PD-1 Blockade Shows Safety and Efficacy in Pretreated Hodgkin Lymphoma
Testing nivolumab and pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma
Two studies with checkpoint inhibitors nivolumab and pembrolizumab demonstrate safe and durable responses in patients with relapsed and treatment-resistant classical Hodgkin lymphoma (cHL), according to data presented at the 56th American Society of Hematology (ASH) Annual Meeting and Exposition (6-9 December 2014, San Francisco, USA).
cHL is characterised by a genetic alteration that likely supports cancer growth by manipulating a common PD-1 immune pathway. This alteration results in increased engagement of PD-1, a receptor on the surface of immune cells. In studies presented at ASH 2014, PD-1 inhibitor nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma, while pembrolizumab demonstrated efficacy and safety in patients who failed previous treatment with brentuximab vedotin.
Preliminary safety, efficacy and biomarker results of a phase I study of nivolumab in patients with relapsed or refractory Hodgkin lymphoma
In the study led by Dr Philippe Armand of the Dana-Farber Cancer Institute in Boston, USA, the researchers hypothesised that nivolumab, a PD-1–blocking antibody, could inhibit tumour immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.
The investigators conducted this phase I study of nivolumab in 23 patients with relapsed or resistant cHL, 87% of whom had failed more than three previous treatment regimens, including stem cell transplant and brentuximab vedotin. Patients received an intravenous infusion of nivolumab every two weeks until their tumours progressed or they experienced excessive toxicity.
At the time of the latest analysis in June 2014, and after an average follow up of 40 weeks, 20 of 23 patients (87%) receiving nivolumab had experienced either complete response (four patients, 17%) or partial response (16 patients, 70%).
The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients).
The drug’s toxicity mirrored that observed in other solid tumours, with no life-threatening toxicity, and 22% of patients experiencing a serious treatment-related adverse event.
Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PD-L1 and PD-L2 and increased expression of these ligands. Reed–Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.
Based on these results, the USA Food and Drug Administration has granted nivolumab breakthrough therapy designation in relapsed cHL, and a large, multi-national phase II study is underway.
The study was published online on 6 December in The New England Journal of Medicine.
The study was supported by Bristol-Myers Squibb, by grants from the USA National Institutes of Health, and by a grant from the Miller Fund.
Preliminary results from a phase Ib study (KEYNOTE-013) of pembrolizumab in patients with classical Hodgkin lymphoma after brentuximab vedotin failure
This study evaluated the PD-1 inhibitor pembrolizumab in 29 heavily pretreated patients with cHL. All patients in the study failed previous treatment with brentuximab vedotin, and 69% of patients enrolled had relapsed after a stem cell transplant.
Patients received pembrolizumab intravenously every two weeks until disease progression, excessive toxicity, or completion of two years of therapy. At the time of analysis in November 2014, 66% of the patients responded to the drug, with six patients (21%) achieving a complete remission and 13 patients (45%) achieving a partial remission.
Pembrolizumab appeared to be well-tolerated, as there were no serious treatment-related adverse events, and only three patients experienced moderate treatment-related adverse events.
According to lead study author Dr Craig Moskowitz of the Memorial Sloan Kettering Cancer Center in New York, USA, “it will be important to further evaluate this drug in combination with others, or perhaps even as a maintenance treatment, to enhance the post-transplant immune response.”
The study was supported by Merck Sharp & Dohme Corp.
Ansell SM, Lesokhin AM, Borello I, et al.
PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma. NEJM 2014; Published online December 6. DOI: 10.1056/NEJMoa1411087