Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With Tyrosine Kinase Inhibitor- (TKI)-Resistant Epidermal Growth Factor Receptor- (EGFR)-Mutated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-789/KEYNOTE-789)
Condition: Non-small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: pembrolizumab; pemetrexed; carboplatin; cisplatin; saline solution
Intervention description: IV infusion; IV infusion; IV infusion; IV infusion; IV infusion
Intervention MeSH terms: Carboplatin; Pembrolizumab; Pemetrexed; Pharmaceutical Solutions
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 492.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PD1; PD-1; PDL1; PD-L1

Summary:

      The purpose of this study is to evaluate the efficacy and safety of pemetrexed plus platinum
      chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in
      the treatment of adults with the following types of tyrosine kinase inhibitor
      (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous
      non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®]
      failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior
      exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation
      status.

      The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has
      superior efficacy compared to saline placebo plus chemotherapy in terms of: 1)
      Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1
      (RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This
      study will be considered to have met its success criteria if the combination of pembrolizumab
      plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS.

      Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab
      extension study, if available.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed diagnosis of Stage IV non-squamous NSCLC.

          -  Documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R.

          -  Investigator-determined radiographic disease progression per RECIST 1.1 after
             treatment with an EGFR TKI therapy: a) Participants previously treated with 1st or 2nd
             generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have confirmed
             documented absence of EGFR T790M mutation; b) Participants with confirmed acquired
             T790M mutation after 1st or 2nd generation EGFR TKI (e.g.
             erlotinib/afatinib/gefitinib) are required to have osimertinib TKI treatment failure
             prior to enrollment; c) Participants previously failed osimertinib TKI treatment as
             1st line therapy are eligible regardless of their EGFR T790M mutation status. Note:
             TKI washout period for all participants is 1 week or 2 half-lives after last treatment
             dose, whichever is longer. TKI washout should be completed prior to first dose of
             study treatment.

          -  Measurable disease per RECIST 1.1 as assessed by the local site
             investigator/radiology.

          -  Provided archival tumor tissue sample or newly obtained (no anti-neoplastic therapy
             since biopsy) core or excisional biopsy of a tumor lesion not previously irradiated.

          -  Life expectancy of at least 3 months.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days
             prior to the first dose of study treatment but before randomization.

          -  Male participants must agree to use contraception during the treatment period and for
             at least 120 days after the last dose of pembrolizumab and up to 180 days after last
             dose of chemotherapeutic agents.

          -  Female participants must not be pregnant, not breastfeeding, and must agree to use
             contraception during the treatment period and for at least 120 days after the last
             dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic
             agents.

          -  Adequate organ function.

        Exclusion Criteria:

          -  Predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the
             predominant cell type; if small cell elements are present, the participant is
             ineligible.

          -  Symptomatic ascites or pleural effusion. A participant who is clinically stable
             following treatment for these conditions (including therapeutic thoraco- or
             paracentesis) is eligible.

          -  Received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1),
             anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent
             directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic
             T-lymphocyte-associated protein-4 [CTLA-4], OX-40, CD137).

          -  Received prior systemic cytotoxic chemotherapy or investigational agent(s), excluding
             EGFR TKIs, for metastatic NSCLC. [Notes: 1) Prior treatment with chemotherapy and/or
             radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was
             completed at least 6 months prior to the diagnosis of metastatic NSCLC. 2) If
             participant received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting study treatment.
             3) Prior exposure to traditional medicine(s) is allowed as long as therapy was
             discontinued at least 4 weeks prior to the first dose of study treatment.]

          -  Received prior radiotherapy within 2 weeks of start of study treatment or has received
             lung radiation therapy of >30 Gray (Gy) within 6 months before the first dose of study
             treatment. Participants must have recovered from all radiation-related toxicities, not
             require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is
             permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous
             system (CNS) disease.

          -  Received a live vaccine within 30 days prior to the first dose of study treatment.

          -  Currently participating in or has participated in a study of an investigational agent
             or has used an investigational device within 4 weeks prior to the first dose of study
             treatment.

          -  Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in
             dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
             immunosuppressive therapy within 7 days prior the first dose of study treatment.

          -  Known additional malignancy that is progressing or has required active treatment
             within the past 5 years. (Note: Participants with basal cell carcinoma of the skin,
             squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ
             (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially
             curative therapy are not excluded.)

          -  Known active untreated CNS metastases and/or carcinomatous meningitis.

          -  Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.

          -  Known sensitivity to any component of cisplatin, carboplatin, or pemetrexed.

          -  Active autoimmune disease that has required systemic treatment in past 2 years.

          -  History of (non-infectious) pneumonitis that required steroids or has current
             pneumonitis.

          -  Active infection requiring systemic therapy.

          -  Known history of human immunodeficiency virus (HIV) infection.

          -  Known history of Hepatitis B or known active Hepatitis C virus.

          -  Known history of active tuberculosis (TB; Bacillus tuberculosis)

          -  Pregnant, breastfeeding or expecting to conceive or father children within the
             projected duration of the study, starting with the screening visit through 120 days
             after the last dose of pembrolizumab and up to 180 days after the last dose of
             chemotherapeutic agents.