On March 14, 2017, the Food and Drug Administration (FDA) approved pembrolizumab for the treatment of refractory Hodgkin lymphoma in children and adults who have been treated with at least three prior therapies.
Pembrolizumab is a type of immunotherapy called a checkpoint inhibitor. This drug consists of an antibody that binds to programmed death receptor-1 (PD-1), preventing the cancer cells from evading detection by the body’s immune system. Treatment with pembrolizumab allows T-cells (the fighter cells) to mount an immune response against the malignant cells.
Since 2014, Pembrolizumab has been FDA approved for the treatment of unresectable or metastatic melanoma, metastatic non-small-cell lung cancer, and recurrent or metastatic head and neck squamous cell carcinoma. The approval of pembrolizumab for the treatment of relapsed Hodgkin lymphoma was made under the FDA’s accelerated approval process.
This approval was based on data from a clinical trial of pembrolizumab in 210 adult patients with Hodgkin lymphoma who had relapsed or refractory disease after autologous stem cell transplant and/or treatment with brentuximab vedotin. With a median follow up of 9.4 months, the overall response rate was 69%, including partial responses in 47% and complete responses in 22% of patients. The approval in pediatrics was based on known safety data and extrapolated efficacy based on the adult trial.
The most common adverse events in the trial were fatigue, fever, cough, musculoskeletal pain, diarrhea, and rash. Among 40 pediatric patients with advanced melanoma, PD-L1 positive tumors, or lymphoma, the side effects and overall safety profile was similar to adults. A “warning and precaution” was added to the label describing the potential complications of graft-versus-host disease (GVHD) in patients undergoing allogeneic stem cell transplant after treatment with pembrolizumab. Death related to GVHD has occurred and physicians are advised to monitor for hepatic veno-occlusive disease and grade 3-4 acute GVHD including hyperacute GVHD.
The recommended dose of pembrolizumab for patients with Hodgkin lymphoma is 200mg every 3 weeks in adults and 2mg/kg (up to 200mg) every 3 weeks in children.
At the Weill Cornell and NewYork-Presbyterian Lymphoma Program, we offer pembrolizumab as one of many treatment choices available for people with Hodgkin lymphoma.
On April 18 the FDA granted the immunotherapy pembrolizumab (Keytruda) the Breakthrough Therapy Designation for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma (cHL). The Breakthrough Therapy Designation indicates that the FDA perceives the drug candidate may represent a substantial improvement over existing therapies and that it warrants additional resources to help expedite the approval process.
What is pembrolizumab?
Pembrolizumab is a humanized monoclonal antibody that binds to programmed death receptor-1 (PD-1). PD-1, also called programmed cell death protein-1, binds to programmed death ligand-1 (PD-L1), initiating inhibitory, immunosuppressive signals in T cells. Tumor cells, like Hodgkin lymphoma cells, often take advantage of this PD-1 by increasing expression of PD-L1, turning off the T cells and helping them to evade a potentially damaging immune response. Pembrolizumab acts by binding to PD-1, blocking its inhibitory actions, thereby activating the T-cell response against cancer cells, and initiating cell death. Pembrolizumab is already approved by the FDA for treatment of patients with unselectable or metastatic melanoma and for patients with non-small cell lung cancer whose tumors express PD-L1.
Why did the FDA grant pembrolizumab a Breakthrough Therapy Designation?
The new designation is based on preliminary date from the KEYNOTE-013 trial, which was last presented at the 2015 meeting of the American Society of Hematology, and the KEYNOTE-087 trial. In KEYNOTE-013, 64% of patients with brentuximab vedotin-refractory cHL responded, including 16% achieving a complete response. Results from the KEYNOTE-087 trial are not yet public but will likely be presented soon.
Were there any side effects?
Side effects were considered manageable and the most common included hypothyroidism, diarrhea, nausea, and pneumonitis.
How can you access pembrolizumab now?
Although the FDA has approved pembrolizumab for melanoma and lung cancer, it has not yet approved pembrolizumab for Hodgkin lymphoma. Patients interested in receiving immune checkpoint inhibitors are advised to seek out clinical trial options. Please visit our clinical trials website or contact our office (646-962-2064) for additional information.
By Peter Martin, MD
Nivolumab and pembrolizumab are members of a class of drugs known as immune checkpoint inhibitors. Both drugs are monoclonal antibodies that bind to and inhibit the programmed death 1 receptor (PD-1) on the surface of T-cells, thereby improving the ability of the immune system to fight against cancer. The concept is especially attractive because it capitalizes on the ability of the immune system to fight cancer rather than relying on drugs that are toxic to cancer cells. Both drugs (as well as other immune checkpoint inhibitors) have demonstrated significant promise in various solid tumors (e.g., melanoma) but are only now entering the world of lymphoma. On December 7, during a morning session at the 56th annual meeting of the American Society of Hematology, we saw some early evidence of the promise that this class of drugs represents.
In the first abstract, Dr. Philippe Armand presented preliminary results from a phase I trial of nivolumab in patients with previously treated Hodgkin lymphoma (HL). These results were simultaneously published in the New England Journal of Medicine and led the FDA to grant nivolumab the breakthrough therapy designation for patients with relapsed/refractory HL. A total of 23 patients with relapsed or refractory HL were enrolled on the trial and every patient experienced reduction of tumor burden, including 70% achieving a partial response and 17% experiencing a complete response. Of the 18 patients who had previously received brentuximab vedotin, the overall response rate was 89%. Longer follow up will be required to better estimate the duration of benefit.
In a second abstract, Dr. Alexander M. Lesokhin presented the results from the same phase I trial of nivolumab in patients with relapsed or refractory lymphoid malignancies, including B-cell and T-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). The overall response rate in patients with B-NHL was 28%, including 40% of patients with DLBCL. Nivolumab appeared less promising in patients with T-NHL and MM.
In a final abstract Dr. Craig H. Moskowitz presented preliminary results from a phase I trial with pembrolizumab in patients with Hodgkin lymphoma after failure of brentuximab vedotin. Almost 70% of patients had also previously received prior autologous stem cell transplantation and the median number of prior therapies was 4. The reported response rate was 53%, including a 20% complete response rate.
The results from these trials confirm the activity and safety of anti-PD-1 antibodies in patients with Hogkin and non-Hodgkin lymphomas. For information regarding ongoing trials at Weill Cornell Medical College with nivolumab for treatment of Hodgkin and non-Hodgkin lymphomas, follow the links for Hodgkin lymphoma, follicular lymphoma, and DLBCL, or contact us at (212) 746-1362. Look to this space for more news concerning nivolumab.