other than NSCLC within 5 years prior to inclusion, 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)
General medical exclusions
Women who are pregnant, lactating, or intending to become pregnant during the study
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis
Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone are eligible for this study.
Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin regimen are eligible for this study
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
Rash must cover less than 10% of body surface area (BSA).
Well controlled disease at baseline only requiring low potency topical steroids.
No acute exacerbations of underlying condition within the previous 12 months (not requiring PUVA [psoralen plus ultraviolet A radiation], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high-potency or oral steroids)
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.
Positive test for HIV. All patients will be tested for HIV prior to inclusion into the study; patients who test positive for HIV will be excluded from the study.
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 [HBcAb] and absence of HBsAg) are eligible only if they are negative for HBV DNA. Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.
Severe infections within 4 weeks prior to inclusion, 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 inclusion; Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to inclusion, unstable arrhythmias, or unstable angina
Major surgical procedure other than for diagnosis within 28 days prior to inclusion or anticipation of need for a major surgical procedure during the course of the study
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 renders the patient at high risk from treatment complications
Symptomatic brain metastases;
Patients with illnesses or conditions that interfere with their capacity to understand, follow and/or comply with study procedures
Concurrent participation in any therapeutic clinical trial
Patient deprived of liberty or placed under the authority of a tutor
Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol
Exclusion criteria related to medications
Any approved anti-cancer therapy, including hormonal therapy within 14 days prior to initiation of study treatment.
Treatment with any other investigational agent with therapeutic intent within 28 days prior to inclusion
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-cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) treatment may be enrolled, provided the following requirements are met:
Last dose of anti-CTLA-4 at least 6 weeks prior to inclusion
No history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3/4)
Treatment with systemic immunostimulatory agents (including, but not limited to, interferons, interleukin 2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to inclusion; Prior treatment with cancer vaccines is allowed.
Treatment with systemic immunosuppressive medications (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to inclusion
Patients who have received acute, low-dose (≤ 10 mg oral prednisone or equivalent), systemic immunosuppressant medications may be enrolled in the study.
The use of corticosteroids (≤10 mg oral prednisone or equivalent) for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
Exclusion criteria related to chemotherapy
History of allergic reactions to cisplatin, carboplatin, or other platinum-containing compounds
Patients with hearing impairment (cisplatin)
Grade ≥ 2 peripheral neuropathy as defined by NCI CTCAE v5.0 (cisplatin)
CRCL < 60 mL/min for cisplatin or < 45 mL/min for carboplatin using the Cockcroft-Gault Method
Exclusion criteria related to Bevacizumab
Medically uncontrolled hypertension (defined as PAS>150 and/or PAD >100 mmHg)
Prior history of hypertensive crisis or hypertensive encephalopathy
Clinically significant cardiovascular disease (within 6 months prior to inclusion) that is uncontrolled by medication or may interfere with administration of trial treatment:
Aortic aneurysm requiring surgical repair
Recent arterial thrombosis
Hemoptysis (>one-half teaspoon of bright red blood per episode (within one months prior to inclusion) (grade 2 hemoptysis)
History of documented haemorrhagic diathesis or coagulopathy
Regular use of aspirin (>325 mg per day),
Nonsteroidal anti-inflammatory agents, or other agents known to inhibit platelet function
History of abdominal or tracheosphageal fistula or perforation within 6 months prior to inclusion
Core biopsy or other minor surgical procedure within 7 days before bevacizumab
Clinical signs or gastrointestinal obstruction or requirement for routine parenteral hydration, nutrition or tube feeding
Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
Major surgery within 28 days before enrolment
Serious, non-healing wound, active ulcer or untreated bone fracture
Proteinuria >1g/24h urine collection
All patient with >2+ protein on dipstick urinalysis at baseline must undergo a 24-hour urine collection and must demonstrate ≤1g of protein in 24 hours.
Known sensitivity to any component of bevacizumab
Radiation therapy within 21 days before enrolment
Adequate hematologic, liver, and renal function required (including creatinine clearance 45 mL/min at baseline and 45 mL/min before the start of any subsequent cycle using the Cockcroft-Gault Method)