Merck has announced that the European Commission has approved Keytruda (pembrolizumab), the company’s anti-PD-1 therapy, for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV. The approval allows marketing of Keytruda in all 28 EU member states plus Iceland, Lichtenstein and Norway, at the approved dose of 200 mg every three weeks until disease progression or unacceptable toxicity.
“Today’s approval brings an important new treatment option to patients in Europe with classical Hodgkin lymphoma who have not responded to existing therapies,” said Dr. Roger Dansey, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. “This milestone underscores our commitment to evaluating Keytruda in diseases with unmet need facing the hematology community.”
“For patients with classical Hodgkin lymphoma who have not been successfully treated with prior therapies – many of whom are young and have a poor prognosis – there are limited options and treating the disease poses significant challenges,” said Pier Luigi Zinzani, M.D., Ph.D., associate professor of hematology, Institute of Hematology “L. e A. Seràgnoli,” University of Bologna. “With this approval, we will now be able to provide these patients with a much-needed new treatment option.”
The approval was based on data in 241 patients from the KEYNOTE-087 and KEYNOTE-013 trials. These multicenter, open-label studies evaluated patients with cHL who failed ASCT and BV, who were ineligible for ASCT because they were unable to achieve a complete or partial remission after salvage chemotherapy and failed BV, or who failed ASCT and did not receive BV. Both studies included patients regardless of PD-L1 expression. Patients with active, non-infectious pneumonitis, an allogeneic transplant within the past five years (or more than five years but with graft-versus-host-disease [GVHD]), active autoimmune disease or a medical condition that required immunosuppression were ineligible for either trial. The major efficacy outcome measures, overall response rate (ORR) and complete remission rate (CRR), were assessed by blinded independent central review according to the 2007 revised International Working Group (IWG) criteria. Secondary efficacy outcome measures were duration of response, progression-free survival, and overall survival.
In KEYNOTE-087, 210 patients received Keytruda (pembrolizumab) at a dose of 200 mg every three weeks until unacceptable toxicity or documented disease progression. Eighty-one percent of patients were refractory to at least one prior therapy, including 35 percent who were refractory to first-line therapy. Additionally, 61 percent of patients had undergone prior ASCT, 38 percent were transplant ineligible; 17 percent had no prior BV use and 36 percent of patients had prior radiation therapy. Efficacy analysis showed an ORR of 69 percent (95% CI: 62.3, 75.2) with a CRR of 22 percent and a partial remission rate (PRR) of 47 percent. The median follow-up time was 10.1 months. Among the 145 responding patients, the median duration of response was 11.1 months (range 0.0+ to 11.1), with 76 percent of responding patients having responses of six months or longer.
In KEYNOTE-013, 31 patients received Keytruda at a dose of 10 mg/kg every two weeks until unacceptable toxicity or documented disease progression. Eighty-seven percent of patients were refractory to at least one prior therapy, including 39 percent who were refractory to first-line therapy. Seventy-four percent of patients had undergone prior ASCT, 26 percent were transplant ineligible, and 42 percent of patients had prior radiation therapy. Efficacy analysis showed an ORR of 58 percent (95% CI: 39.1, 75.5) with a CRR of 19 percent and a PRR of 39 percent. The median follow-up time was 28.7 months. Among the 18 responding patients, the median duration of response was not reached (range 0.0+ to 26.1+), with 80 percent of patients with a response of six months or longer and 70 percent of patients with a response of 12 months or longer.
The safety analysis supporting the European approval of Keytruda (pembrolizumab) was based on 3,194 patients with advanced melanoma, NSCLC or cHL across four doses (2 mg/kg every three weeks, 200 mg every three weeks, or 10 mg/kg every two or three weeks) in clinical studies. The most common adverse reactions (greater than 10%) with Keytruda were fatigue (22%), pruritus (15%), rash (13%), diarrhea (12%) and nausea (10%). The majority of adverse reactions reported were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.
Hodgkin lymphoma is a type of lymphoma that develops in the white blood cells, called lymphocytes, which are part of the immune system. Hodgkin lymphoma can start almost anywhere – most often in lymph nodes in the upper part of the body, with the most common sites being in the chest, neck or under the arms. Worldwide, there were approximately 66,000 new cases of Hodgkin lymphoma and 25,500 people died from the disease in 2012. Classical Hodgkin lymphoma accounts for about 95 percent of all cases of Hodgkin lymphoma in developed countries.
Keytruda is a humanized monoclonal antibody that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. Keytruda blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Keytruda is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications.