A Randomized Phase 2 Trial of Nivolumab and Stereotactic Ablative Body Radiotherapy (SABR) in Advanced Non-Small Cell Lung Cancer, Progressing After First- or Second-Line Chemotherapy (NIVORAD).

Abstract

Synergy and abscopal phenomena have been observed with radiation and immunotherapy in pre-clinical and early clinical studies. Nivolumab, a PD-1 receptor antibody, improved overall survival in advanced NSCLC progressing after chemotherapy. We hypothesized that the addition of SABR might increase the activity of nivolumab. The aim of NIVORAD was to determine the activity and safety of treating a site of disease with a single fraction of SABR during therapy with nivolumab in advanced NSCLC progressing after 1 or 2 lines of chemotherapy. Adults with metastatic NSCLC progressing after 1 or 2 lines of chemotherapy and a disease site suitable for SABR were randomly assigned (2:1) to either nivolumab 240mg 2-weekly until disease progression or prohibitive toxicity given together with a single fraction of SABR (18-20 Gy on day 8-14 of cycle 1); or, the same regimen of nivolumab without SABR. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints included objective tumor response rate (OTRR), overall survival (OS), PFS at 1 year and 2 years, and adverse events (AEs). The planned sample size of 120 provided 80% power with a 1-sided type 1 error rate of 5% to distinguish the observed proportions alive and progression free at 6 months from benchmarks of 50% (worthy of pursuit) versus 35%. The study was closed early because of slow accrual. Fifty of the planned 120 participants were recruited from MAR2017 to JUN2019 (median age 66 years; male 58%; ECOG PS 0 32%, PS 1 68%; current smoker 30%) and randomly assigned to either nivolumab plus SABR (n = 34) or nivolumab alone (n = 16). Median follow-up was 25 months. PFS was similar among those assigned nivolumab plus SABR versus nivolumab alone (HR = 0.82, 95% CI 0.44 to 1.54, P = 0.6; PFS at 6mo 44% vs 43%, at 1y 27% vs 19%, and at 2y 16% vs 6%, respectively). OTRR (8/34 [24%] vs 4/16 [25%]) and OS (HR 0.94, P = 0.9) were also similar in the two treatment groups, as were the numbers of participants with grade 3-4 AEs: 24/30 (80%) vs 12/16 (75%) respectively. There were no treatment-related deaths in either arm. Nivolumab plus SABR demonstrated similar activity and safety to nivolumab alone in NSCLC progressing after 1 or 2 lines of chemotherapy, with a potential signal of long-term efficacy, although the study was underpowered to detect this. Research should focus on identifying more active regimens of SABR and immunotherapy worthy of further evaluation.