Phase II Trial of Pembrolizumab Plus Gemcitabine, Vinorelbine, and Liposomal Doxorubicin as Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma

Alison J. Moskowitz, MD; Gunjan Shah, MD; Heiko Schöder, MD; Nivetha Ganesan, MPH; Esther Drill, PhD; Helen Hancock, NP; Theresa Davey, PA; Leslie Perez, RN; Sunyoung Ryu, RN; Samia Sohail, MBS; Alayna Santarosa, MPH; Natasha Galasso, MSW; Rachel Neuman, MBA; Brielle Liotta, BS; William Blouin, MBA; Anita Kumar, MD; Oscar Lahoud, MD; Connie L. Batlevi, MD; Paul Hamlin, MD; David J. Straus, MD; Ildefonso Rodriguez-Rivera, MD; Colette Owens, MD; Philip Caron, MD; Andrew M. Intlekofer, MD; Audrey Hamilton, MD; Steven M. Horwitz, MD; Lorenzo Falchi, MD; Erel Joffe, MD; William Johnson, DO; Christina Lee, MD; M. Lia Palomba, MD; Ariela Noy, MD; Matthew J. Matasar, MD; Georgios Pongas, MD; Gilles Salles, MD; Santosha Vardhana, MD; Beatriz Wills Sanin, MD; Gottfried von Keudell, MD; Joachim Yahalom, MD; Ahmet Dogan, MD; Andrew D. Zelenetz, MD; and Craig H. Moskowitz, MD


J Clin Oncol. 2021;39(28):3109-3117. 

In This Article

Abstract and Introduction


Purpose: We conducted a phase II study evaluating pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembro-GVD) as second-line therapy for relapsed or refractory (rel/ref) classical Hodgkin lymphoma (cHL) ( identifier: NCT03618550).

Methods: Transplant eligible patients with rel/ref cHL following first-line therapy were treated with two to four cycles of pembrolizumab (200 mg intravenous [IV], day 1), gemcitabine (1,000 mg/m2 IV, days 1 and 8), vinorelbine (20 mg/m2 IV, days 1 and 8), and liposomal doxorubicin (15 mg/m2, days 1 and 8), given on 21-day cycles. The primary end point was complete response (CR) following up to four cycles of pembro-GVD. Patients who achieved CR by labeled fluorodeoxyglucose-positron emission tomography (Deauville ≤ 3) after two or four cycles proceeded to high-dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). HDT/AHCT was carried out according to institutional standards, and brentuximab vedotin maintenance was allowed following HDT/AHCT.

Results: Of 39 patients enrolled, 41% had primary ref disease and 38% relapsed within 1 year of frontline treatment. 31 patients received two cycles of pembro-GVD, and eight received four cycles. Most adverse events were grade 1 or two, whereas few were grade 3 and included transaminitis (n = 4), neutropenia (n = 4), mucositis (n = 2), thyroiditis (n = 1), and rash (n = 1). Of 38 evaluable patients, overall and CR rates after pembro-GVD were 100% and 95%, respectively. Thirty-six (95%) patients proceeded to HDT/AHCT, two received pre-HDT/AHCT involved site radiation, and 13 (33%) received post-HDT/AHCT brentuximab vedotin maintenance. All 36 transplanted patients are in remission at a median post-transplant follow-up of 13.5 months (range: 2.66–27.06 months).

Conclusion: Second-line therapy with pembro-GVD is a highly effective and well-tolerated regimen that can efficiently bridge patients with rel/ref cHL to HDT/AHCT.


Classical Hodgkin lymphoma (cHL) is often cured with frontline therapy; however, up to 25% of patients with advanced stage and up to 10% with early stage will have relapsed or refractory (rel/ref) disease.[1–3] The standard approach for these patients is second-line therapy (SLT) followed by consolidation with high-dose therapy and autologous hematopoietic cell transplant (HDT/AHCT). The role of HDT/AHCT in rel/ref cHL was established by two randomized studies, published in 1993 and 2002, which showed that 55% of patients who respond to second-line cytotoxic chemotherapy can be cured with HDT/AHCT.[4,5] More recent studies show considerably better outcomes for rel/ref disease with a 2-year progression-free survival (PFS) of about 70% or better.[6,7] Two main factors account for the improved outcomes observed in recent studies: the establishment of pre-HDT/AHCT labeled fluorodeoxyglucose-positron emission tomography (FDG-PET) response as the single most important prognostic factor predicting post-HDT/AHCT outcome and the introduction of SLT containing newer agents for cHL, such as brentuximab vedotin (BV).

We previously reported that the 5-year event-free survival for rel/ref cHL patients with negative pre-HDT/AHCT functional imaging (gallium or FDG-PET) was 75% compared with 31% for patients with persistent abnormalities on functional imaging.[8] Numerous other groups reported similar findings, suggesting that normalization of FDG-PET following SLT should be a goal for patients proceeding to HDT/AHCT.[9–14] There is no single standard SLT for cHL, and traditional options include platinum-based regimens such as ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP) and gemcitabine-based regimens such as ifosfamide, gemcitabine, and etoposide (IGEV), gemcitabine, dexamethasone, and cisplatin (GDP), or gemcitabine, vinorelbine, and doxil (GVD).[15–19] Although these traditional second-line chemotherapy-based regimens induce complete responses (CRs) in about 50%-60% of patients, modern regimens incorporating BV, programmed cell death protein-1 (PD-1) blockade, and/or bendamustine produce CR rates ranging from 67% to 75%.[6,7,15,17,19–25]

Data regarding the incorporation of PD-1 blockade into SLT are limited. The most established regimen is BV plus nivolumab, which has the advantage of outpatient administration and good tolerability. Importantly, it is highly effective, associated with a CR rate of 67% and a 3-year PFS of 77%.[26] One disadvantage of this regimen is that it includes BV, which is increasingly being used in the frontline setting, making it less desirable for SLT.

Building upon the high activity observed with the checkpoint inhibitors pembrolizumab and nivolumab in rel/ref cHL, we aimed to develop a novel immunotherapy-based SLT regimen for cHL.[27,28] We sought to develop an SLT regimen that is well-tolerated, outpatient administrated, and associated with high CR rates. We chose the GVD regimen as the backbone for use in this study for its favorable toxicity profile and outpatient compatibility. GVD was first evaluated in a phase I or II multicenter study sponsored by the Cancer and Leukemia Group B in both transplant-naïve and previously transplanted patients. The overall response rate (ORR) by computed tomography (CT) alone was 70%.[17] Each drug in the GVD regimen can potentially stimulate tumor-specific immune responses through various mechanisms, and thus, we hypothesized that the off-target immunologic effects of GVD would enhance the efficacy of pembrolizumab in patients with cHL.[29] In this phase II study, we aimed to establish the safety and efficacy of pre-HDT/AHCT pembrolizumab combined with GVD for rel/ref cHL.

Relevance section written by JCO Editor-in-Chief Jonathan W. Friedberg, MD.