KEYNOTE‐598.

Study name	A phase 3, randomized, double‐blind study of pembrolizumab plus ipilimumab vs pembrolizumab plus placebo in previously untreated, stage IV, metastatic Non‐small Cell Lung Cancer subjects whose tumors are PD‐L1 positive (TPS ≥ 50%) (KEYNOTE‐598)
Methods	Open‐label, parallel assignment, Phase 3 RCT
Participants	548 participants Inclusion criteria Has a histologically‐ or cytologically‐confirmed diagnosis of Stage IV metastatic NSCLC (American Joint Committee on Cancer version 8) Has measurable disease per RECIST 1.1 as determined by investigator Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Has a life expectancy of >3 months Has provided archival tumour tissue sample or newly obtained core or excisional biopsy of a tumour lesion not previously irradiated Female participants of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study therapy Female and male participants of reproductive potential must agree to use contraception starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication Male participants must refrain from donating sperm starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication Exclusion criteria Has received prior systemic chemotherapy/other targeted or biological antineoplastic therapy treatment for their Stage IV metastatic NSCLC Has a tumour that harbours an epidermal growth factor receptor (EGFR)‐sensitising (activating) mutation or an anaplastic lymphoma kinase (ALK) translocation Is currently participating in or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study therapy Has received prior therapy with an anti‐Programmed Cell Death Receptor 1 (PD‐1), Programmed Cell Death Receptor Ligand 1 (anti‐PD‐L1), or anti‐ Programmed Cell Death Receptor Ligand 2 (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) Has received prior radiotherapy within 2 weeks of start of study therapy or received lung radiation therapy of >30 Gray (Gy) within 6 months of the first dose of study therapy Has recovered from all radiation‐related toxicities, does not require corticosteroids, and has not had radiation pneumonitis Is receiving systemic steroid therapy ≤7 days prior to the first dose of study therapy or receiving any other form of immunosuppressive medication Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of curatively treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or curatively resected in situ cancers Has known untreated central nervous system (CNS) metastases and/or carcinomatous meningitis Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease‐modifying agents, corticosteroids, or immunosuppressive drugs) Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (i.e., doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study therapy Has a history of (non‐infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease Has had an allogeneic tissue/solid organ transplant Has received a live vaccine within 30 days prior to the first dose of study therapy Has an active infection requiring systemic therapy Has a known history of human immunodeficiency virus (HIV) infection Has a known history of hepatitis B or known active hepatitis C virus infection Has a known history of active tuberculosis Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial Is a regular user of any illicit drugs or had a recent history of substance abuse Is pregnant or breast feeding or expecting to conceive or father starting from the first dose of study medication, throughout the study period, and for up to 120 days after the last dose of study medication Has severe hypersensitivity to pembrolizumab and/or any of its excipients and/or to ipilimumab and/or any of its excipients Has a ROS1 translocation
Interventions	Intervention pembrolizumab + ipilimumab Participants receive 200 mg of pembrolizumab by intravenous (IV) infusion on Day 1 of each 3‐week cycle for up to 35 cycles of treatment plus 1 mg/kg of ipilimumab by IV infusion on Day 1 of each 6‐week cycle for up to 18 cycles of treatment. Comparator: pembrolizumab + placebo Participants receive 200 mg of pembrolizumab by IV infusion on Day 1 of each 3‐week cycle for up to 35 cycles of treatment plus placebo by IV infusion on Day 1 of each 6‐week cycle for up to 18 cycles of treatment.
Outcomes	Primary outcome measures Overall survival (OS) (time frame: up to approximately 2 years). OS is the time from randomisation to death due to any cause. Progression‐free survival (PFS) (time frame: up to approximately 2 years). PFS is the time from randomisation to first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) by Blinded Independent Central Review (BICR). Secondary outcome measures Objective response rate (ORR) (time frame: up to approximately 2 years). ORR is the proportion of the participants who achieve complete response (CR) or partial response (PR) per RECIST 1.1 by BICR. Duration of response (DOR) (time frame: up to approximately 2 years). DOR is the time from first documented evidence of CR or PR per RECIST 1.1 by BICR until disease progression per RECIST 1.1 by BICR or death. Time to true deterioration (TTD) in cough, pain in chest, and shortness of breath (time frame: on study day 1 prior to initiation of study therapy (baseline) and up to approximately 2 years). Time to true deterioration is defined as the time to the first onset of a 10‐point or greater score decrease from study day 1 prior to initiation of study therapy (baseline) in any one of the 3 symptoms, confirmed by a second adjacent 10‐point or greater score decrease from baseline. Incidence of adverse events (AEs) (time frame: from time of signing the informed consent form (ICF) until the end of follow‐up (up to approximately 118 Weeks)). Percentage of participants experiencing any unfavourable and unintended sign, symptom, disease, or worsening of pre‐existing condition temporally associated with study therapy and irrespective of causality to study therapy. Incidence of discontinuations (time frame: from time of signing the ICF until the end of study therapy (up to approximately 105 Weeks)). Percentage of participants discontinuing study drug due to an AE.
Starting date	Actual study start date: December 14, 2017 Estimated study completion date: February 2024
Contact information
Notes	https://clinicaltrials.gov/ct2/show/NCT03302234