Low-Dose Radiation Therapy with Nivolumab in Patients with Relapsed/Refractory Hodgkin Lymphoma: Results of the Phase II Radvax Trial

Background: Patients (pts) with relapsed or primary refractory (r/r) Hodgkin lymphoma (HL) who do not achieve complete response (CR) to PD-1 inhibitors have limited options. Suboptimal response to checkpoint blockade may be a result of T-cell exhaustion and lack of immune recognition. Prior clinical trials have shown that a novel "vaccine-like" (RadVax) approach using radiation therapy (RT) in combination with PD-1 inhibitors may be a promising strategy to stimulate immunogenicity for solid malignancies. Lymphomas have not been formally studied with this strategy. HL is unique in its high sensitivity to both RT and PD-1 inhibitors. Here we report the initial results of a prospective trial testing the combination of nivolumab and very low-dose RT (VLDRT) with 4 Gy x 2 fractions in pts with r/r HL who achieve less than CR to nivolumab monotherapy.

Methods: This phase II, single-arm, single-institution, investigator-initiated open label clinical trial (NCT03495713) tested nivolumab with VLDRT in pts with pathologically confirmed r/r classic HL. Eligible pts were >18 years old, had ECOG performance status of <2, and had ≥2 sites of measurable disease, with at least 1 site outside the intended VLDRT field. Initially, only pts who were not previously exposed to PD-1 inhibitors were enrolled, treated with nivolumab and underwent response assessment at 8-12 weeks to determine eligibility for VLDRT. The trial was later amended to include pts already on nivolumab if their pre-enrollment PET/CT showed failure to achieve CR. Nivolumab 3 mg/kg IV was given every 2 weeks or 480 mg every 4 weeks at the discretion of the treating physician and it was continued throughout the duration of the study. Response assessment was obtained 8-12 weeks after VLDRT using Lugano criteria. The primary outcome was overall CR rate at 8-12 weeks following VLDRT; secondary outcomes included overall survival (OS), progression free survival (PFS), and adverse events (AE).

Results: Between 11/2018 and 8/2021, 7 pts were enrolled, with median age of 29 years (range 20-51). Characteristics are described in Table 1. Five pts had a history of prior radiation. All pts received nivolumab monotherapy as the 5^th line of systemic therapy. Subject 1 achieved CR on initial assessment following nivolumab and was not eligible for VLDRT. Of the remaining 6 pts, 3 showed progressive disease (PD) and 3 stable disease (SD) to nivolumab monotherapy and were eligible to proceed with VLDRT. Post-VLDRT response assessment in the non-radiated lesions showed partial response (PR) in 2 (33%) pts (their prior response to nivolumab was SD in 1 and PD in 1), SD in 2 (33%), and PD in 2 (33%) (Table 2). No subject had disease progression within the VLDRT fields at time of last imaging, with a median time to imaging follow-up of 17 months. All 7 pts are alive at the time of last follow-up, with a median clinical follow-up of 22 months. There were no unexpected toxicities with the RadVax approach using VLDRT. All pts reported grade 1 AEs, and 4 pts reported grade 2 AEs, similar to those reported with nivolumab monotherapy. Blood specimens were collected for future correlative studies.

Conclusions: Based on results from this small cohort of pts with r/r HL who did not achieve CR to nivolumab monotherapy, VLDRT may enhance response in non-irradiated sites in a subset of pts. We also demonstrated that VLDRT in combination with nivolumab achieved durable local control for r/r HL, which may merit further evaluation in the palliative setting. Future investigations including larger number of pts and any correlatives will be necessary to explore the potential benefit of the RadVax approach in r/r HL.

LaRiviere:Merck: Research Funding. Schuster:AbbVie: Research Funding; Adaptive Biotechnologies: Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Fate Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Genmab: Consultancy; Incyte: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Legend Biotech: Consultancy; Loxo Oncology: Consultancy; Merck: Research Funding; MorphoSys: Consultancy; Mustang Biotech: Consultancy; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmacyclics: Research Funding; Regeneron: Consultancy; Roche: Consultancy, Research Funding; TG Therapeutics: Research Funding. Chong:Beigene: Consultancy; Novartis: Consultancy; KITE: Consultancy; Tessa: Consultancy; Juno/BMS: Consultancy. Landsburg:Calithera: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Curis, Inc: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Plastaras:Merck: Research Funding. Svoboda:TG: Research Funding; SEAGEN: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Consultancy; BMS: Consultancy, Research Funding; Atara: Consultancy; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADCT: Consultancy.