Pembrolizumab Plus Vorinostat Induces Responses in Patients with Hodgkin Lymphoma Who Are Refractory to Prior PD-1 Blockade
Authors: Herrera Alex F. , Chen Lu , Budde L. Elizabeth , Armenian Saro , Nikolaenko Liana , Chen Robert , Daniels Shari , Kennedy Neena , Peters Lacolle , Rosen Steven T. , Forman Stephen J , Popplewell Leslie L. , Kwak Larry W. , Mei Matthew 
Published: November 2021

Abstract
Introduction: Despite a high response rate to PD1 blockade in patients (pts) with relapsed/refractory (RR) Hodgkin lymphoma (HL), the complete response (CR) rate is low and most patients will progress. Pts who are refractory to PD1 blockade have limited treatment options and poor outcomes. Histone deacetylase inhibitors (HDACi) have immunomodulatory effects, including enhancing antigen presentation, recruiting T-cells into tumors, and promoting T-cell function. Preclinical models in melanoma and lung cancer demonstrated enhanced anti-tumor activity when HDACi were combined with PD1 blockade. We conducted a phase I study evaluating the safety and efficacy of pembrolizumab plus vorinostat, an HDACi, in pts with RR HL, diffuse large B-cell lymphoma, and follicular lymphoma. Here, we report the results of pts with RR HL.
Methods: Adult pts with RR HL who had failed at least 1 prior line of therapy and were transplant-ineligible were enrolled to receive IV pembrolizumab and oral vorinostat in 21-day cycles. Prior anti-PD1 exposure was allowed. Anti-PD1 refractory was defined as stable disease (SD) or progressive disease (PD) as best response or PD during anti-PD1 therapy after objective response. Pts were treated in a dose-escalation cohort with 2 dose levels (DL) using a Rolling 6 design and then onto an expansion cohort with treatment at the recommended phase 2 dose (RP2D). In DL1, vorinostat was administered orally at 100mg BID on days 1-5 and 8-12 and in DL2, vorinostat was administered at 200mg BID on days 1-5 and 8-12. Pembrolizumab dose was 200mg IV every 3 weeks in all DLs. Treatment could continue for a maximum of 2 years. The primary endpoint was safety and determination of the RP2D. Responses were assessed by investigators using PET-CT according to the 2014 Lugano Classification.
Results: 32 HL pts were enrolled, including 2 at DL1 and 30 at DL2 (RP2D). At baseline, 69% were male, 72% were Caucasian, the median age was 35 years (range 18-79), and 75% had stage III-IV disease. The median number of prior therapies was 4 (range 2-12), 94% had prior brentuximab vedotin (BV), 66% were BV refractory, 78% had prior PD1 blockade and 56% were PD1 refractory. Baseline characteristics are shown in Table 1.
The median number of cycles was 8.5 (range 1-36). The most common adverse events (AEs, any grade, Gr) were hypertension (72%), fatigue (63%), hyponatremia (63%), nausea (63%), diarrhea (47%), thrombocytopenia (44%), anemia (41%). The most common Gr 3+ AEs included hypertension (9%), neutropenia (6%), thrombocytopenia (6%), hypophosphatemia (6%), and lymphopenia (6%). Immune-related AEs included 4 pts with Gr 1-2 thyroiditis, 1 pt with Gr 1 rash, and 1 pt with Gr 3 esophagitis/duodenitis. 1 pt had vorinostat dose reduction for neutropenia. 20/32 pts discontinued treatment; treatment was discontinued for disease progression in 11 pts, stem cell transplant in 6 pts, patient preference in 2 pts, and completion of 2 years of therapy in 1 pt.
Among 30 evaluable pts (2 too early), the best overall response rate (ORR) was 73% and the CR rate was 33% (Table 2). Among anti-PD1 naïve/sensitive pts (n=14), the ORR and CR rate were 93% and 64%. Among pts who were refractory to prior PD1 blockade (n=18), the ORR and CR rate were 56% and 6%. 10 evaluable anti-PD1 refractory pts had PD1 blockade as their most recent therapy (median 35 days between PD and study treatment start), and 6 (60%) had an objective response to pembro/vorinostat (all partial responses). The median follow-up time in 28 surviving pts was 18 months (mo, range 1-41). The median duration of response, progression-free survival (PFS), and overall survival (OS) in all RR HL patients were 14 mo, 14.9 mo, and not reached. The 1-year PFS and OS were 52% and 93%.
Conclusions: Pembrolizumab and vorinostat was tolerable and produced a high ORR and CR rate in pts with anti-PD1 naïve/sensitive RR HL. A majority of pts with anti-PD1 refractory RR HL had objective responses, including pts who had progressed while receiving PD1 blockade as their most recent therapy.
Figure 1 Figure 1.

Disclosures
Herrera: ADC Therapeutics: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Tubulis: Consultancy; Takeda: Consultancy; Genentech: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Kite, a Gilead Company: Research Funding; Gilead Sciences: Research Funding; Karyopharm: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Budde: Kite Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Research Funding. Nikolaenko: Rafael Pharmaceuticals: Research Funding; Pfizer: Research Funding. Chen: AstraZeneca: Current Employment; Autolus: Ended employment in the past 24 months. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Popplewell: Pfizer: Other: Travel; Hoffman La Roche: Other: Food; Novartis: Other: Travel. Kwak: Pepromene Bio, Inc.: Consultancy, Current equity holder in publicly-traded company. Mei: TG Therapeutics: Research Funding; Epizyme: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Morphosys: Research Funding; BMS: Research Funding; Beigene: Research Funding.

OffLabel Disclosure:
Vorinostat is not FDA-approved for use in patients with Hodgkin lymphoma