Where does PD-1 blockade fit in HL therapy?

Abstract

Genetic alterations of the PD-L1/PD-L2 locus on chromosome 9p24.1 are a defining biological feature of classical Hodgkin lymphoma (HL). The resulting programmed death-ligand 1 (PD-L1) expression on Hodgkin Reed-Sternberg cells as well as the PD-L1 expressed in the HL microenvironment result in an ineffective host antitumor immune response and make HL a ripe target for programmed cell death-1 (PD-1) blockade. Anti-PD-1 antibody monotherapy has been effective and well tolerated in patients with relapsed or refractory (rel/ref) HL, with the majority of patients experiencing an objective response (approximately two-thirds of patients) and a median duration of response of 16.6 months in the study with the longest follow-up. Based on these data, nivolumab and pembrolizumab were approved by the US Food and Drug Administration (FDA) for the treatment of advanced rel/ref HL. Evidence has emerged that patients with HL benefit from continued PD-1 blockade beyond disease progression according to traditionally defined response criteria, and that the addition of, or switch to, chemotherapy after anti-PD-1 antibody failure can potentially re-induce clinical response. Subsequent studies have evaluated novel anti-PD-1-based combination regimens as well as the use of anti-PD-1 antibody therapy earlier in the course of a HL patient's therapy, including first salvage therapy for rel/ref disease (eg, nivolumab plus brentuximab vedotin) and even first-line treatment (eg, nivolumab added to doxorubicin, vinblastine, dacarbazine chemotherapy). The current role of PD-1 blockade in HL is as monotherapy in patients with advanced rel/ref disease, but the results of ongoing studies and the evolving treatment landscape in HL will determine the role of PD-1 blockade in the future.