Clinical Trial 20163

• Overview

  Study Title:

  EA5163/S1709 INSIGNA: A Randomized, Phase III Study of Firstline Immunotherapy alone or in Combination with Chemotherapy in Induction/Maintenance or Postprogression in Advanced Nonsquamous Non©\Small Cell Lung Cancer (NSCLC) with Immunobiomarker SIGNature©\driven Analysis

  Summary:

  This phase III trial studies whether pembrolizumab alone as a first-line treatment, followed by pemetrexed and carboplatin with or without pembrolizumab after disease progression is superior to induction with pembrolizumab, pemetrexed and carboplatin followed by pembrolizumab and pemetrexed maintenance in treating patients with stage IV non-squamous non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as pemetrexed and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving first-line pembrolizumab followed by pemetrexed and carboplatin with or without pembrolizumab works better in treating patients with non-squamous non-small cell cancer.

  Objective:

  The co-primary objective is to evaluate overall survival (OS) in each of the 2 experimental arms (Arms A and B) to control (Arm C). Secondary Objectives: To evaluate progression-free survival (PFS) per RECIST 1.1 for Arm C versus each of Arms A and B. To evaluate best objective response rates per RECIST 1.1 for Arm C versus each of Arms A and B. To estimate toxicity within each of the treatment arms via the CTCAE criteria. To compare outcomes between Arms A and B. To compare outcomes by treatment arm within subgroups defined by a cutpoint of PD-L1 expression at ¡Ý 50%.

• Treatments

  Therapies:

  Immunotherapy; Therapy (NOS)

  Medications:

  Alimta (Pemetrexed); MK-3475 (Keytruda); Paraplatin (carboplatin); Pemetrexed (); carboplatin ()

• Inclusion Criteria

  • Histologically or cytologically confirmed stage IV non-squamous non‐small cell lung cancer (NSCLC) (includes M1a, M1b stage disease, American Joint Committee on Cancer [AJCC] 8th edition). Participants with stage IIIB and IIIC disease are eligible if they are not candidates for combined chemotherapy and radiation
  • PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells. If PD-L1 expression TPS is unevaluable or the testing could not be completed, the participants are not eligible. The assay must have been performed by a Clinical Laboratory Improvement Act (CLIA) (or equivalent) certified laboratory
  • Measurable or non-measurable disease. The presence of malignant pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to study registration.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  • Participants with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better
  • Lab values as outlined per protocol
  • Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. CNS progression counts as progression and patients must move on to the next phase after CNS treatment. Participants with asymptomatic new (at screening) or progressive brain metastases (active brain metastases at screening) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy.
  • Participants are eligible if off steroids for at least 14 days prior to protocol treatment.
  • Palliative radiation to non-target lesions (bone metastasis) is allowed if patient develops symptoms
  • Anticonvulsants are allowed
  • Patients with asymptomatic, sub-centimeter brain metastasis who at the discretion of investigators do not need immediate CNS directed therapies are eligible.

• Exclusion Criteria

  • Must NOT have received the following: (a) Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Participants treated with any prior checkpoint inhibitors for metastatic lung cancer are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy) or immunotherapy for locally advanced stage III disease is allowed if at least 6 months have elapsed between the last dose of the prior therapy and study registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 14 days has passed between completion of local therapy and study registration . Registration prior to treatment during the 14 days is allowed. Palliative radiation must be to non-target lesions. (b) Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required
  • Known EGFR mutations (except exon 20 insertion), BRAF mutations (V600) or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors are excluded
  • Must not have known pre-existing and clinically active interstitial lung disease, or a known history of (non infectious) pneumonitis that required steroids, or current pneumonitis
  • Must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, etc.)
  • Must not have history of auto-immune condition requiring ongoing or intermittent systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Must not have any other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise participant safety or interfere with the evaluation of the safety of the study drug
  • Must not receive any other investigational agents during the course of therapy
  • Must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk of MK-3475 (pembrolizumab). Participants must also not expect to conceive or father children from the time of registration, while on study treatment, and until at least 120 days after the last dose of study treatment
  • All females of childbearing potential must have a blood test or urine study within 72 hours prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has achieved menarche at some point; has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Women of childbearing potential and sexually active males must use an accepted and effective method of contraception or abstain from sexual intercourse from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
  • Must not have a known history of active tuberculosis (TB)
  • Must not have a diagnosis of immunodeficiency or receive systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol treatment
  • Must not have received a live vaccine within 30 days prior to randomization. Seasonal flu vaccines that do not contain live virus are permitted.

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