Front-line Chemo-immunotherapy with Nivolumab and Dose-Adjusted (DA) EPOCH in Peripheral T-cell Lymphoma: A Phase I Trial

Abstract

Introduction:Dose-adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, doxorubicin, and cyclophosphamide) is a frequently used first line chemotherapy regimen for peripheral T-cell lymphomas (PTCLs), but relapses are common and long-term outcomes are poor. Checkpoint blockade (CPB) immunotherapy has shown modest single agent efficacy in relapsed PTCLs. In other hematologic malignancies the combination of CPB and cytotoxic chemotherapy is promising. Methods: We conducted a Phase I trial to assess safety, spectrum of immune-related toxicity, and efficacy of nivolumab (Nivo) in combination with DA-EPOCH as front-line therapy for PTCLs. Patients received Nivo (360 mg) followed by DA-EPOCH every 21 days for six cycles. Patients were allowed to receive one cycle of standard-of-care chemotherapy prior to enrollment. Results:18 patients were enrolled: 7 PTCL-not otherwise specified (NOS), 6 nodal T-cell lymphomas with a T-follicular helper phenotype, 2 primary cutaneous gamma/delta T-cell lymphoma, 2 ALK negative anaplastic large cell lymphoma, and 1 subcutaneous panniculitis like T-cell lymphoma. Fifteen had an intermediate or high-risk International Prognostic Index. Immune related (ir) adverse events (AEs) of all grades occurred in 14 and 7 patients experienced ≥ grade 3 irAEs. Eight patients required discontinuation of Nivo due to irAEs. Of the 6 patients who received a cycle of anthracycline-based combination chemotherapy prior to enrollment, none experienced an irAE resulting in Nivo dose hold or discontinuation, compared to 8 of 12 patients whose first cycle was Nivo+DA-EPOCH. There were no hyperprogression events. Interim and end of therapy overall response rates were 94% and 89%, respectively (11 complete responses, 5 partial responses, and 2 progressive diseases). With a median follow up of 707 days, median progression free and overall survival is 434 and 714 days, respectively. Conclusions: Front-line Nivo + DA-EPOCH showed good feasibility and acceptable safety when Nivo was started after chemotherapy but was associated with frequent dose-limiting irAEs when administered synchronously. Efficacy was encouraging with lengthy responses in very high risk PTCL subtypes. Further investigation of front-line line CPB-chemotherapy combinations in PTCL is warranted using a sequential approach. The trial is registered with ClinicalTrials.gov, NCT 03586999.