Phase 1 Study in R/R Hodgkin Lymphoma Shows Significant Responses to Pembrolizumab Plus Oral Vorinostat

In preclinical studies, HDAC inhibitors have been shown to have immunomodulatory effects— including enhancing antigen presentation, recruiting T cells into tumors, and promoting T-cell function—when combined with PD-1 inhibitors.

Phase 1 results presented at the 2021 American Society of Hematology Annual Meeting & Exposition show that adult patients with relapsed or refractory (R/R) Hodgkin lymphoma (HL) who were transplant ineligible had significant responses to intravenous pembrolizumab taken with oral vorinostat, a histone deacetylase (HDAC) inhibitor.

In preclinical studies, HDAC inhibitors have been shown to have immunomodulatory effects— including enhancing antigen presentation, recruiting T cells into tumors, and promoting T-cell function—when combined with PD-1 inhibitors, according to investigators from City of Hope, led by Alex F. Herrera, MD.

Oral vorinostat (Zolinza; Merck) is being studied with pembrolizumab in R/R HL as well as in diffuse large B-cell lymphoma and follicular lymphoma. Herrera reported on the phase 1 results involving 32 patients with R/R HL.

According to the abstract, these patients were heavily pretreated. The median number of prior therapies was 4 (range, 2-12), with 94% having had prior brentuximab vedotin, with 66% refractory; 78% had prior PD-1 blockade, with 56% refractory to PD-1 inhibition. At baseline, 75% had stage III-IV disease; 69% were male and 72% were White, with a median age of 35 years (range, 18-79).

Study design. Patients were treated in a dose-escalation cohort with 2 dose levels (DLs) using a Rolling 6 design, followed by an expansion cohort with treatment at the recommended phase 2 dose. At the first DL, vorinostat was given orally at 100 mg a day for days 1 to 5 and 8 to 12; at the phase 2 DL, patients received 200 mg a day of vorinostat on days 1 to 5 and 8 to 12. The pembrolizumab doses were 200 mg intravenously every 3 weeks on both DLs. Treatment continued for a maximum of 2 years. Primary end points were safety and the determination of response to the phase 2 dose.

Safety results. The median number of cycles was 8.5 (range, 1-36). The most common adverse events (AEs) were hypertension (72%), fatigue (63%), hyponatremia (63%), nausea (63%), diarrhea (47%), thrombocytopenia (44%), and anemia (41%). The most common AEs of grade ≥3 included hypertension (9%), neutropenia (6%), thrombocytopenia (6%), hypophosphatemia (6%), and lymphopenia (6%). Immune-related AEs included with grade 1-2 thyroiditis (four patients), grade 1 rash (one patient), and grade 3 esophagitis/duodenitis (one patient).

One patient had vorinostat dose reduction due to neutropenia. Twenty of 32 patients discontinued treatment: 11 due to disease progression, 6 due to stem cell transplant, 2 due to patient preference, and 1 due to completion of 2 years of therapy.

Responses. It was too early to evaluate the responses of 2 patients. For the 30 patients who could be evaluated, investigators reported the following results:

  • The best overall response rate (ORR) was 73%; the complete response (CR) rate was 33%. Among patients who were naïve to anti–PD-1 agents or sensitive to them, the ORR was 93% and the CR rate was 64%. Among patients who were refractory to prior PD-1 therapy, the ORR was 56% and CR was 6%.
  • Ten evaluable patients were anti-PD1 refractory patients with PD1 blockade as their most recent therapy prior to the study, and all had partial responses.
  • Median follow-up time in 28 surviving patients was 28 months (range, 1-41).
  • Patients had 1-year progression-free survival (PFS) of 52% and an overall survival (OS) of 93%.
  • Median duration of response, PFS, and OS in all R/R HL patients were 14 months, 14.9 months, and not reached, respectively.

The investigators concluded, “Pembrolizumab and vorinostat was tolerable and produced a high ORR and CR rate in patients with anti–PD-1 naïve/sensitive R/R HL. A majority of patients with anti–PD-1 refractory R/R HL had objective responses, including patients who had progressed while receiving PD-1 blockade as their most recent therapy.”


Herrera AF, Chen L, Budde LE, et al. Pembrolizumab plus vorinostat induces responses in patients with Hodgkin lymphoma who are refractory to prior PD-1 blockade. Presented at: 63rd American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 234.

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