Updated Results of an Investigator-Initiated Phase II Study of Pembrolizumab and Romidepsin for Patients with Relapsed or Refractory T-Cell Lymphoma (TCL) with Survival Analysis

Background: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous and aggressive group of non-Hodgkin lymphomas. For most subtypes, relapsed/refractory PTCL (r/r TCL) have a poor prognosis and newer therapies have not been approved since 2014. This makes it imperative to develop new, effective therapies for PTCL. Individually, Pembrolizumab and Romidepsin have modest activity in (r/r TCL). Based on their mechanism of action, we hypothesized that their combination may cause synergistic priming of the immune system leading to durable responses. Herein, we report the updated results including survival analysis of the phase I/II study in patients with r/r TCL who had disease progression after at least one prior systemic regimen (NCT03278782).

METHODS: Between February 2018-April 2022, 38 patients were enrolled in this study (6 patients in phase I and 32 in phase II portions)We reported the safety and efficacy results in the first 20 patients at the 2020 ASH Annual Meeting. The study schedule was Pembrolizumab at 200 mg on day 1 and Romidepsin 14 mg/m2 on days 1 and 8, in a 21-day cycle. The maximum number of cycles was 35. Adverse events were monitored and graded according to the NCI Common Terminology Criteria for Adverse Events version 4.0 guidelines. The primary endpoint for the phase II part is overall response (OR: CR+PR); the 6 patients enrolled in the phase I part were included in the response assessment. Secondary objectives included progression free survival (PFS) and overall survival (OS). Outcome assessment were performed utilizing Lugano Revised Response Criteria. Kaplan-Meier method was used to estimate PFS and OS. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used.

RESULTS: The number of patients in the intention to treat population (ITT) for the primary endpoint of overall response (Table 1) was 38; the median age was 67 with a male predominance (57.9%). Majority of the patients (86.8%) were >60 years. LDH was elevated in 68.4% and 63.2% of patients had Stage III/IV disease. The median PD-L1 expression was 7.5% (IQR 0-30, max 95). Twenty-eight patients completed more than 1 cycle; among the 10 patients who completed only 1 cycle; 6 died within the first month due to poor PS and PD. The most common ≥ grade 3 adverse events were infections (n=11) and thrombocytopenia (n=10). Three patients stopped therapy due to development of immune related adverse events (iRAEs) - Grade 1 cytokine storm (n=1), Grade 3 gastritis (n=1), Grade 4 colitis (n=1); 2 patients with Grade 2 pneumonitis continued treatment after resolution with steroids. Two patients experienced hyper-progression within the first 10 days of treatment. The interim CR at the end of 3 cycles was 28.9% and final CR at the end of 6 cycles was 34.2% with a final ORR of 39.5%. All 5 patients with iRAEs remain in CR. At a median follow-up of 33.5 months, the median OS was 52.4 months (95% CI: 28 ~ NA months); 23 patients (60.5%) remain alive. The median PFS time was 29.5 months (95% CI: 14.7 ~ NA months); the number of events were 10, 7, 3, 2, 1 in the first 5 years respectively. 2 patients were successfully bridged to allogeneic SCT. There were more responders in other races (57%) compared to whites (34%).

CONCLUSIONS: The combination of Romidepsin and Pembrolizumab leads to high response rates and prolonged remissions. The combination improves PFS and OS compared to approved single agents in patients with r/r TCL. Additional studies evaluating the role of the tumor microenvironment will be reported at the Annual Meeting.

Nair:Incyte Corporation: Honoraria. Steiner:BMS: Research Funding; Seagen: Research Funding; GSK: Research Funding; Rafael Pharmaceuticals: Research Funding. Lee:Seagen: Research Funding; Octernal Therapeutics: Research Funding; Celgene: Research Funding; Briston-Myers Squibb: Research Funding; Janssen: Honoraria; Guidepoint Global: Honoraria; Deloitte: Honoraria; Olson Research: Honoraria; Korean Society of Cardiology: Honoraria; Curio Science: Honoraria; Cancer Experts: Honoraria; Aptitude Health: Honoraria; Takeda: Research Funding; Pharmcyclics: Research Funding; Century Therapeutics: Membership on an entity's Board of Directors or advisory committees. Strati:Hutchinson MediPharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Roche Genentech: Consultancy; TG Therapeutics: Consultancy; Kite Gilead: Consultancy; Astrazeneca Acerta: Research Funding; ALX Oncology: Research Funding; Sobi: Research Funding. Ahmed:Seagen: Research Funding; Merck: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Chimagen: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Tessa Therapeutics: Consultancy, Research Funding. Nieto:Astra Zeneca: Research Funding; Affimed: Other: Scientific advisory Board, Research Funding; Secura Bio: Research Funding. Westin:Iksuda: Consultancy; ADC Therapeutics: Consultancy, Research Funding; MorphoSys/Incyte Corporation: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; MonteRosa: Consultancy; Calithera: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Abbvie/GenMab: Consultancy; SeaGen: Consultancy. Nastoupil:ADC Therapeutics, BMS, Caribou Biosciences, Epizyme, Genentech/Roche, Gilead/Kite, Genmab, Janssen, MEI, Morphosys, Novartis, Takeda: Honoraria; BMS, Caribou Biosciences, Epizyme, Genentech, Gilead/Kite, Genmab, Janssen, IGM Biosciences, Novartis, Takeda: Research Funding; Genentech/Roche, MEI, Takeda: Other: DSMC. Samaniego:TG Therapeutics: Honoraria. Fowler:Celgene: Consultancy, Research Funding; BostonGene Corporation: Current Employment, Other: Leadership; Roche: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Jain:Eli Lilly and Company: Consultancy, Honoraria; Kite Pharma: Consultancy, Research Funding; Beigene: Research Funding; AstraZeneca: Research Funding; Aptitude Health: Membership on an entity's Board of Directors or advisory committees; Pharmacy Times: Membership on an entity's Board of Directors or advisory committees. Wang:Eastern Virginia Medical School: Honoraria; IDEOlogy Health: Honoraria; LLC TS Oncology: Honoraria; Oncology Specialty Group: Honoraria; Studio ER Congressi: Honoraria; Meeting Minds Experts: Honoraria; Practice Point Communications (PPC): Honoraria; Vinverx: Research Funding; Dava Oncology: Honoraria; Medscape: Honoraria; Molecular Templates: Research Funding; OncLive: Honoraria; Moffit Cancer Center: Honoraria; MJH Life Sciences: Honoraria; Physicians Education Resources (PER): Honoraria; Loxo Oncology: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Genmab: Research Funding; Celgene: Research Funding; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Pepromene Bio: Consultancy; Oncternal: Consultancy, Research Funding; Milken Institute: Consultancy; Merck: Honoraria; Lilly: Consultancy, Research Funding; Leukemia & Lymphoma Society: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; InnoCare: Consultancy, Research Funding; Deciphera: Consultancy; BioInvent: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Acerta Pharma: Honoraria, Research Funding; AbbVie: Consultancy. Vega:Allogene: Research Funding; Crisp Therapeutics: Research Funding; Geron Corporation: Research Funding. Flowers:EMD: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Janssen Pharmaceutical: Research Funding; Sanofi: Research Funding; Acerta: Research Funding; Guardant: Research Funding; V Foundation, Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding; National Cancer Institute: Research Funding; Eastern Cooperative Oncology Group: Research Funding; Pfizer: Research Funding; Kite: Research Funding; Iovance: Research Funding; Amgen: Research Funding; Burroughs Wellcome Fund: Research Funding; Ziopharm: Research Funding; Cellectis: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Xencor: Research Funding; Morphosys: Research Funding; NPower: Current holder of stock options in a privately-held company; 4D: Research Funding; Spectrum: Consultancy; SeaGen: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; Gilead: Consultancy, Research Funding; Genmab: Consultancy; Genentech/Roche: Consultancy, Research Funding; Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Denovo Biopharma: Consultancy; Celgene: Consultancy, Research Funding; BeiGene: Consultancy; Abbvie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding. Neelapu:Merck: Consultancy, Honoraria, Other: Personal fees, Research Funding; Pfizer: Consultancy, Honoraria, Other: Personal fees; Acerta: Research Funding; Unum Therapeutics: Consultancy, Honoraria, Other: Personal fees, Research Funding; Kite: Consultancy, Honoraria, Other: Personal fees, Research Funding; Celgene: Consultancy, Honoraria, Other: Personal fees, Research Funding; Cell Medica/Kuur: Consultancy, Honoraria, Other: Personal fees; Adicet Bio: Consultancy, Honoraria, Other: Personal fees, Research Funding; Bluebird Bio: Consultancy, Honoraria; Takeda Pharmaceuticals: Patents & Royalties: related to cell therapy.; Karus Therapeutics: Research Funding; Allogene Therapeutics: Consultancy, Honoraria, Other: Personal fees, Research Funding; Calibr: Consultancy, Honoraria, Other: Personal fees; Bristol Myers Squibb: Consultancy, Honoraria, Other: Personal fees, Research Funding; Novartis: Consultancy, Honoraria, Other: Personal fees; Incyte: Consultancy, Honoraria, Other: Personal fees; Precision Biosciences: Consultancy, Honoraria, Other: Personal fees, Research Funding; Legend Biotech: Consultancy, Honoraria, Other: Personal fees; Medscape: Consultancy, Honoraria; Aptitude Health: Consultancy, Research Funding; Bio Ascend: Consultancy, Honoraria; Poseida: Research Funding; Cellectis: Research Funding. Iyer:Salarius Pharmaceuticals, Inc.: Consultancy.