Abscopal Effect of Radiotherapy and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma: Results of the International GHSG Phase II Aern Trial

Background: Failure of anti-PD1 treatment (aPD1) in patients with relapsed or refractory classical Hodgkin lymphoma (rrHL) is a clear unmet medical need. Whether the addition of local radiotherapy (RT) to continued aPD1 is feasible, effective and able to induce a systemic (“abscopal”) response (AR) in this setting is unknown. Methods: The international GHSG phase II AERN trial (NCT03480334) enrolled rrHL patients with failure of aPD1 as last line of therapy. Patients were enrolled latest 4 weeks after the last aPD1 dose without any intermittent therapy. After enrollment, all patients received 240mg nivolumab at 2-weekly intervals for a maximum of 18 months. Administration of 20Gy RT in 2Gy fractions to a single lesion started within days after the first nivolumab dose on trial. The primary endpoint was centrally determined AR at first restaging after completion of 20Gy local RT and 6x nivolumab (RE-6). AR was defined as a response of at least one lesion ≥5 cm distant from the RT-lesion and outside the 10% isodose of the RT-field. Secondary endpoints included toxicity, objective response rate (ORR), progression-free (PFS) and overall survival (OS). Results: A total of 25 patients (40% female) with a median age of 37 years (range: 25-90) that had received a median of 4 (range 2-15) prior lines of therapy and predominantly presented with stage III/IV HL (88%) were enrolled. Most patients had prior received autologous stem-cell transplantation (72%) , brentuximab vedotin (72%) and/or RT (72%). As required, all patients failed aPD1 (nivolumab: 60%, pembrolizumab: 40%) as last line of therapy. Most patients (96%) had experienced progressive disease immediately before enrollment and only one patient was included due to stable disease >6 months as best response to aPD1. With a median treatment duration on study of 6.9 months (0-17.5), patients received a median of 14 (1-36) nivolumab infusions. One patient withdrew consent after the first nivolumab infusion and did not start RT on trial. All other patients received photon RT starting a median of 6 days (3-9) after the first nivolumab infusion on trial. Treatment was well tolerated with skin and mucosa reactions being the most frequent adverse events (all ≤grade 2) and overall, no new safety signals emerged. Of the 24 patients centrally evaluable at RE-6, 11 (45.8%, 95%CI: 35.8-71.8%) achieved an AR, meeting the predefined efficacy endpoint. ORR was 37.5% (1 complete, 8 partial response) and 6 patients had stable disease (25.0%; disease control rate 62.5%). At RE-6 mean change in the sum of product of diameters (SPD) was -23.9% (range: +56% to -81%). The majority of patients (71%) experienced a reduction of total metabolic tumor volume (MTV, SUV 4.0) with a median MTV reduction of -53.4% (range: +547% to -100%). With a median observation time of 16.1 months, the 12- and 18-month PFS estimates were 29.2% (95%CI: 11-47) and 12.5% (95%CI: 0-26), respectively. With a median follow-up for survival of 20.2 months, the 12- and 18-month OS rates were 100% and 76% (95%CI: 55-97), respectively. Out of five deaths, three were due to toxicity of subsequent allogeneic stem-cell transplantation and two due to rrHL. Ongoing analyses of longitudinal blood samples show significant associations of T- and NK-cell subsets with AR at RE-6 and additionally indicate a correlation between TARC dynamics and response. Conclusions: In this prospective trial, the addition of local RT to aPD1 is feasible and effective, resulting in a systemic anti-tumor effect outside the RT field in approximately half of the rrHL patients failing aPD1 treatment alone. While partial responses and even a complete remission were observed, PFS appears to be limited and most patients required subsequent alternative treatment.