Ensayos clínicos

Inclusion Criteria:

• Age ≥ 18 years at time of signing Informed Consent Form
• Ability to comply with the study protocol, in the investigator’s judgement
• Pathologically documented Stage II, IIIA, or select IIIB (T3N2 only) NSCLC of squamous or non-squamous histology
• Staging should be based on the 8th edition of the American Joint Committee on Cancer (AJCC) / Union Internationale Contre le Cancer (UICC) NSCLC staging system.
  • – T4 primary NSCLC will be allowed only on the basis of size (tumors > 7 cm). Invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, and separate tumor nodules in a different ipsilateral lobe is not permitted.
• Patients with mixed NSCLC histology (squamous and non-squamous) or NSCLC not otherwise specified are eligible.
• Patients may be screened based on clinical stage, but mandatory preoperative documentation of N2 nodal involvement by invasive mediastinal staging; e.g., CT-guided biopsy, endobronchial ultrasound (EBUS), mediastinoscopy, is required for PET-positive N2 nodes. Pre-operative staging of levels 5/6 nodes is optional.
• Solid or subsolid appearance of NSCLC on CT scan with no appearance of purely ground-glass opacity (GGO)
• For subsolid lesions, the tumor size (i.e., clinical T stage) should be measured based on solid component only, exclusive of the GGO component.
• Evaluation by the operating attending surgeon and involved medical oncologist prior to study enrollment to verify study eligibility for R0 resection with curative intent 
• PFTs within 6 months of planned resection and repeated at screening, if clinically indicated, including lung volumes, spirometry, and a diffusion capacity
  • If PFTs were performed before 6 months of planned resection or have never been performed, they must be performed during the screening period.
  • Abnormal PFTs may be further evaluated with quantitative ventilation/perfusion scanning or cardiopulmonary exercise testing.
  • Postoperative percent predicted forced expiratory volume in 1 second (FEV1) and diffusion capacity must be ≥ 40% and/or maximal oxygen consumption (VO2max) should be > 10 mL/kg/min.
• Adequate cardiac function to be eligible for surgical resection with curative intent If clinically indicated, patients with underlying ischemic, valvular, or other significant heart diseases should be evaluated preoperatively by a cardiologist.
• Measurable disease as assessed by the investigator per RECIST v1.1
• Eligibility to receive a platinum-based chemotherapy regimen
• Availability of a representative tumor specimen suitable for determination of PD-L1 status via central testing (results of PD-L1 testing are not required for patient to be randomized into the study)
• A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least a minimum of 3 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report before or within 4 weeks after randomization. Any additional slides beyond the required minimum of 3 slides are strongly encouraged for other exploratory biomarker research. If archival tumor tissue is unavailable, tumor tissue must be obtained from a biopsy performed at screening.
• ECOG Performance Status of 0 or 1
• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
  • ANC ≥ 1.5 x 109/L (1500/µL) without granulocyte colony-stimulating factor support
  • Lymphocyte count ≥ 0.5 x 109/L (500/µL)
  • Platelet count  ≥ 100 x 109/L (100,000/µL) without transfusion
  • Hemoglobin  ≥ 90 g/L (9.0 g/dL)
    • Patients may be transfused to meet this criterion.
  • AST, ALT, and ALP ≤ 2.5 x upper limit of normal (ULN)
  • Serum bilirubin ≤ 1.5 x ULN with the following exception:
    • Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN
  • Creatinine clearance ≥ 45 mL/min (calculated using the Cockcroft-Gault formula)
    • For patients intended to receive cisplatin: creatinine clearance ≥ 60 mL/min
  • Serum albumin ≥ 25 g/L (2.5 g/dL)
  • For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
• Negative HIV test at screening
• Negative hepatitis B surface antigen (HBsAg) test at screening
• Negative total hepatitis B core antibody (HBcAb) test at screening, or a positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
  • The HBV DNA test will be performed only for patients who have a positive total HBcAb test.
• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
  • The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating eggs, as defined below:
  • Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the last dose of atezolizumab, 30 days after the last dose of nab-paclitaxel, or 6 months after the last dose of pemetrexed, gemcitabine, carboplatin, or cisplatin, whichever is later. Women must refrain from donating eggs during this same period.
  • A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not  undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.
  • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
  • With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period for 6 months after the last dose of nab-paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin, whichever is later, to avoid exposing the embryo. Men must refrain from donating sperm during this same period.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods)  and withdrawal are not acceptable methods of contraception of preventing drug exposure.

Exclusion Criteria:

• Illness or condition that may interfere with a patient’s capacity to understand, follow, and/or comply with study procedures.
• Any prior therapy for lung cancer, including chemotherapy, or radiotherapy.
• Major surgical procedure, other than for diagnosis, within 28 days prior to initiation of study treatment, or anticipation of need for non-protocol-mandated major surgical procedure during the study.
• Non-squamous NSCLC histology with an activating mutation in the epidermal growth factor receptor (EGFR) or with an anaplastic lymphoma kinase (ALK) fusion oncogene.
  • Patients with non-squamous NSCLC histology that have unknown EGFR and/or ALK status require test results at screening. ALK and/or EGFR may be assessed locally or at a central laboratory (for China, testing will only be performed at a central laboratory);
  • If samples are submitted for central testing, additional tissue, cytology, and/or plasma samples are required.
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:
  • Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study;
  • Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study;
  • Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
    • Rash must cover < 10% of body surface area;
    • Disease is well controlled at baseline and requires only low-potency topical corticosteroids;
    • No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
• Active tuberculosis.
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
• History of malignancy other than NSCLC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment.
  • Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• Prior allogeneic stem cell or solid organ transplantation
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab.
• Current treatment with anti-viral therapy for HBV.
• Treatment with investigational therapy within 42 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment.
• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
  • Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study after Medical Monitor approval has been obtained;
  • Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study..
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation.
• Known allergy or hypersensitivity to any component of the chemotherapy regimen the patient will be assigned to.
• For patients intended to receive cisplatin, any significant hearing impairment per the investigator’s clinical judgement.
• Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after last dose of atezolizumab, 30 days after the last dose of nab-paclitaxel, or 6 months after last dose of pemetrexed, gemcitabine, carboplatin, or cisplatin.
  • Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.