European Commission Approves Merck’s KEYTRUDA® (pembrolizumab) as Adjuvant Therapy for Adults with Resected Stage III Melanoma

European Approval Based on Significant Recurrence-Free Survival Benefit Demonstrated with KEYTRUDA in the Pivotal Phase 3 EORTC1325/KEYNOTE-054 Trial

First Approval for KEYTRUDA in an Adjuvant Setting in the European Union

KENILWORTH, NJ, USA I December 17, 2018 I Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the European Commission has approved KEYTRUDA, the company’s anti-PD-1 therapy, for the adjuvant treatment of adults with stage III melanoma and lymph node involvement who have undergone complete resection. This approval is based on data from the pivotal Phase 3 EORTC1325/KEYNOTE-054 trial, conducted in collaboration with the European Organisation for Research and Treatment of Cancer (EORTC). An updated recurrence-free survival (RFS) data analysis, conducted at the request of the European Medicines Agency, demonstrated that KEYTRUDA significantly prolonged RFS, reducing the risk of disease recurrence or death by 44 percent compared to placebo in the overall population of patients with resected, high-risk stage III melanoma (HR=0.56; 98% CI, 0.44-0.72; p<0.0001).

“Merck’s long-term commitment to melanoma patients includes a particular focus on bringing new treatment options to these patients earlier in the treatment paradigm,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “This approval, which is the first for KEYTRUDA in the adjuvant setting in the European Union, builds upon the foundation established by KEYTRUDA in the advanced and metastatic melanoma settings.”

The approval allows marketing of KEYTRUDA in this new indication in all 28 EU member states plus Iceland, Lichtenstein and Norway, at the approved dose of 200 mg every three weeks until disease recurrence, unacceptable toxicity, or for a duration of up to one year. KEYTRUDA is also approved in Europe as a monotherapy for the treatment of advanced (unresectable or metastatic) melanoma in adults.

“Melanoma patients, particularly those with stage III disease, often have a high risk of recurrence, and the collaborative study from EORTC and Merck demonstrated a significant reduction in the risk of cancer returning after surgery,” said Dr. Alexander Eggermont, study chair, Director General at the Gustave Roussy Cancer Institute, Professor of Oncology, University of Paris-Saclay. “This approval in the adjuvant setting marks another important milestone in the treatment of melanoma.”

Data Supporting the Approval

The approval was based on data from the EORTC1325/KEYNOTE-054 trial, a Phase 3, multicenter, randomized, double-blind, placebo-controlled study sponsored by Merck and conducted in collaboration with the EORTC. The study is evaluating adjuvant therapy with KEYTRUDA compared to placebo in patients with completely resected melanoma (stage IIIA [>1 mm lymph node metastasis], IIIB or IIIC according to American Joint Committee on Cancer (AJCC) 7th edition). In total, the study enrolled 1,019 adult patients who were randomly assigned (1:1) to receive either an intravenous infusion of KEYTRUDA 200 mg (n=514) or placebo (n=505) every three weeks for up to one year until disease recurrence or unacceptable toxicity. Co-primary endpoints were RFS for all patients and RFS in patients whose tumors express PD-L1. Recurrence-Free Survival was defined as the time from randomization until the date of first recurrence (local, regional or distant metastasis) or death, whichever occurred first.

In the updated analysis of data, with an additional 7 months of follow-up in comparison to the initial data cut off from the EORTC1325/KEYNOTE-054 trial, KEYTRUDA significantly prolonged RFS, reducing the risk of disease recurrence or death by 44 percent compared to placebo in the overall study population (HR=0.56; 98% CI, 0.44-0.72; p<0.0001). In the overall intent-to-treat population, the 12-month RFS rate was 76 percent in the KEYTRUDA group and 61 percent in the placebo group. At 18 months, the RFS rates were 72 percent and 54 percent, respectively.

Based on the previously reported final RFS analysis, for the co-primary endpoint of RFS in patients with PD-L1 positive tumors (n=853), KEYTRUDA demonstrated significantly prolonged RFS, resulting in a reduced risk of recurrence or death of 46 percent (HR=0.54; 95% CI, 0.42-0.69) compared to placebo. The 6-month RFS rate was 84 percent in the KEYTRUDA group and 75 percent in the placebo group. In addition to analysis of patients whose tumors express PD-L1, pre-defined subgroup analyses were performed in patients whose tumors were PD-L1 negative, BRAF mutation positive or BRAF mutation negative, and according to stage. The RFS benefit was demonstrated regardless of BRAF mutation status, PD-L1 status, or stage (according to AJCC 7th edition). A post-hoc subgroup analysis was performed based on stage according to AJCC 8th edition, but there is limited data on subjects with Stage IIIA according to AJCC 8th edition.

Also based on final RFS analysis, in patients with BRAF positive tumors (n=507), the 6-month RFS rate was 83 percent in the KEYTRUDA group and 73 percent in the placebo group. For this patient population, the RFS was significantly longer, resulting in a reduced risk of recurrence or death of 51 percent with KEYTRUDA (HR=0.49; 95% CI, 0.36-0.67) compared to placebo. This RFS benefit demonstrated with KEYTRUDA monotherapy was consistent in patients with BRAF-negative tumors.

The safety of KEYTRUDA as monotherapy has been evaluated in 4,948 patients with advanced melanoma, resected Stage III melanoma (adjuvant therapy), non-small cell lung cancer, classical Hodgkin lymphoma, urothelial carcinoma, or head and neck squamous cell carcinoma across four doses (2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks) in clinical studies. In this patient population, the median observation time was 7.3 months (range: 1 day to 31 months) and the most frequent adverse reactions with KEYTRUDA were fatigue (34.1%), rash (22.7%), nausea (21.7%) and diarrhea (21.5%) and pruritus (20.2%). The majority of adverse reactions reported for monotherapy were of Grade 1 or 2 severity. The most serious adverse reactions were immune-related adverse reactions and severe infusion-related reactions.

About EORTC

European Organisation for Research and Treatment of Cancer (EORTC) conducts clinical research in cancer, defining new standards of practice for better treatment and care of cancer patients. EORTC network comprises more than 5,500 multidisciplinary collaborators in more than 930 hospitals and institutions in 27 countries. Through translational and clinical research, EORTC offers an integrated approach to therapeutic strategies, drug evaluation programs, outcomes research and quality of life. For more information, visit www.eortc.org.

About Melanoma in Europe

Melanoma is the most serious form of skin cancer and is characterized by the uncontrolled growth of pigment-producing cells. Worldwide, the incidence of melanoma has been increasing over the past four decades in many populations, and it is estimated that in 2018 there will be more than 287,000 new melanoma cases and over 60,000 people will die from the disease. In Europe, the five-year survival rate for advanced or metastatic melanoma (stage IV) is estimated to be about five to 22 percent.

About Merck’s Commitment to Melanoma

Merck’s long-term commitment to melanoma includes a broad clinical development program studying KEYTRUDA as monotherapy and in combination with other novel mechanisms. The program, which is comprised of more than 4,500 patients across 10 Merck-sponsored clinical studies, is evaluating KEYTRUDA across most settings and stages of the disease.

About KEYTRUDA® (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that 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.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 850 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA® (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) ≥50%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

In metastatic NSCLC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, as appropriate.

Head and Neck Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In HNSCC, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. In adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

SOURCE: Merck

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