Clinical Trials

Inclusion Criteria:

• Are ≥ 18 years of age at the time of signing the informed consent.
  • In Japan, if a patient is < 20 years, the written informed consent from his/her parent or guardian will be required in addition to the patient’s written consent.
• Participants must have measurable or non-measurable but evaluable disease assessed by the Investigator. Participants must have histologically documented NSCLC who present with Stage III locally advanced, unresectable disease (International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology], v8).
• 3. Availability of tumor material (< 6 months old) adequate for biomarker analysis is mandatory for all participants and central laboratory confirmation is required. For participants enrolled in the safety run-in, PD-L1 expression will be tested retrospectively by a central laboratory. For participants enrolled in the expansion part of the study, PD-L1 expression must be tested by the central laboratory and results available before randomization. Only results from the central laboratory testing will be used for randomization and if PD-L1 status is non-evaluable, the participant is not eligible for this study. Tumor samples obtained by endoscopic biopsies, core needle biopsies, excisional biopsies, punch biopsies, and surgical specimens that are < 6 months old and adequate for biomarker analysis are acceptable. Biopsies obtained by fine needle aspiration are not acceptable.
• Participants with tumor harboring an EGFR sensitizing (activating) mutation, ALK translocation, ROS-1 rearrangement are eligible. These tests are not required for enrollment in the study.
• Participants with ongoing post-obstructive pneumonia due to the tumor are eligible.
• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable T4 disease):
  • When pleural fluid is visible on both the CT scan and on a chest x-ray, a thoracentesis is required to confirm that the pleural fluid is cytologically negative;
  • Participants with exudative pleural effusions are excluded, regardless of cytology;
  • Participants with effusions that are minimal; i.e., are too small to safely tap are eligible.
• Participants must be at least 3 weeks from prior thoracotomy (if performed).
• Participants must have adequate pulmonary function defined as a forced expiratory volume in 1 second (FEV1) ≥ 1.2 liters or ≥ 50% of predicted normal volume measured within 3 weeks prior to randomization. If participants do not meet the above criteria, treatment with inhaled steroids and bronchodilators can be initiated if clinically indicated and eligibility can be reassessed after 1-2 weeks.
• ECOG performance status of 0 to 1 at Screening and on the day of first dose.
• Life expectancy ≥ 12 weeks.
• Have adequate organ function as indicated by the following laboratory values:
  • Adequate hematological function defined by absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL;
  • Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN), an aspartate aminotransferase (AST) level ≤ 3.0 × ULN, an alanine aminotransferase (ALT) level ≤3.0 × ULN and alkaline phosphatase ≤ 2.5 ULN;
  • Adequate renal function defined by creatine ≤ 1.5 × ULN or calculated creatinine clearance (CrCl) ≥ 50 mL/min for participant with Cr > 1.5 × ULN (GFR can also be used).
    • Note: CrCl  should be calculated per institutional standard. If no local guideline is available, CrCl should be calculated using the Cockcroft-Gault Method:
    • CrCl = ((140-age) * weight (kg) * (0.85 for females only)) / (72 * creatinine).
  • Adequate coagulation function defined as international normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN unless the participant is receiving anticoagulant therapy and activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy.
• Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.
  • Male Participants:
    • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e agree to the following during the study intervention period and for at least 6 months after the last dose of study intervention
    • Refrain from donating sperm; PLUS, either:
      • Abstain from intercourse with a WOCBP;
        • OR
      • Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, since a condom may break or leak.
  • Female Participants:
    • Are not pregnant or breastfeeding, and at least one of the following conditions applies:
      • Not a WOCBP.
        • OR
      • If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, for the following time periods:
        • Before the first dose of the study intervention(s), if using hormonal contraception:
        • Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses; OR
        • Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay.
        • During the intervention period.
      • Contraceptive measures should be continued as per guidance specified in labeling document for approved chemotherapies. If not specified, continue measures similar to investigational agent i.e., after the study intervention period (i.e., after the last dose of study intervention is administered) for at least 4 months after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period.
    • Have a negative pregnancy test, as required by local regulations, on W1D1 before the first dose of study intervention.
    • Additional requirements for pregnancy testing during and after study intervention are in SoA.
    • The Investigator reviews the medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
• Can give signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

Exclusion Criteria: 

• Participants with mixed small cell with non-small cell lung cancer histology.
• Greater than minimal, exudative, or cytologically positive pleural effusions.
• Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study drug.
• Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis).
• History of organ transplant that requires therapeutic immunosuppression.
• Significant acute or chronic infections including, among others:
  • Known history of positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (testing at Screening is not required). If an Investigator has a strong suspicion of HIV infection without known history for a participant in Screening, however participant refuses testing, discuss with Medical Monitor to assess eligibility. (Note: HIV testing is not mandated for study inclusion; however, if it is performed at any point in Screening or while on study, a site must consent the participant for HIV testing as per local standard guidance);
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (HBV surface antigen positive and HBV core antibody positive with reflex to positive HBV DNA, or HBV core antibody positive alone with reflex to positive HBV DNA, or positive HCV antibody with reflex to positive HCV RNA) at Baseline. Discuss with the Medical Monitor if history of HBV or HCV  infection is known. If medically indicated, participants infected with HBV must be treated and on a stable dose of antivirals (e.g, entecavir, tenofovir, or lamivudine; adefovir or interferon are not allowed) at study entry and with planned monitoring and management according to appropriate labeling guidance. Participants on active HCV therapy at study entry must be on a stable dose without documented clinically significant impaired liver function test or hematologic abnormalities (must meet criteria above) and with planned monitoring and management according to appropriate labeling guidance. HBV and/or HCV viral titers must be monitored according to SoA in these participants.
  • Participants with active tuberculosis (history of exposure or history of positive tuberculosis test; plus presence of clinical symptoms, physical, or radiographic findings).
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, active uveitis or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent. Participants with history of bleeding diathesis or recent major bleeding events considered by the Investigator as high risk for investigational drug treatment are also excluded.
• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before randomization.
• Known clinical history of tuberculosis, lung sarcoidosis and Interstitial Lung Diseases.
• History of another primary malignancy within 3 years prior to starting study drug, except for adequately treated basal or squamous cell carcinoma of the skin, adequately treated carcinoma in situ, e.g., cancer of the cervix in situ, superficial bladder cancer. History of other localized malignancies treated with curative intent needs to be discussed with the Medical Monitor.
• Uncontrolled neuropathy Grade 2 or greater regardless of cause.
• Significant hearing loss and participants unwilling to accept potential for further hearing loss (Investigator should consider treating the participant with carboplatin/paclitaxel).
• Any prior systemic cytotoxic chemotherapy for their NSCLC or any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints) such as anti-PD-(L)1, or anti-CTLA-4 antibody.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Systemic steroid administration required to manage toxicities arising from radiation therapy delivered as part of the cCRT for locally advanced NSCLC is allowed.
• Active autoimmune disease that has required systemic treatment in past 1 year (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), OR is receiving systemic steroid therapy < 3 days prior to the first dose of study intervention or receiving any other form of immunosuppressive medication. Participants requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at low doses (typically ≤ 10 mg of prednisone or equivalent per day). Equivalent hydrocortisone doses are also permitted if administered as a replacement therapy. Corticosteroid use on study as a premedication for IV contrast allergies/reactions (related to scans) is allowed and must be documented. This must be discussed with Medical Monitors for clinical indications in which participants may require a higher dose. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes Type I, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.  Consult Medical Monitor for other autoimmune diseases.
• Receipt of live attenuated vaccination within 30 days of receiving study drug.
• Use of a prohibited concomitant drug within 4 weeks randomization.
• Known severe hypersensitivity (Grade ≥ 3 National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) to study interventions or any components in their formulations, or uncontrolled asthma (i.e., 3 or more features of partially controlled asthma).
• Participation in another clinical study with an investigational product within the last 4 weeks.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• ≥ 10% weight loss within the past month.
• Female patients who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control.
• Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study drug or interpretation of participant safety or study results.