S203: ABSCOPAL EFFECT OF RADIOTHERAPY AND NIVOLUMAB IN RELAPSED OR REFRACTORY HODGKIN LYMPHOMA: PRE-PLANNED INTERIM ANALYSIS OF THE INTERNATIONAL GHSG PHASE II AERN TRIAL (2022)

Background: Failure of anti-PD1 checkpoint blockade in relapsed or refractory Hodgkin lymphoma (r/r HL) constitutes an unmet medical need. It has been postulated that anti-PD1 and localized radiotherapy (RT) may work synergistically to induce a systemic anti-lymphoma effect resulting in distant and systemic (“abscopal”) response outside the RT field. Aims: We aimed to formally investigate safety and efficacy of nivolumab and RT in r/r HL failing anti-PD1 treatment in a proof-of-concept study. Methods: AERN is an ongoing international investigator-sponsored two stage phase II trial enrolling adult patients with histologically confirmed r/r HL (NCT03480334). All patients must have failed anti-PD1 treatment by either showing progressive disease (PD) or stable disease (SD) >6 months as best response at the time of enrollment. Presence of two distinct FDG-avid lesions with one eligible for 20Gy localized RT and the other >5cm apart and outside the prescribed 95%isodose for measurement of an abscopal response must be confirmed by the GHSG reference panel. After enrollment patients receive 240mg nivolumab 2-weekly and 20Gy RT in 2Gy fractions is started on day 6 after the first infusion on trial. Treatment is continued until PD or unacceptable toxicity or for a maximum of 1.5 years. The primary endpoint is abscopal response rate (ARR) at first interim restaging after six infusions, secondary endpoints include objective response rate (ORR), progression-free survival (PFS), overall survival and safety. Target enrollment are nine and 20 patients in a Simon’s two-stage desig. A pre-planned interim analysis was conducted after completion of stage I and is reported herein. Results: Of 11 patients enrolled into stage I of the trial, two terminated trial participation early (screening failure, withdrawal of informed consent) and nine patients at a median age of 34 (range 25-82) years were evaluable for stage I. All patients presented with stage III/IV and a median of 4 (3-15) prior lines of treatment. While all patients had received prior anti-PD1 antibodies (100%), the majority also received brentuximab vedotin (89%) and high-dose chemotherapy plus autologous stem-cell transplantation (ASCT, 56%). Trial treatment was well tolerated. The most frequently reported °1/2 toxicities were those affecting the skin (55%), one case of °3 gastrointestinal and no °4/5 toxicities. Patients received a median of 19 (7-36) nivolumab infusions with a median treatment duration of 9 (3-18) months. At first interim restaging, five patients had an abscopal response (ARR 56%, 95%CI 16.9-74.9%) by central response assessment and 56% achieved a PR (ORR 56%). Most patients experienced a reduction in disease burden at first interim restaging with a mean decrease of SPD -36.3% (0 to -81.2%). Four out of five patients discontinuing treatment experienced PD at the last restaging. With a median observation time of 15.5 months, the 1-year PFS was 42.3% and all patients were alive at data cut off. Summary/Conclusion: Treatment with nivolumab and 20Gy RT at a single lesion was well tolerated and led to an abscopal response in the majority of patients (56%) previously failing anti-PD1 treatment for r/r HL. An ORR of 56% and 1-year PFS of 42.3% further highlight the potential of this innovative treatment strategy. After meeting the primary efficacy endpoint in this pre-planned interim analysis, AERN trial enrollment is currently continuing internationally.