Results from a phase I trial of pembrolizumab plus vorinostat in relapsed/refractory B-cell non-Hodgkin lymphoma

Abstract

Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors (HDACi) exhibit favorable immunomodulatory effects and demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in pre-clinical models. We therefore developed a phase I study to evaluate the safety and preliminary efficacy of Pembrolizumab with Vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase 2 dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma (NHL)). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered on twice daily on days 1-5 and 8-12 (dose-level (DL)1: 100mg; DL2: 200mg) and Pembrolizumab (200mg) was administered on day 1 of each 3-week cycle. Of 6 patients treated at DL1, 1 had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome (SJS)), and 1 of 6 had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, 9 had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11%/22% for FL and 45%/55% for all DLBCL. Amongst DLBCLs, the CR and ORR was 80%/80% for PMBL and 17%/33% for non-PMBL. In conclusion, Pembrolizumab with Vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL.