Phase 3  

ORIENT-11; NCT03607539


PD-1 Inhibitor

A Randomized, Double-Blinded, Phase 3 Study of Pemetrexed Plus Platinum Chemotherapy With or Without Sintilimab (IBI308) in First-line Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer Subjects*

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Key Inclusion Criteria
  • Patients ≥18 years and ≤75 years with histologically or cytologically confirmed locally advanced (stage IIIB/IIIC), metastatic, or recurrent (stage IV) nonsquamous non-small cell lung cancer (NSCLC) who are inoperable and cannot receive curative concurrent chemoradiotherapy according to the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer 8th edition TNM staging of lung cancer
  • Life expectancy of at least 3 months
  • At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. A measurable lesion located in the field of previous radiation therapy or after local treatment may be selected as a target lesion if it is confirmed to have progressed
  • Confirmation by histological or cytological specimens that EGFR or ALK-directed therapy is not indicated (documented evidence of absence of tumor EGFR sensitivity mutation and absence of ALK gene rearrangements)
  • Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
  • No prior systemic antineoplastic therapy for advanced disease; patients are allowed to have received prior adjuvant chemotherapy, but the time between disease recurrence and completion of the last dose of chemotherapy has to be at least 6 months
  • Adequate hematologic function, defined as absolute neutrophil count ≥1.5 × 109/L, platelet count ≥100 × 109/L, and hemoglobin ≥9 g/dL (no blood transfusion or erythropoietin within 7 days)
  • Adequate liver function, defined as total bilirubin levels ≤1.5 x normal upper limit (ULN) and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤2.5 x ULN in all patients; or for recorded liver patients with metastasis, AST, and ALT levels ≤5 x ULN
  • Adequate renal function, defined as serum creatinine ≤1.5 x ULN or measured or calculated creatinine clearance ≥60 mL/min according to Cockcroft-Gault formula
  • Coagulation function is adequate (defined as international normalized ratio or prothrombin time [PT] ≤1.5 x ULN) if the subject is receiving anticoagulant therapy, as long as the PT is within the proposed range for the anticoagulant
  • Females of childbearing age should be negative for urine or serum pregnancy test within 72 hours prior to the first study drug administration. If the urine pregnancy test results are positive or cannot be confirmed as negative, a blood pregnancy test is required
  • If there is a risk of conception, male and female patients must use highly effective contraception (ie, a method with a failure rate of <1% per year) for at least 180 days after stopping study treatment

Key Exclusion Criteria
  • Predominantly squamous cell histology NSCLC; mixed cell types must be primarily (≥90%) adenocarcinoma cells. If small cell elements are present, the subject cannot be enrolled
  • Currently participating in interventional clinical research or treatment, or receiving other research drugs or using research equipment within 4 weeks before the first dose
  • Previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 agents, or agents directed at another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
  • Received a traditional Chinese medicine with antitumor effect, or an immunomodulatory drug (thymosin, interferon, interleukin) within 2 weeks before the first dose, or received major surgery within 3 weeks before the first dose
  • Pulmonary radiation therapy of >30 Gy within 6 months prior to the first dose
  • Completed palliative radiotherapy within 7 days prior to the first dose
  • Clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction, and peritoneal metastasis
  • Received a physical organ or blood system transplant
  • Clinically uncontrollable pleural effusion/peritoneal effusion
  • Known to have severe allergic reactions (grade ≥3) to the active ingredients of sintilimab, pemetrexed, cisplatin, carboplatin, and/or any excipients
  • Active autoimmune diseases requiring systemic treatment (eg, using a disease-modifying drug, corticosteroid, or immunosuppressant) within 2 years prior to the first dose. Alternative therapies (such as thyroxine, insulin, or physiological corticosteroids for adrenal or pituitary insufficiency) are not considered systemic treatments
  • Diagnosis of immunodeficiency, or receiving systemic steroid therapy or any other form of immunosuppressive therapy, within 7 days prior to the first dose of study treatment. Physiological doses of corticosteroids (≤10 mg/day of prednisone or equivalent) are permitted
  • Not fully recovered from the toxicity and/or complications caused by any intervention before starting treatment (ie, ≤ grade 1 or to baseline, excluding fatigue or alopecia)
  • Other malignant tumors within 5 years prior to the first dose, with the exception of radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ
  • Active central nervous system (CNS) metastasis and/or cancerous meningitis. Patients with asymptomatic brain metastases or stable symptoms after treatment of brain metastatic lesions may participate in the study as long as all of the following criteria are met: measurable disease outside the CNS; no meningeal, midbrain, pontine, medullary, or spinal metastases; clinically stable for at least 2 weeks; and discontinuation of hormonal therapy 14 days prior to the first dose of study treatment. Patients with known untreated, asymptomatic brain metastases can be enrolled, but regular imaging assessments of the brain must be performed
  • A history of noninfectious pneumonitis requiring corticosteroid therapy within 1 year prior to the first dose of study treatment or has current interstitial lung disease
  • Active infections that require systemic treatment
  • Unable or unwilling to receive folic acid or vitamin B12 supplementation
  • Known cases of mental illness or substance abuse that may have an impact on compliance with the test requirements
  • Known HIV infection or untreated active hepatitis B or C
  • Vaccination of live vaccine within 30 days before the first dose (cycle 1, day 1)
    • Inactivated virus vaccines for seasonal influenza are permitted; however, live attenuated influenza vaccines administered intranasally are not allowed

This clinical trial is being conducted in China.
Sintilimab 100 mg or 200 mg is administered intravenously (IV) Q3W on day 1 of a 21-day cycle.
Pemetrexed 500 mg/m2 is administered IV Q3W on day 1 of a 21-day cycle.
Platinum is administered IV Q3W on day 1 of a 21-day cycle for the first four cycles.
Placebo 100 mg or 200 mg is administered IV Q3W on day 1 of a 21-day cycle.
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The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.