Type of information: Positive opinion for the granting of a Market Authorisation in the EU
Product name: Keytruda®
Compound: pembrolizumab (MK-3475)
Therapeutic area: Cancer - Oncology
- 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)
- patients with advanced melanoma who have been previously treated with ipilimumab
- first-line treatment of advanced melanoma
- melanoma in adults with lymph node involvement who have undergone complete resection
- • On October 18, 2018, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending a change to the terms of Keytruda®.
The CHMP adopted a new indication as follows:
Keytruda® as monotherapy is indicated for the adjuvant treatment of melanoma in adults with lymph
node involvement who have undergone complete resection.
- • On December 18, 2015, Merck&Co announced that the FDA has approved an expanded indication for Keytruda® (pembrolizumab) to include the first-line treatment of patients with unresectable or metastatic melanoma. This approval marks the second FDA-approved indication in advanced melanoma for Keytruda® , which is now the first anti-PD-1 therapy approved for previously untreated advanced melanoma patients regardless of BRAF status.
- The FDA-approved dose of Keytruda® is 2 mg/kg every three weeks. In a Phase 3 trial, KEYNOTE-006, patients with unresectable or metastatic melanoma who were treated withKeytruda® experienced superior overall survival compared to those treated with ipilimumab. In this study supporting the first-line approval, patients given Keytruda® 10 mg/kg every two weeks demonstrated a 37 percent reduction in the risk of death and those given Keytruda® 10 mg/kg every three weeks demonstrated a 31 percent reduction in the risk of death, both compared to ipilimumab (hazard ratio: 0.63 [95% CI: 0.47, 0.83; p<0.001] and hazard ratio: 0.69 [95% CI: 0.52, 0.90; p=0.004], respectively). Immune-mediated adverse reactions occurred with Keytruda® including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis. Based on the severity of the adverse reaction, Keytruda® should be withheld or discontinued and corticosteroids administered.
- The approval was based on data from a multicenter, controlled, Phase 3 study, KEYNOTE-006, which evaluated Keytruda® compared to ipilimumab in 834 patients with unresectable or metastatic melanoma with progression of disease; no prior therapy with ipilimumab; and prior therapy with at most one other systemic treatment. Patients were randomized (1:1:1) to receive Keytruda® at a dose of 10 mg/kg every two (n=279) or three weeks (n=277) until disease progression or unacceptable toxicity, or ipilimumab, the standard of care at the time of the study, at a dose of 3 mg/kg every three weeks for four doses unless discontinued earlier for disease progression or unacceptable toxicity (n=278). The primary efficacy outcome measures were OS and progression-free survival (PFS) (as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1). Secondary efficacy outcome measures were overall response rate (ORR) and response duration. Keytruda® 10 mg/kg every two or three weeks showed superior OS compared to ipilimumab (hazard ratio: 0.63 [95% CI: 0.47, 0.83; p<0.001] and hazard ratio: 0.69 [95% CI: 0.52, 0.90; p=0.004], respectively). Median PFS was 5.5 months (95% CI: 3.4, 6.9), 4.1 months (95% CI: 2.9, 6.9), and 2.8 months (95% CI: 2.8, 2.9) with Keytruda® 10 mg/kg every two weeks, Keytruda® 10 mg/kg every three weeks and ipilimumab, respectively. For PFS, both schedules for Keytruda® 10 mg/kg every two or three weeks resulted in superior outcomes compared to ipilimumab (hazard ratio: 0.58 [95% CI: 0.46, 0.72; p<0.001] and hazard ratio: 0.58 [95% CI: 0.47, 0.72; p<0.001], respectively). Keytruda® every two or three weeks demonstrated a 42 percent reduction in the risk of disease progression or death as compared to ipilimumab. The ORR was 34 percent (95% CI: 28, 40) with Keytruda® 10 mg/kg every two weeks and 33 percent (95% CI: 27, 39) with Keytruda® 10 mg/kg every three weeks, as compared with 12 percent (95% CI: 8, 16) with ipilimumab. Keytruda® 10 mg/kg every two weeks and three weeks achieved partial response rates of 29 percent and 27 percent, respectively, and complete response rates of 5 percent and 6 percent, respectively; there was a 10 percent partial response rate and 1 percent complete response rate for ipilimumab. Among the 94 patients randomized to Keytruda® 10 mg/kg every two weeks with an objective response, response durations ranged from 1.4+ to 8.2 months. Among the 91 patients randomized to Keytruda®10 mg/kg every three weeks with an objective response, response durations ranged from 1.4+ to 8.1+ months.
- Eighty percent of patients had PD-L1 positive melanoma, 18 percent had PD-L1 negative melanoma, and 2 percent had unknown PD-L1 status (positive: greater than or equal to 1 percent of tumor cells using an Investigational Use Only assay). BRAF mutations were reported in 36 percent of patients, of which 46 percent were previously treated with a BRAF-inhibitor. Patients with BRAF V600E mutated melanoma were not required to have received prior BRAF inhibitor therapy.
- The most commonly reported adverse reactions were fatigue (28% with Keytruda® vs. 28% with ipilimumab), diarrhea (26% with Keytruda®), rash (24% with Keytruda® vs. 23% with ipilimumab), and nausea (21% with Keytruda®). Corresponding incidence rates are listed for ipilimumab only for those adverse reactions that occurred at the same or lower rate than with Keytruda®.
- Severe and life-threatening infusion-related reactions have been reported in 3 (0.1%) of 2,117 patients. Monitor patients for signs and symptoms of infusion related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. For Grade 3 or 4 reactions, stop infusion and permanently discontinue Keytruda®.
- Based on its mechanism of action, Keytruda® can cause fetal harm when administered to a pregnant woman. If used during pregnancy, or if the patient becomes pregnant during treatment, apprise the patient of the potential hazard to a fetus. Advise females of reproductive potential to use highly effective contraception during treatment and for four months after the last dose of Keytruda®.
- Additionally, the FDA approved an update to the product labeling for Keytruda® for the treatment of patients with ipilimumab-refractory advanced melanoma. This update is based on results from the randomized Phase 2 trial, KEYNOTE-002, which demonstrated Keytruda® was superior to investigator’s choice chemotherapy. KEYNOTE-002 is a multicenter, randomized controlled study of Keytruda® (pembrolizumab) 2 mg/kg every three weeks or 10 mg/kg every three weeks compared to investigator‘s choice chemotherapy (dacarbazine, temozolomide, carboplatin plus paclitaxel, paclitaxel, or carboplatin) in 540 patients with unresectable or metastatic melanoma with progression of disease; refractory to two or more doses of ipilimumab and, if BRAF V600 mutation positive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last dose of ipilimumab. Patients on chemotherapy who experienced progression of disease were offered Keytruda® . Median PFS was 2.9 months (95% CI: 2.8, 3.8), 2.9 months (95% CI: 2.8, 4.7), and 2.7 months (95% CI: 2.5, 2.8) with Keytruda® 2 mg/kg every three weeks (n=180), Keytruda® 10 mg/kg every three weeks (n=181) and chemotherapy (n=179), respectively. Doses of Keytruda® 2 mg/kg or 10 mg/kg every three weeks were superior compared to chemotherapy for the PFS primary endpoint (hazard ratio: 0.57 [95% CI: 0.45, 0.73; p<0.001] and hazard ratio: 0.50 [95% CI: 0.39, 0.64; p<0.001], respectively). Keytruda® 2 mg/kg every three weeks demonstrated a 43 percent reduction in the risk of disease progression or death compared to chemotherapy. There was no statistically significant difference between Keytruda® and chemotherapy in the interim OS analysis. The ORR was 21 percent (95% CI: 15, 28) with Keytruda® 2 mg/kg every three weeks and 25 percent (95% CI: 19, 32) with Keytruda® 10 mg/kg every three weeks, as compared with 4 percent (95% CI: 2, 9) with chemotherapy. Keytruda® 2 mg/kg and 10 mg/kg every three weeks achieved partial response rates of 19 percent and 23 percent, respectively, and complete response rates of 2 percent and 3 percent, respectively; there was a 4 percent partial response rate and no complete responses for chemotherapy. Among the 38 patients randomized to Keytruda® 2 mg/kg with an objective response, response durations ranged from 1.3+ to 11.5+ months. Among the 46 patients randomized to Keytruda® 10 mg/kg with an objective response, response durations ranged from 1.1+ to 11.1+ months.
- • On May 22, 2015, 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 advanced (unresectable or metastatic) melanoma, as both first-line therapy and in previously treated patients. The positive opinion was based on data from more than 1,500 patients with advanced melanoma treated with Keytruda® as monotherapy in three studies – from a large Phase 1b study, KEYNOTE-001; from a randomized, controlled study KEYNOTE-002; and an interim analysis from a second, randomized, controlled study, KEYNOTE-006. In KEYNOTE-001, the largest Phase 1b study to date of an anti-PD-1 antibody, Keytruda® demonstrated durable objective responses in patients with advanced melanoma. KEYNOTE-002, a Phase 2 study, showed Keytruda® was superior to chemotherapy for progression-free survival in ipilimumab refractory advanced melanoma. KEYNOTE-006, a Phase 3 study, showed Keytruda® was superior to ipilimumab for overall survival, progression-free survival, and overall response rate. The trial was stopped early in March 2015 based on the recommendation of the study’s independent Data Monitoring Committee as it had met its two primary endpoints. The CHMP recommended approval of Keytruda® monotherapy at a dose of 2 mg/kg every three weeks, which is the currently approved dose for advanced melanoma in the U.S. The Committee also looked at safety information from over 1,000 patients enrolled in clinical studies and considered that the safety profile of Keytruda® appears manageable. A follow-up plan to monitor the safety and efficacy of Keytruda® was agreed by the CHMP. The applicant received scientific advice on quality and clinical aspects of the application from the CHMP.
- • On September 4, 2014, the FDA granted accelerated approval to Keytruda® (pembrolizumab) for treatment of patients with advanced or unresectable melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on the results of a multicenter, open-label, randomized (1:1), dose-comparative, activity-estimating cohort conducted within Trial P001. In this cohort, 173 patients with unresectable or metastatic melanoma with disease progression within 24 weeks of the last dose of ipilimumab and, if BRAF V600 mutation positive, prior treatment with a BRAF inhibitor, were randomized to receive pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84) intravenously once every 3 weeks until disease progression or unacceptable toxicity. Key exclusion criteria were an autoimmune disease, a medical condition that required immunosuppression, and/or a history of severe immune-mediated adverse reactions from treatment with ipilimumab. Severe immune-mediated adverse reactions were defined as any CTCAE Grade 4 toxicity requiring treatment with corticosteroids or Grade 3 toxicity requiring corticosteroid treatment (greater than 10 mg/day prednisone or equivalent dose) for greater than 12 weeks. Among the 173 patients, the median age was 61 years (64% less than age 65); 40% female; 97% White; and 66% and 34% with an ECOG performance status 0 and 1, respectively. Disease characteristics were BRAF V600 mutation positive (17%), elevated lactate dehydrogenase (39%), M1c (82%), brain metastases (9%), and two or more prior therapies for advanced or metastatic disease (73%). The major efficacy endpoints were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as assessed by a blinded independent review committee and duration of response (DOR). The ORR was 24% (95% CI: 15, 34) in the 2 mg/kg arm, consisting of one complete response and 20 partial responses. Among the 21 patients with an objective response, 3 (14%) had disease progression at 2.8, 2.9, and 8.2 months after initial response. The remaining 18 patients (86%) have ongoing responses, ranging from 1.4+ to 8.5+ months; 8 patients have ongoing responses of 6 months or longer. Similar ORR results were observed in the 10 mg/kg arm.
- The most common (greater than or equal to 20%) adverse reactions among patients receiving pembrolizumab 2 mg/kg every 3 weeks were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea.
- The most frequent (greater than or equal to 2%) serious adverse drug reactions observed with pembrolizumab were renal failure, dyspnea, pneumonia, and cellulitis. Additional clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hypophysitis, hyperthyroidism, hypothyroidism, nephritis, and hepatitis.
- As a condition of this accelerated approval, Merck&Co is required to conduct a multicenter, randomized trial establishing the superiority of pembrolizumab over standard therapy to verify and describe the clinical benefit of pembrolizumab. Merck has two ongoing multicenter, randomized, controlled, therapeutic confirmatory trials in patients with unresectable or metastatic melanoma, either ipilimumab refractory (Trial P002) or ipilimumab naïve (Trial P006), each with co-primary endpoints of progression-free survival and overall survival.
- • On June 30, 2014, Merck &Co announced the European Medicines Agency (EMA) has accepted for review a Marketing Authorization Application (MAA) for pembrolizumab (MK-3475), the company’s investigational anti-PD-1 antibody, for the treatment of advanced melanoma. If approved by the European Commission (EC), pembrolizumab has the potential to be the first anti-PD-1 therapy in Europe. Additional regulatory filings in other countries outside of Europe are planned by the end of 2014.
- • On May 6, 2014, Merck&Co has announced that the FDA has accepted for review the Biologics License Application (BLA) for MK-3475, Merck’s anti-PD-1 antibody, for the treatment of unresectable or metastatic melanoma in patients who have been previously treated with ipilimumab. The FDA granted Priority Review designation with a PDUFA date of October 28, 2014, and the MK-3475 BLA will be reviewed under the FDA’s Accelerated Approval program. The FDA previously granted MK-3475 Breakthrough Therapy designation for advanced melanoma. If approved by the FDA, MK-3475 has the potential to be the first anti-PD-1 antibody in a new class of immune checkpoint modulators. Merck also announced it plans to file a Marketing Authorization Application for MK-3475 in Europe for advanced melanoma by the end of 2014.
- MK-3475 development program is currently ongoing in 30 tumor types as monotherapy and in combination. It is anticipated that by the end of 2014, the MK-3475 development program will grow to more than 24 clinical trials across 30 different tumor types, enrolling an estimated 6,000 patients at nearly 300 clinical trial sites worldwide, including four new Phase 3 studies. Ongoing and planned late-stage monotherapy and combination studies include:
- -Seven Phase 3 registrational trials spanning advanced melanoma (adjuvant, ipilimumab-naïve, and ipilimumab-refractory), advanced non-small cell lung cancer (NSCLC) (previously-treated and previously-untreated), advanced head & neck cancer and advanced bladder cancer;
- -Ten combination studies, including advanced melanoma, advanced NSCLC, advanced renal cell carcinoma, HER2+ breast cancer and other solid tumors.
- Merck also said that based on encouraging preclinical data, it plans to initiate a Phase 1 dose-ranging study with its investigational anti-GITR agonistic antibody, MK-4166, in patients with advanced malignances. GITR (glucocorticoid-induced TNFR receptor) is an activating immune checkpoint receptor, which is believed to stimulate immune activity against cancer cells. This will be the second investigational immune checkpoint antibody within Merck’s immuno-oncology discovery program to enter clinical development.
- • On January 13, 2014, Merck &Co has announced it has started a rolling submission to the FDA of a Biologics License Application for MK-3475, the company’s investigational anti-PD-1 immunotherapy, for patients with advanced melanoma who have been previously treated with ipilimumab. A rolling submission allows completed portions of the application to be submitted and reviewed by the FDA on an ongoing basis. The company expects to complete the application in the first half of 2014.
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: 2014-09-04/2015-12-18
UE authorization: 2015-05-22
Favourable opinion UE:
Favourable opinion USA:
Orphan status USA:
Orphan status UE:
Pediatric exclusivit _USA:
Pediatric exclusivity UE: