Phase II Study of Pembrolizumab Plus GVD As Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma

ABSTRACT

Introduction: The standard approach for relapsed or refractory (RR) classical Hodgkin lymphoma (cHL) following front-line treatment failure is second line therapy (SLT) aimed to achieve complete response (CR), followed by consolidation with high dose therapy and autologous hematopoietic cell transplantation (HDT/AHCT). No one standard SLT exists and options include regimens containing platinum, gemcitabine, and more recently brentuximab vedotin (BV). Complete response rates associated with these regimens range from 50-70%. Due to the increasing use of BV in the front-line setting, development of SLT regimens that are both highly effective and BV-sparing are needed. Programmed death-1 (PD-1) inhibitors are highly active in RR cHL and have the potential to enhance the efficacy of standard chemotherapy. Here we report the results of our phase II study evaluating a novel anti-PD-1-based regimen, pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin (pembrolizumab-GVD), as SLT for RR cHL. Methods: Transplant eligible patients (pts) with RR cHL following failure of 1-line of therapy were eligible. Treatment consisted of 2 to 4 cycles of pembrolizumab (200mg IV, day 1), gemcitabine (1000mg/m2 IV, days 1 and 8), vinorelbine (20mg/m2 IV, days 1 and 8) and liposomal doxorubicin (15mg/m2, days 1 and 8), given on 21-day cycles. Pts who achieved CR by PET (Deauville ≤3) after 2 or 4 cycles proceeded to HDT/AHCT. HDT/AHCT was carried out according to institutional standards and BV maintenance was allowed following HDT/AHCT. The primary endpoint was CR rate after 2 or 4 cycles of pembrolizumab-GVD. Enrollment occurred according to a Simon 2-stage design with sample size based upon a projected CR rate of 70%. In stage 1, 23 pts enrolled and 12 or more CRs were required to proceed to stage II;in stage II, an additional 16 pts enrolled. Out of a total of 39 pts, 24 CRs were required to declare this regimen promising. Results: Among 39 patients enrolled, 37 are evaluable for toxicity (2 pts have not yet started treatment) and 34 are evaluable for response (4 pts too early, 1 pt found to have composite lymphoma after enrollment). Of 37 treated pts, median age is 36 (range 21-71), 43% are male, 23 (62%) had advanced stage disease, and 15 (41%) had primary refractory disease. With regard to RR cHL risk factors (B-symptoms, extranodal disease, and relapse/refractory disease within 1 year of initial treatment), 4(11%) had no risk factors (RFs), 21 (57%) had 1 RF, 9 (24%) had 2 RFs, and 3 (8%) had all 3 RFs. Treatment was well tolerated with most adverse events being grade 1 or 2 (see figure 1). Grade 3 AEs included rash (n=1), elevated AST/ALT (n=3), oral mucositis (n=2), and neutropenia (n=3). Figure 2 shows the outcome for all 37 treated pts. Among 34 evaluable pts, 31 (91%) achieved CR after 2 cycles and 3 achieved partial response. An additional 1 pt achieved CR after 4 cycles of pembrolizumab-GVD, therefore in total, 32 of 34 (94%) achieved CR following pembrolizumab-GVD. 4 pts with CR after 2 cycles received an additional 2 cycles of pembrolizumab-GVD in order to delay HDT/AHCT during the height of the COVID-19 pandemic (n=3) or due to refusing HDT/ASCT (n=1). To date, 32 have undergone HDT/AHCT following 2 (n=27) or 4 (n=5) cycles of treatment. 1 pt is awaiting HDT/AHCT;1 pt refused HDT/ASCT and received pembrolizumab maintenance instead. 2 pts received involved site radiation therapy to initial area of relapsed disease prior to planned HDT/AHCT and 10 pts received post-HDT/ASCT maintenance with BV. Median follow-up post-HDT/AHCT is 9 mos (range 0.03-20.9 mos) and all pts remain in remission to date. Conclusion: Second-line therapy with pembrolizumab-GVD is a highly effective and well-tolerated regimen that can efficiently bridge pts with RR cHL to HDT/AHCT. Updated results including all 39 enrolled pts will be presented at the meeting. Given the high CR rate observed with pembrolizumab-GVD, an expansion cohort evaluating 8 cycles of pembrolizumab maintenance (instead of HDT/AHCT) for patients who achieve CR af er 4 cycles of pembrolizumab-GVD is planned. [Formula presented] Disclosures Moskowitz Merck Consultancy;Incyte Research Funding;Miragen Therapeutics Consultancy;Seattle Genetics Consultancy;Imbrium Therapeutics, L.P. Consultancy;Merck Research Funding;Seattle Genetics Research Funding;Bristol-Myers Squibb Research Funding. Shah Amgen Inc. Research Funding;Janssen Research Funding. Kumar AbbVie Research Funding;Celgene Honoraria, Other Honoraria for Advisory Board;Seattle Genetics Research Funding;Astra Zeneca Honoraria, Other Honoraria for Advisory Board;Celgene Research Funding;Kite Pharmaceuticals Honoraria, Other Honoraria for Advisory Board;Adaptive Biotechnologies, Research Funding;Pharmacyclics Research Funding. Lahoud MorphoSys Other Advisory Board. Batlevi Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite Consultancy;Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech Research Funding. Hamlin J&J Pharmaceuticals Research Funding;Portola Research Funding;Incyte Research Funding;Portola Pharmaceutics Consultancy;Juno Therapeutics Consultancy;Karyopharm Consultancy;Celgene Consultancy;Molecular Templates Research Funding. Straus Karyopharm Therapeutics Membership on an entity's Board of Directors or advisory committees;Imedex, Inc. Speakers Bureau;Targeted Oncology Consultancy, Speakers Bureau;NY Lymphoma Rounds Consultancy;Takeda Pharmaceuticals Research Funding, Speakers Bureau;OncLive Speakers Bureau;Elsevier Membership on an entity's Board of Directors or advisory committees, Other CME writer;ASH Other Conference in December 2019 on HL to other physicians during ASH;Seattle Genetics Consultancy, Membership on an entity's Board of Directors or advisory committees. Horwitz ASTEX Consultancy;Verastem Consultancy, Research Funding;Myeloid Therapeutics Consultancy;Miragen Consultancy;Kura Oncology Consultancy;Janssen Consultancy;GlaxoSmithKline Consultancy;Daiichi Sankyo Research Funding;C4 Therapeutics Consultancy;Affirmed Consultancy;Vividion Therapeutics Consultancy;Beigene Consultancy;Portola Consultancy, Research Funding;Mundipharma Consultancy;Innate Pharma Consultancy;Corvus Consultancy;Trillium Consultancy, Research Funding;Seattle Genetics Consultancy, Research Funding;Millenium/Takeda Consultancy, Research Funding;Kyowa Hakka Kirin Consultancy, Research Funding;Infinity/Verastem Research Funding;Forty Seven Consultancy, Research Funding;Celgene Consultancy, Research Funding;Aileron Consultancy, Research Funding;ADCT Therapeutics Consultancy, Research Funding. Falchi Genmab Research Funding;Roche Research Funding. Joffe Epizyme Membership on an entity's Board of Directors or advisory committees;AstraZeneca Membership on an entity's Board of Directors or advisory committees. Noy Pharmacyclics Research Funding;Pharmacyclics Consultancy;Janssen Consultancy;Rafael Pharma Research Funding;NIH Research Funding;Morphosys Consultancy;Medscape Consultancy;Targeted Oncology Consultancy. Matasar Teva Consultancy;Genentech, Inc. Consultancy, Honoraria, Research Funding;Merck Consultancy;Bayer Consultancy, Honoraria, Research Funding;Juno Therapeutics Consultancy;F. Hoffmann-La Roche Ltd Consultancy, Honoraria, Research Funding;GlaxoSmithKline Honoraria, Research Funding;IGM Biosciences Research Funding;Janssen Honoraria, Research Funding;Pharmacyclics Honoraria, Research Funding;Immunovaccine Technologies Honoraria, Research Funding;Rocket Medical Consultancy, Research Funding;Takeda Consultancy, Honoraria;Daiichi Sankyo Consultancy;Seattle Genetics Consultancy, Honoraria, Research Funding. Vardhana Other Other SAV has received honoraria from Agios Pharmaceuticals and Rheos Pharmaceuticals, is an advisor for Immunai and has consulted for ADC Therapeutics. von Keudell Genentech Research Funding;Bayer Research Funding;Pharmacyclics Research Funding. Zelenetz Novartis Consultancy;Janssen Consultancy;Celge e Consultancy;Amgen Consultancy;Adaptive Biotechnology Consultancy;BeiGene Membership on an entity's Board of Directors or advisory committees;Roche Research Funding;Gilead Research Funding;Genentech/Roche Consultancy;Gilead Consultancy;Sandoz Research Funding;Celgene Research Funding;MEI Pharma Research Funding;MorphoSys Research Funding. OffLabel Disclosure Pembrolizumab as second-line therapy for Hodgkin lymphoma