OREANDA-NEWS. April 21, 2015. Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced results from the randomized, pivotal Phase 3 study, KEYNOTE-006, in the treatment of unresectable advanced melanoma. In the study, KEYTRUDA® (pembrolizumab) was statistically superior to ipilimumab for progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). On March 24, 2015, Merck announced that KEYNOTE-006 would be stopped early based on these data (link). The results will be presented today at the American Association for Cancer Research (AACR) Annual Meeting by Dr. Antoni Ribas of Jonsson Comprehensive Cancer Center, University of California, Los Angeles (abstract # CT101), included in the AACR press program, and were also published today in the New England Journal of Medicine.

“Improving survival is the ultimate objective in treating patients with cancer. In this important study in advanced melanoma, KEYTRUDA was statistically superior to ipilimumab for progression-free survival and overall survival, and also demonstrated a lower frequency of severe adverse events.” said Dr. Caroline Robert, head of dermatology at Gustave Roussy, Villejuif and Paris-Sud University Cancer Campus, Grand Paris and lead author of the New England Journal of Medicine publication.

In mid-2015, Merck plans to submit a supplemental Biologics License Application (sBLA) for KEYTRUDA based on KEYNOTE-006 for the first-line treatment of advanced melanoma. Merck recently submitted data from KEYNOTE-002 in ipilimumab-refractory advanced melanoma as part of a supplemental application. KEYTRUDA was the first anti-PD-1 therapy approved in the United States and is currently indicated in the United States for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Please see below for complete indication and selected safety information for KEYTRUDA.

“Our goal with the KEYTRUDA development program is to help improve long-term disease control and survival for people suffering from a wide range of cancers,” said Dr. Roger Perlmutter, president, Merck Research Laboratories. “The KEYNOTE-006 study compared two immunotherapies that target distinct immune checkpoint pathways, PD-1 and CTLA-4. In this study, our anti-PD-1 antibody, KEYTRUDA, improved overall survival by more than 30 percent compared to ipilimumab, an anti-CTLA-4 antibody, in the treatment of advanced melanoma. We look forward to filing these data with the FDA and health authorities around the world.”

KEYNOTE-006 Results in the Front-Line Treatment of Advanced Melanoma

KEYNOTE-006 is a global, open-label, randomized, pivotal, Phase 3 study (ClinicalTrials.gov, NCT01866319) of 834 patients from 16 countries with unresectable stage III or IV advanced melanoma with no more than one prior systemic therapy. Patients received KEYTRUDA 10 mg/kg every two weeks (n=279), KEYTRUDA 10 mg/kg every three weeks (n=277), or four cycles of ipilimumab 3 mg/kg every three weeks (n=278). The primary endpoints were PFS and OS; secondary endpoints were ORR, duration of response, and safety. Tumor response was assessed at week 12, then every six weeks thereafter by independent central review per RECIST 1.1. This first presentation of data from KEYNOTE-006 is based on interim analyses conducted for PFS with a data cut-off of September 3, 2014 (median follow-up, 7.9 months) and for OS with a data cut off of March 3, 2015 (median follow-up, 13.8 months).

Data Showed KEYTRUDA was Statistically Superior to Ipilimumab for PFS, OS and ORR

The median PFS for KEYTRUDA was 5.5 months (2-week group) and 4.1 months (3-week group) compared to 2.8 months for ipilimumab (HR 0.58, P<0.00001 for the KEYTRUDA groups vs. ipilimumab, 95% CI, 0.46-0.72 for 2-week group and 0.47-0.72 for 3-week group, respectively). The estimated 6-month PFS rates for the KEYTRUDA and ipilimumab arms were 47.3 percent, 46.4 percent and 26.5 percent, respectively. One-year OS for KEYTRUDA was 74.1 percent (2-week group) and 68.4 percent (3-week group) compared to 58.2 percent for ipilimumab (HR 0.63 [95% CI, 0.47-0.83, P=0.00052] for the 2-week group and HR 0.69 [95% CI, 0.52-0.90, P=0.00358] for the 3-week group). At the time of analysis, median overall survival was not reached in any treatment group.

ORR for KEYTRUDA was 33.7 percent (2-week group) and 32.9 percent (3-week group) compared to 11.9 percent for ipilimumab (P=0.00013 for 2-week group; P=0.00002 for 3-week group); complete response rates were 5.0 percent, 6.1 percent, and 1.4 percent, respectively. Responses were ongoing in 89.4 percent (2-week group) and 96.7 percent (3-week group) of KEYTRUDA-treated patients and in 87.9 percent of ipilimumab-treated patients. Median duration of response was not reached for KEYTRUDA 3-week group (42+ to 246+) and ipilimumab (33+ to 239+).

The efficacy and safety profiles were similar between the two KEYTRUDA schedules evaluated in the study. Two previous studies, KEYNOTE-001 and KEYNOTE-002, demonstrated that the efficacy and safety were similar among the KEYTRUDA doses and schedules evaluated; 10 mg/kg every two weeks, 10 mg/kg every three weeks, and 2 mg/kg every three weeks (the currently approved dose in the U.S.).

Safety Findings from KEYNOTE-006

The safety profile of KEYTRUDA in this study was generally consistent with the safety described in the prescribing information. The most common treatment-related adverse events of any grade occurring in the KEYTRUDA groups were fatigue, diarrhea, rash, and pruritus. For ipilimumab, the most frequent treatment-related adverse events were pruritus, diarrhea, fatigue, and rash. Grade 3 to 4 treatment-related adverse events occurred in 13.3 percent (2-week group) and 10.1 percent (3-week group) of patients treated with KEYTRUDA and in 19.9 percent for ipilimumab. Discontinuation due to treatment-related adverse events was less frequent with KEYTRUDA (2-week group and 3-week group) than with ipilimumab (4.0%, 6.9%, and 9.4%, respectively). One death in the ipilimumab group was attributed to study treatment.

Treatment-related adverse events of an autoimmune or immune-related nature most frequently observed with KEYTRUDA (2-week group and 3-week group) were hypothyroidism (10.1% and 8.7%) and hyperthyroidism (6.5% and 3.2%). With ipilimumab, colitis occurred in 8.2 percent of patients. Grade 3 to 4 inflammatory or immune-mediated treatment events reported in more than 1 percent of KEYTRUDA-treated patients (2-week group and 3-week group) were colitis (1.4% and 2.5%) and hepatitis (1.1% and 1.8%), and in ipilimumab-treated patients were colitis (7.0%) and hypophysitis (1.6%).

About KEYTRUDA® (pembrolizumab)

KEYTRUDA (pembrolizumab) is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, KEYTRUDA releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response.

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merck is advancing a broad and fast-growing clinical development program for KEYTRUDA with more than 85 clinical trials – across more than 30 tumor types and over 14,000 patients – both as a monotherapy and in combination with other therapies.

Selected Important Safety Information for KEYTRUDA®

Pneumonitis occurred in 12 (2.9%) of 411 patients with advanced melanoma receiving KEYTRUDA (the approved indication in the United States), including Grade 2 or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively. Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 pneumonitis.

Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients respectively, receiving KEYTRUDA. Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA. Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hypophysitis occurred in 2 (0.5%) of 411 patients, including a Grade 2 case in 1 and a Grade 4 case in 1 (0.2% each) patient, receiving KEYTRUDA. Monitor for signs and symptoms of hypophysitis. Administer corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for Grade 2; withhold or discontinue for Grade 3; and permanently discontinue KEYTRUDA for Grade 4 hypophysitis.

Nephritis occurred in 3 (0.7%) patients receiving KEYTRUDA, consisting of one case of Grade 2 autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal failure (0.5%), one Grade 3 and one Grade 4. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 nephritis.

Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases in 2 (0.5%) and 1 (0.2%) patients respectively, receiving KEYTRUDA. Hypothyroidism occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, receiving KEYTRUDA. Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer corticosteroids for Grade 3 or greater hyperthyroidism. Withhold KEYTRUDA for Grade 3; permanently discontinue KEYTRUDA for Grade 4 hyperthyroidism. Isolated hypothyroidism may be managed with replacement therapy without treatment interruption and without corticosteroids.

Other clinically important immune-mediated adverse reactions can occur. The following clinically significant, immune-mediated adverse reactions occurred in less than 1% of patients treated with KEYTRUDA: exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising in a patient with inflammatory foci in brain parenchyma, adrenal insufficiency, myasthenic syndrome, optic neuritis, and rhabdomyolysis.

For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement of the adverse reaction to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Restart KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

Based on its mechanism of action, KEYTRUDA may 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 4 months after the last dose of KEYTRUDA.

For the treatment of advanced melanoma, KEYTRUDA was discontinued for adverse reactions in 6% of 89 patients who received the recommended dose of 2 mg/kg and 9% of 411 patients across all doses studied. Serious adverse reactions occurred in 36% of patients receiving KEYTRUDA. The most frequent serious adverse drug reactions reported in 2% or more of patients were renal failure, dyspnea, pneumonia, and cellulitis.

The most common adverse reactions (reported in ?20% of patients) were fatigue (47%), cough (30%), nausea (30%), pruritus (30%), rash (29%), decreased appetite (26%), constipation (21%), arthralgia (20%), and diarrhea (20%).

The recommended dose of KEYTRUDA is 2 mg/kg administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity. No formal pharmacokinetic drug interaction studies have been conducted with KEYTRUDA. It is not known whether KEYTRUDA is excreted in human milk. Because many drugs are excreted in human milk, instruct women to discontinue nursing during treatment with KEYTRUDA. Safety and effectiveness of KEYTRUDA have not been established in pediatric patients.

About Melanoma

Melanoma, the most serious form of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The incidence of melanoma has been increasing over the past four decades – approximately 232,130 new cases were diagnosed worldwide in 2012. In the U.S., melanoma is one of the most common types of cancer diagnosed and is responsible for the vast majority of skin cancer deaths. In 2014, an estimated 76,100 people were expected to be diagnosed and an estimated 9,710 people were expected to die of the disease in the U.S. alone. The five-year survival rates for advanced or metastatic melanoma (Stage IV) are estimated to be 15 to 20 percent.

Our Focus on Cancer

Our goal is to translate breakthrough science into biomedical innovations to help people with cancer worldwide. For Merck Oncology, helping people fight cancer is our passion, supporting accessibility to our cancer medicines is our commitment, and pursuing research in immuno-oncology is our focus to potentially bring new hope to people with cancer. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

About Merck

Today’s Merck is a global healthcare leader working to help the world be well. Merck is known as MSD outside the United States and Canada. 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 healthcare through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

Forward-Looking Statement

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