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.

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.”

Reference

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. https://ash.confex.com/ash/2021/webprogram/Paper150031.html