ABSTRACT
Background: While time-limited novel agent combinations have demonstrated high overall response rates and durable responses for patients with chronic lymphocytic leukemia (CLL), they also have high rates of adverse events and possibly overtreat many favorable risk patients. Meanwhile, patients receiving indefinite ibrutinib monotherapy are at risk for cumulative toxicity and acquired resistance with continuous exposure. To address these challenges, we utilized an 'add-on' approach to combination therapy after a period of ibrutinib monotherapy exposure. We examined the addition of umbralisib (a selective PI3Kδ and casein kinase-1epsilon [CK1ϵ] inhibitor) and ublituximab (a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity;U2) to ibrutinib in CLL patients with detectable minimal residual disease (MRD) after an initial period of treatment with ibrutinib monotherapy. With this strategy, we aimed to induce undetectable MRD (uMRD), minimize the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and achieve a durable treatment-free observation (TFO) period in CLL patients who would most benefit from combination therapy. Methods: This is a phase II, multicenter, open label clinical trial (NCT04016805). Eligible patients were receiving ongoing ibrutinib, in any line of therapy, for a minimum duration of 6 months and had detectable residual CLL in the peripheral blood via MRD assay (flow cytometry with a cutoff of 10
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