Among the most exciting data in lymphoma management presented at the 2014 American Society of Hematology (ASH) Annual Meeting were the study results of the checkpoint (PD-1) inhibitors nivolumab and pembrolizumab for the treatment of Hodgkin lymphoma (HL).
The programmed death-1 (PD-1) receptor is a member of the CD28 family. It is expressed on the surface of activated T cells and has two ligands: PD-L1 and PD-L2. Many tumor types express PD-L1, which binds to PD-1 receptors on activated T cells and induces T cell exhaustion. Blockade of the PD-1/PD-L1 interaction has shown very promising results in several types of cancers. In classical HL, the malignant Hodgkin Reed-Sternberg (RS) cells are admixed within an extensive inflammatory/immune cell infiltrate. Despite this brisk T cell-rich infiltrate, there is little evidence of an effective anti-tumor immune response.
Recent studies suggest that HL relies on the PD-1 signaling pathway to evade anti-tumor immunity. Genetic analyses have shown that RS cells frequently exhibit amplification of 9p24.1 and as a result, over-express the associated gene products PD-L1 and PD-L2. This amplification event also involves the Jak2 locus and in turn, increased activity of the Jak/STAT pathway further drives PD-L1 expression. Other mechanisms, in particular the Epstein-Barr virus (EBV) infection, can also lead to PD-L1 over-expression on the tumor cell surface. As a result of those mechanisms, HL tumor cells very frequently over-express PD-L1 and PD-L2 on their surface. This strongly suggests that this tumor has an unusual and genetically determined dependence on PD-1 for survival
Nivolumab, a fully human immunoglobulin (Ig) G4 anti–PD-1 antibody, blocks the interaction between the PD-1 receptor and its ligands, PD-L1 and PD-L2. Dr. Philippe Armand presented the results from a phase I trial comprising 23 patients with Hodgkin lymphoma who received 3 mg/kg of nivolumab. The primary endpoint was safety and tolerability, and the secondary endpoint was the response rate.
As is typical for the relapsed, refractory HL population, these patients were heavily pretreated: 78 percent had undergone a prior transplantation and 78 percent had previously received brentuximab vedotin. Eight patients had received more than six prior regimens. There were no drug-related grade 4 events.
In general, the safety profile was similar to that seen in solid tumors. The overall response rate was 87 percent, which included a 17 percent complete response rate. Several patients had stable disease. Evaluation of the median duration of response in these patients is ongoing. All of the ten patients who were evaluated for the 9p24 abnormality had evidence of this abnormality. This study shows that nivolumab can be safely administered and can achieve a high response rate in this patient population.
Pembrolizumab — a humanized IgG4 antibody against PD-1 — is also being evaluated extensively in Hodgkin and non-Hodgkin lymphomas. As with nivolumab, there is a dual ligand blockade of both PD-L1 and PD-L2. Memorial Sloan Kettering Cancer Center (MSK) led a phase IB trial of pembrolizumab comprising 29 HL patients who had previously failed treatment with brentuximab vedotin. The primary endpoint was the complete response rate and a secondary endpoint was safety and tolerability.
Among the 29 patients enrolled, 20 patients are still receiving therapy. The median duration of response had not been reached at the time the data were presented; however, the treatment program was well tolerated. The clinical benefit rate was 86 percent, including a complete response rate of 21 percent and a partial response rate of 45 percent. Among the six patients with stable disease, a few have been receiving treatment for nearly a year.Back to top
Both nivolumab and pembrolizumab have demonstrated outstanding activity in patients with heavily pretreated HL. MSK is currently participating in a registration trial with nivolumab, and the Lymphoma Service also plans to combine nivolumab with brentuximab vedotin as a stand-alone salvage regimen in HL.Back to top