Final Result of DIAL (NCI10089), Randomized Phase 2 trial of Varlilumab combined with Nivolumab in patients with relapsed/refractory aggressive B‐cell non‐Hodgkin lymphoma

Introduction: The prognosis for patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL) is poor. The efficacy of combining nivolumab (PD-1 inhibitor) and varlilumab (CD27 agonist) was tested in this population in the multi-center randomized phase II DIAL study (Dual Immunomodulation in Aggressive Lymphoma). Methods: Patients with r/r B-NHL were randomized to treatment with nivolumab alone or combined with varlilumab (Figure 1A). Cross-over (group 1 to 2) was allowed for progression. Primary endpoint was overall response (ORR) per LYRIC criteria, by intention-to-treat. A sample size of 48 patients per arm would provide 80% power to detect increase in ORR from 25% to 45% using a one-sided test (p = 0.15). Pre-specified interim analysis occurred after half of patients completed first radiologic assessment. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Exploratory endpoints included tumor genomic assessment and immune profiling of blood and tumor. Results: 51 patients were enrolled (25 in group 1; 26 in group 2) between November 2017 and August 2022 with median follow-up of 8.8 months. Mean age was 65.5 years, 36 (71%) were male, and 90% of patients had at least 3 prior lines of therapy. Prior CAR-T cell therapy was confirmed in 33 (65%) patients. Baseline characteristics were balanced between arms. There were no treatment-associated deaths. Proportion of grade ≥3 AEs were similar in both groups. ORR was achieved in 6 patients (12%), not statistically different between arms; 4 responses were complete (Figure 1B). Seven patients crossed over (1 responded after crossing). Median OS (9.3 vs. 7.3 months; p = 0.24; Figure 1C) did not differ between arms and median PFS (2.6 vs. 1.4 months; p = 0.04; Figure 1D) was statistically higher in group 1. Subgroup analysis of patients with confirmed prior CAR-T cell therapy showed similar ORR compared to overall cohort (5/33; 15%), not statistically different between arms; 3 responses were complete (Figure 1B). In this subgroup, median OS (9.3 vs. 10.9 months; p = 0.5) and PFS (2.8 vs. 1.4 months; p = 0.05) did not differ between arms. Correlative analysis results including CyTOF, whole exome, and whole transcriptome sequencing will be presented at conference. The trial met pre-specified futility criterion on interim analysis and is permanently closed. The research was funded by: National Cancer Institute (NCI), Department of Defense (DOD), Mayo Clinic, Lymphoma Research Foundation (LRF). Keywords: Aggressive B-cell non-Hodgkin lymphoma, Immunotherapy Conflicts of interests pertinent to the abstract. A. Lazaryan Consultant or advisory role: Sanofi P. Ramakrishnan Geethakumari Consultant or advisory role: Kite Pharma, Bristol Myers Squibb, Rafael Pharma, Pharmacyclics LLC, ADC Therapeutics, Cellectar Biosciences, Ono Pharma R. Karmali Consultant or advisory role: BMS, Gilead Sciences/Kite Pharma, Janssen, Pharmacyclics, Morphosys, Epizyme, Genentech/Roche, Calithera, Miltenyi, Lilly Oncology Research funding: BMS, Takeda, BeiGene, Gilead Sciences/Kite, Calithera Other remuneration: Speakers Bureau: AstraZeneca, BeiGene, Morphosys