Inclusion Criteria:

• Age ≥18 years at the time of screening. In Japan, patients must be ≥20 years at the time of screening.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this p rotocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations. For patients aged <20 years and enrolling in Japan, a written informed consent should be obtained from the patient and his or her legally acceptable representative.
• Histologically or cytologically documented Stage IV NSCLC not amenable to curative surgery or radiation (according to Version 8 of the IASLC Staging Manual in Thoracic Oncology 2016).
• Patients must have tumors that lack activating EGFR mutations (eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation) and ALK fusions. If a patient has squamous histology or is known to have a tumor with a KRAS mutation, then EGFR and ALK testing is not required.
• No prior chemotherapy or any other systemic therapy for metastatic NSCLC.  Patients who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for advanced disease are eligible, provided that progression  has occurred >12 months from end of last therapy (*see exclusion criterion below).
• Tumor PD-L1 status, confirmed by a reference laboratory using the Ventana SP263 PD-L1 immunohistochemistry (IHC) assay, must be known prior to randomization. As such, all patients must be able to undergo a fresh tumor biopsy during screening or to provide an available tumor sample taken <3 months prior to enrollment.  Tumor lesions used for newly acquired biopsies during screening period should not be the same lesions used as RECIST target lesions, unless there are no other lesions suitable for biopsy; and in this instance only core needle (not excisional/incisional) biopsy is allowed. For patients with a single target lesion, if biopsy is collected prior to screening imaging for baseline tumor assessment, allow approximately 2 weeks before imaging scans are acquired. Samples with limited tumor content and fine needle aspirate specimens are not acceptable. Specimens from metastatic bone lesions are typically unacceptable unless there is a significant soft tissue component.  The tumor specimen submitted to establish eligibility should be of sufficient quantity to allow for PD-L1 IHC, TMB and other exploratory biomarker analyses (also see Section 5.5.2) and is preferred in formalin-fixed paraffin-embedded blocks.
• World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at enrollment and randomization.
• Life expectancy ≥12 weeks at randomization (Day 1).
• Body weight >30 kg.
• At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have a short axis ≥15 mm) with CT or MRI and that is suitable for accurate repeated measurements as per RECIST 1.1 guidelines.
• No prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
• Adequate organ and marrow function as defined below: Hemoglobin ≥9.0 g/dL without transfusion 4 weeks prior to the screening and randomization:
  • Absolute neutrophil count ≥1.5 × 109/L;
  • Platelet count ≥100 × 109/L;
  • Serum bilirubin ≤1.5 × ULN. This will not apply to patients with confirmed Gilbert’s syndrome, who will be allowed in consultation with their physician;
  • ALT and AST ≤2.5 × ULN; for patients with hepatic metastases, ALT and AST;
  • ≤ × ULN;
  • Calculated creatinine clearance (CL) ≥40 mL/min as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine collection;
  • For patients receiving cisplatin: CL ≥50 mL/min as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine collection;
  • Males:    Creatinine clearance = Weight (kg) × (140 - Age)     (mL/min) 72 × serum creatinine (mg/dL);
  • Females:     Creatinine clearance = Weight (kg) × (140 - Age) × 0.85     (mL/min) 72 × serum creatinine (mg/dL).
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female premenopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy);
  • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced oophorectomy with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy).

Exclusion Criteria:

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Previous IP assignment in the present study.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• Participation in another clinical study with an IP during the last 12 months.
• Mixed small-cell lung cancer and NSCLC histology, sarcomatoid variant.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
• *No radiation therapy is allowed, unless it is 1) definitive radiation that had been administered at least 12 months prior, 2) palliative radiation to brain, with associated criteria for stability or lack of symptoms (see also exclusion criterion 16), or 3) palliative radiation to painful bony lesions (this must comprise less than 30% of the bone marrow).
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of the IP.
  • Note: Local surgery of isolated lesions for palliative intent is acceptable.
• History of allogeneic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia;
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement or psoriasis not requiring systemic treatment;
  • Any chronic skin condition that does not require systemic therapy;
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician;
  • Patients with celiac disease controlled by diet alone.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, ILD, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, that substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Medical contraindication to platinum-based doublet chemotherapy.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of the IP and of low potential risk for recurrence;
  • Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease;
  • Adequately treated carcinoma in situ without evidence of disease (eg, cervical cancer in situ).
• History of leptomeningeal carcinomatosis.
• Spinal cord compression.
• Brain metastases. Patients with suspected brain metastases at screening should have an intravenous (IV) contrast-enhanced MRI (preferred) or IV contrast-enhanced CT of the brain prior to study entry. If brain metastases are detected patients must be treated before randomization. Randomization is only permitted if patients with brain metastases have:
  • Confirmed stable condition 4 weeks after the intervention using imaging;
  • Returned neurologically to baseline;
  • Completed associated steroids at least 5 days prior to randomization;
  • Brain metastases will not be recorded as RECIST Target Lesions at baseline.
• History of active primary immunodeficiency.
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
  • Intra-nasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
  • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent;
  • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication, cytotoxic chemotherapy premedication).
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of the IP.
  • Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of the IP.
• Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment.
• Judgment by the Investigator that the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements.