Type of information: Granting of a Market Authorisation in the EU
Product name: Keytruda®
Compound: pembrolizumab (MK-3475)
Therapeutic area: Cancer - Oncology - Rare diseases
- monoclonal antibody/immune checkpoint inhibitor. Keytruda® (pembrolizumab - MK-3475) is an investigational, highly selective monoclonal anti-PD-1 antibody designed to restore the natural ability of the immune system to recognize and target cancer cells by selectively achieving dual ligand blockade (PD-L1 and PD-L2) of the PD-1 protein. By blocking PD-1, MK-3475 enables activation of the immune system’s T-cells that target cancer by essentially releasing a brake on the immune system. MK-3475 is currently being studied in three clinical trials for advanced melanoma including a Phase III trial of MK-3475 versus ipilimumab in ipilimumab-naïve advanced melanoma patients (PN 006). Enrollment is complete in the advanced melanoma cohorts in the company’s Phase IB trial (PN 001) and the Phase II trial (PN 002) comparing two doses of MK-3475 versus chemotherapy in patients with advanced melanoma who have progressed after prior therapy. Pembrolizumab is being evaluated across more than 30 types of cancers, as monotherapy and in combination. It is anticipated that by the end of 2014, the pembrolizumab development program will grow to more than 24 clinical trials, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide.
- In April 2013, MK-3475 has received a Breakthrough Therapy designation for advanced melanoma from the FDA.
- Keytruda® is the first approved drug that blocks the PD-1 cellular pathway.
Company: Merck&Co (USA - NJ)
- adult patients with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant and brentuximab vedotin , or who are transplant-ineligible and have failed brentuximab vedotin
- adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more prior lines of therapy.
- • On May 5, 2017, Merck&Co 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 who have failed autologous stem cell transplant and brentuximab vedotin , or who are transplant-ineligible and have failed brentuximab vedotin. 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.
- 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 classical Hodgkin lymphoma who failed autologous stem cell transplant and brentuximab vedotin, who were ineligible for autologous stem cell transplant because they were unable to achieve a complete or partial remission after salvage chemotherapy and failed brentuximab vedotin, or who failed v and did not receive brentuximab vedotin. 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), 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 brentuximab vedotin 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 autologous stem cell transplant, 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, non small cell lung cancer or classical Hodgkin lymphoma 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.
- • On March 24, 2017, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of Keytruda® (pembrolizumab) for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant and brentuximab vedotin, or who are transplant-ineligible and have failed brentuximab vedotin.
- • On March 14, 2017, the FDA granted accelerated approval to pembrolizumab for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma , or those who have relapsed after three or more prior lines of therapy. Approval was based on data from 210 adult classical Hodgkin lymphoma patients enrolled in a multicenter, non-randomized, open-label clinical trial (KEYNOTE-087 study). Patients had refractory or relapsed disease after autologous stem cell transplantation (ASCT; 129 patients) and/or brentuximab vedotin (175 patients), and received a median of four prior systemic therapies (range: 1, 12). With a median follow-up of 9.4 months (range: 1-15), the overall response rate was 69% (95% CI: 62, 75). This included partial responses in 47% of patients and complete responses in 22%. The estimated median response duration was 11.1 months (range 0+ to 11.1). Efficacy in pediatric patients was extrapolated from results observed in adults.
- Safety was evaluated in 210 adults with classical Hodgkin lymphoma. In adults, the most common (at least 20%) adverse reactions were fatigue, pyrexia, cough, musculoskeletal pain, diarrhea, rash and hypertransaminasemia. Additional common adverse reactions (at least 10%) included dyspnea, arthralgia, vomiting, nausea, pruritus, hypothyroidism, upper respiratory tract infections, headache, peripheral neuropathy, hyperbilirubinemia and increased creatinine. Other immune-mediated adverse reactions occurring in 0.5%-9% of patients included infusion reactions, hyperthyroidism, pneumonitis, uveitis, myositis, myelitis and myocarditis. Fifteen percent had an adverse reaction requiring systemic corticosteroid therapy. Pembrolizumab was discontinued due to adverse reactions in 5% of patients, and treatment was interrupted due to adverse reactions in 26%.
- A new “Warning and Precaution” was added for complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT) after pembrolizumab. Transplant-related deaths have occurred, and health care professionals should follow patients closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host-disease (GVHD), severe (grade 3 to 4) acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions. FDA has required the sponsor to further study the safety of allogeneic HSCT after pembrolizumab therapy.
- The recommended dose and schedule of pembrolizumab for classical Hodgkin lymphoma is 200 mg every 3 weeks for adults and 2 mg/kg (up to 200 mg) every 3 weeks for pediatric patients.
- • On December 30, 2015, the FDA has granted orphan drug designation for Keytruda® (pembrolizumab) for the treatment of Hodgkin lymphoma.
Submission of marketing authorization application USA :
Submission of marketing authorization application UE:
Withdrawal of marketing authorization application USA:
Withdrawal of marketing authorization application UE:
US authorization: 2017-03-14
UE authorization: 2017-05-05
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA: 2015-12-30
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: