title: Treatment Design and Rationale for a Randomized Trial of Cisplatin and Etoposide Plus Thoracic Radiotherapy Followed by Nivolumab or Placebo for Locally Advanced Non-Small-Cell Lung Cancer (RTOG 3505).
abstract: Radiation Therapy Oncology Group (RTOG) 3505 is a randomized phase 3 study of concurrent chemoradiation followed by immune checkpoint inhibitor therapy or placebo in patients with locally advanced non-small-cell lung cancer (NSCLC). Patients with surgically unresectable stage 3 NSCLC will receive thoracic radiotherapy to 60 Gy with concurrent cisplatin 50 mg/m2intravenously (I.V.) on days 1, 8, 29, and 36, and etoposide 50 mg/m2I.V. on days 1 to 5 and days 29 to 33. Between 4 and 12 weeks after completion of concurrent chemoradiation, eligible patients will be randomized to the anti-programmed death 1 (PD-1) monoclonal antibody nivolumab 240 mg I.V. or placebo every 2 weeks for up to 1 year. The primary end points are overall survival (OS) and progression-free survival (PFS), as determined by central independent radiology review. Secondary objectives include toxicity assessment, patient-reported outcomes and quality of life, and OS and PFS in programmed death ligand 1 (PD-L1) expressors (≥ 1%) and PD-L1 nonexpressors (< 1%). Assuming a rate of 16.7% due to ineligibility and dropout before randomization, a total of 660 patients will be enrolled to ensure 550 patients will be randomized after completion of chemoradiation. This sample size will provide ≥ 90% power to detect a hazard ratio of 0.7 for OS with 2-sided type I error of 0.04, and to detect a hazard ratio of 0.667 for PFS 2-sided type I error of 0.01. (NCT02768558).
authors.affiliation: Harold C. Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: david.gerber@utsouthwestern.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Gerber
authors.affiliation: University of California San Diego, San Diego, CA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Urbanic
authors.affiliation: University of Pennsylvania, Philadelphia, PA.
authors.forename: Corey
authors.initials: C
authors.lastname: Langer
authors.affiliation: Johns Hopkins University, Baltimore, MD; RTOG Foundation, Philadelphia, PA.
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.affiliation: Bristol-Myers Squibb, New York, NY.
authors.forename: I-Fen
authors.initials: IF
authors.lastname: Chang
authors.affiliation: Thomas Jefferson University, Philadelphia, PA.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.affiliation: Henry Ford Hospital, Detroit, MI.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Movsas
authors.affiliation: University of Wisconsin Carbone Cancer Center, Madison, WI.
authors.forename: Robert
authors.initials: R
authors.lastname: Jeraj
authors.affiliation: Emory University Medical Center, Atlanta, GA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Washington University School of Medicine, St. Louis, Mo.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Bradley
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000401:mortality / Q000628:therapy*; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D005047:Etoposide / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000401:mortality / Q000628:therapy*; D008875:Middle Aged; D009367:Neoplasm Staging; D000077594:Nivolumab; D015990:Placebo Effect; D016016:Proportional Hazards Models; D012107:Research Design; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000077594:Nivolumab; D005047:Etoposide; D002945:Cisplatin
keywords: Abscopal effect; Checkpoint inhibitor; Coprimary end points; Immunotherapy; Programmed death 1 (PD-1)