SAN francisco – PD-1 checkpoint inhibitors, which have shown remarkable efficacy against advanced malignant melanoma, appear to hold similar promise in the treatment of relapsed or refractory Hodgkin’s lymphoma, results from two early studies suggest.
In a phase I study, the PD-1 blocking antibody nivolumab produced an 87% response rate in 23 heavily pre-treated patients with relapsed Hodgkin’s lymphoma (HL). In a separate phase Ib study, pembrolizumab, which blocks the PD-1 and PD-2 ligands, produced a 66% overall response rate, 21% complete remission rate, and 86% clinical benefit rate among 29 patients with HL for whom therapy with brentuximab vedotin (Adcetris) had failed.
The studies were presented at a media briefing prior to the presentation of data in oral sessions at the annual meeting of the American Society of Hematology.
“Classical Hodgkin lymphoma appears to be a tumor with genetically determined vulnerability to PD-1 blockade. We hope that PD-1 blockade in the future can become an important part of the treatment of patients with Hodgkin lymphoma,” said Dr. Phillipe Armand from the Dana-Farber Cancer Institute in Boston, an investigator for the nivolumab study.
Evidence from preclinical studies suggests that the Reed-Sternberg malignant cells characteristic of HL may use the PD-1 (programmed death 1) pathway to evade detection by immune cells, as suggested by pathologic studies showing the cells surrounded by an extensive but ineffective infiltrate of inflammatory cells.
“We’ve wondered for a long time how Hodgkin lymphoma could attract such a brisk immune response and yet have this immune response fail to kill the tumor,” he said.
Genetic Achilles heel
Genetic analyses had shown that HL frequently has a mutation that results in amplification of a region on chromosome 9 (9p24.1) which leads to increased expression of PD-1 ligands 1 and 2, and leads to a downregulation or weakening of the immune response. The mutation appears to work through the Janus kinase (JAK)-signal transducer and activator transcription (STAT) signalling. These findings suggested to researchers that classical HL has a genetically driven and, ideally, targetable dependence on the PD-1 pathway for survival, Dr. Armand explained.
To test this idea, he and colleagues studied 23 patients with relapsed or refractory HL that had been heavily pre-treated who were part of an independent expansion cohort of a study of nivolumab in hematologic malignancies. Of these patients, 78% were enrolled after a relapse following autologous stem cell transplantation, and 22% after treatment with brentuximab vedotin had failed.
The patients received nivolumab 3 mg/kg every 2 weeks until they had either a complete response, tumor progression, or excessive side effects. In all, 20 of the 23 patients (87%) had an objective response to the single-agent therapy, including 4 (17%) complete responses and 16 (70%) partial responses. The remaining three patients (13%) had stable disease.
The longest time on study at the data cutoff point was 72 weeks. Among all responders, 60% had a response by 8 weeks of therapy, 48% are ongoing, and 43% of patients are still on treatment.
Drug-related adverse events were reported in 18 patients, most commonly rash and decreased platelet count. Five patients had grade 3 events. There were no drug-related grade 4 events or deaths.
In an editorial accompanying the study, which was also published online in The New England Journal of Medicine, Dr. Mario Sznoll and Dr. Dan L. Longo from the Yale University School of Medicine in New Haven, Connecticut write that “with recent data showing impressive clinical activity of PD-1 or PD-L1 antagonists in subgroups of patients with a variety of different cancers, the critical and foundational role of immune interventions in cancer treatment is no longer deniable,” (NEJM, Dec. 6, 2014 [DOI: 10.1056/NEJMoa1411087]).
Dr. Craig H. Moskowitz from Memorial Sloan-Kettering Cancer Center in New York City discussed results of the second study, dubbed KEYNOTE-013 (A Phase Ib Multi-Cohort Trial of MK-3475 in Subjects With Hematologic Malignancies).
In this study, patients with HL who were not transplant eligible or for whom transplant had failed and who either had a relapse or were refractory to therapy with brentuximab vedotin received 19 mg/kg IV infusion of pembrolizumab every 2 weeks until complete response, partial response/stable disease, or disease progression.
Of the 31 patients enrolled, 29 were available for the analysis. As of the data cutoff in November 2014, 6 patients (21%) had achieved a complete remission, and 13 (45%) had a partial response, for an overall response rate of 66%. The median time to response was 12 weeks, and as of the data cutoff 17 of 19 patients had ongoing responses. The median response duration has not yet been reached. An additional 6 patients (21%) had stable disease, leading to an overall clinical benefit rate (responses plus stable disease) of 86%.
The patients generally tolerated the drug well. There were 4 treatment-related adverse events in 3 patients, including axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 treatment-related events or deaths.
Of the tumor samples evaluable, all expressed PD-L1, supporting the rationale for PD-1 blockade in this population, Dr. Moskowitz said.
The results of both his and Dr. Armand’s study support the continued development of PD-1 inhibitors in various subsets of patients with classical Hodgkin’s lymphoma, he said.