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)

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/m² intravenously (I.V.) on days 1, 8, 29, and 36, and etoposide 50 mg/m² I.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.