Pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin as second-line therapy in relapsed or refractory Hodgkin lymphoma: 5-year update of a multicenter, Phase 2 trial

Abstract Background: The incorporation of novel agents such as brentuximab vedotin (BV) and immune checkpoint blockade (ICB) into salvage therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) has significantly improved long-term outcomes for patients. A phase II trial assessed the safety and efficacy of pembrolizumab, gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD) in transplant-eligible patients with rel/rel cHL, and demonstrated a complete response (CR) rate of 95% and progression-free survival (PFS) of 100% at 13.5 months. Herein, we present an updated analysis of this phase II trial at 5 years (ClinicalTrials.gov identifier: NCT03618550). Methods: This was an investigator-initiated, single-arm, phase II trial conducted at Memorial Sloan Kettering Cancer Center and the University of Miami Sylvester Comprehensive Cancer Center. Eligible patients had biopsy-proven rel/ref cHL following a single line of multi-agent chemotherapy, were aged at least 18 years, and had an Eastern Cooperative Oncology Group (ECOG) performance score of <2. Patients received pembrolizumab 200mg intravenous (IV) (day 1), gemcitabine 1,000mg/m2IV (days 1 and 8), vinorelbine 20mg/m2(days 1 and 8), and liposomal doxorubicin 15mg/m2IV (days 1 and 8) in 21-day cycles. Those who achieved CR following two or four cycles of pembrolizumab-GVD proceeded to high-dose therapy with BEAM (carmustine, etoposide, cytarabine, melphalan) and autologous hematopoietic stem cell transplantation (HDT/AHCT). The primary endpoint was CR following salvage pembrolizumab-GVD; secondary endpoints were PFS and overall survival (OS). Results: 39 patients were enrolled. The median age was 38 (range 21 to 71), and 46% of patients were men. At the time of enrollment, 41% of patients had Lugano stage I or II disease, while 59% of patients had stage III or IV disease. Twelve patients (31%) had extranodal disease. Sixteen (41%) patients had primary refractory disease, while 23 patients (59%) had relapsed disease, with 15 of 23 patients relapsing within 1 year. Most patients received ABVD in the front-line setting; no patients received immune checkpoint blockade as part of front-line therapy. Thirteen patients (33%) received maintenance post-ASCT with BV (n=12) or BV-nivolumab (n=1, as part of a clinical trial), for a median of 5 cycles (range 1-11). Two patients (5%) received radiation therapy (RT) prior to HDT/ASCT. Of 38 response-evaluable patients, the CR and overall response rate (ORR) after up to 4 cycles of pembrolizumab-GVD were 95% and 100%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, with 24 of 36 patients (67%) experiencing engraftment syndrome post-transplant requiring treatment with systemic steroids. After a median follow-up of 57 months, 1 of 38 patients experienced disease recurrence (23 months after HDT/AHCT), and two of 38 patients died from non-relapse related causes (41 months and 33 months after HDT/AHCT, from sudden cardiac death during exercise and complications of auto-immune hemolytic anemia, respectively). Estimated 5-year PFS and OS were 91% and 94%, respectively. No new safety signals were identified with extended follow-up. Conclusion: Pembrolizumab-GVD followed by consolidative HDT/AHCT achieves durable and long-term responses in patients with rel/ref cHL, with a manageable safety profile. Based on the robust long-term outcomes seen in this study, our group is evaluating whether HDT/AHCT can be omitted, with a randomized study comparing HDT/AHCT versus pembrolizumab maintenance in patients who achieve CR to pembrolizumab-GVD currently underway.