Pembro-CORE: Interim analysis of a phase II PET-adapted trial omitting high-dose chemotherapy with PD-1-based salvage in first-relapsed Hodgkin lymphoma

Abstract

Abstract Introduction: Relapsed and refractory classic Hodgkin lymphoma (cHL) is typically treated with salvage chemotherapy, followed by high-dose chemotherapy (HD-CT) and autologous stem cell transplantation (ASCT). This standard approach, however, achieves long-term remission in only about 60% of patients. Moreover, severe short- and long-term side effects remain major concerns. Recent studies suggest high response rates of up to 95% and unprecedented progression-free survival (PFS) with anti-programmed cell death protein 1 (PD-1)-based salvage regimens such as pembrolizumab, gemcitabine, vinorelbine, and liposomal doxorubicin (P-GVD). Therefore, we hypothesize that anti-PD1-based chemotherapy combinations might allow patients who achieve a negative PET during therapy to be spared from the highly toxic HD-CT. Methods: Pembro-CORE (NCT04838652) is a multicenter phase II trial investigating a HD-CT free approach for first-relapsed cHL by combining the anti-PD1-antibody pembrolizumab with salvage chemotherapy. Initiated in March 2024 at four German centers, the trial has enrolled 23 patients to date. Patients receive an initial cycle of pembrolizumab followed by two cycles of P-ICE (pembrolizumab, ifosfamide, carboplatin, etoposide). After PET restaging, complete responders continue with two more cycles of P-ICE, while patients failing to achieve a complete response switch to two cycles of P-DHAP (pembrolizumab, dexamethasone, high-dose cytarabine, cisplatin). A second PET restaging after five cycles determines further treatment; PET-positive cases are treated outside the study per standard of care (SOC). Complete responders in the P-DHAP arm may receive two additional cycles of P-DHAP consolidation and undergo a third restaging. Persistent PET positivity at the third restaging leads to SOC treatment. Treatment concludes with eight consolidation cycles of pembrolizumab until final staging. The primary endpoint is the complete metabolic response rate (CMR), defined as the proportion of patients achieving a Deauville score of 1–3 after treatment with one infusion of pembrolizumab followed by either four cycles of P-ICE or two cycles of P-ICE followed by two cycles of P-DHAP. This measures the proportion of patients who can avoid HD-CT. Results: A total of 23 of the planned 29 patients were enrolled at the time of the interim analysis (data cutoff 14th July 2025) (60.9 % male, 39.1 % female; mean age 37.2 ± 10.8 years). At baseline, 73.9 % had ECOG 0 and 26.1 % ECOG 1. At relapse, Ann Arbor stages I–IV were distributed as 8.7 %, 43.5 %, 26.1 % and 21.7 %, respectively; GHSG risk-group at first diagnosis was advanced in 47.8 %, early-unfavorable in 47.8 % and early-favorable in 4.3 %. B-symptoms at relapse occurred in 26.1 %. First-line regimens comprised 2×eBEACOPP + 2×ABVD (47.8 %), eBEACOPP-like (47.8 %) or ABVD-like (4.3 %) protocols, with a median of four cycles (range 2–8) administered. At the first restaging (with n=20 patients evaluable), 50% had a CMR and 50% had a partial response and underwent further treatment with two cycles of P-ICE or P-DHAP, respectively. At the time of data cutoff, 15 patients had already reached the primary endpoint - either four cycles of P-ICE or two cycles of P-ICE followed by two cycles of P-DHAP. At this time point, 93.3 % of patients achieved a complete response. A total of nine serious adverse events were reported. Of these, only one was confirmed as immune-related (immune-mediated colitis). Other events included acute kidney injury (n=2), febrile neutropenia (n=2), respiratory tract infections (n=2), and viral dermatitis (n=1). In addition to the patient with colitis, another patient had to withdraw from the trial due to possibly immune-related elevation of liver enzymes. Four patients had progressive disease in the interim or end-of-treatment staging. Conclusion: The interim analysis of the Pembro-CORE trial demonstrates promising early results for a PET-adapted, HD-CT-free treatment strategy in first-relapsed cHL. A high CMR of 93.3% was observed among evaluable patients reaching the primary endpoint restaging. However, thus far four patients showed relapse in imaging-based assessment. Updated data will be presented at the conference.