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Merck Announces First Presentation of Early Data on the Investigational Use of KEYTRUDA(R) (pembrolizumab) in Patients with Advanced Bladder Cancer at ESMO 2014

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Merck (NYSE:MRK) , known as MSD outside the United States and Canada, today announced the first presentation of data on the investigational use of KEYTRUDA(R) (pembrolizumab) – the company’s anti-PD-1 therapy – in PD-L1 positive, advanced urothelial cancer (also known as bladder cancer). The early findings presented showed a confirmed overall response rate of 24 percent with KEYTRUDA as monotherapy, as measured by RECIST v1.1, central review (n= 7/29: 95% CI, 10.3-43.5) including a complete response rate of 10 percent (3/29). At the time of analysis, response durations ranged from 16+ to 40+ weeks with six of the seven responders continuing on therapy. In the ongoing study, 64 percent (61/95) of patients screened had tumors that were determined to be positive for PD-L1 expression.

These data, from a cohort of the ongoing Phase 1b KEYNOTE-012 study, were presented today, as part of a late-breaking oral session, by Dr. Elizabeth R. Plimack, Fox Chase Cancer Center, Philadelphia, at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain (ABSTRACT #LBA23).

KEYTRUDA is indicated in the United States at a dose of 2 mg/kg 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.

“Although at this stage the dataset is small, we are encouraged by the response rate, complete response rate, and the durability of the response in patients suffering from advanced bladder cancer,” said Dr. Alise Reicin, vice president, oncology, Merck Research Laboratories. “As communicated previously, based on these data Merck will initiate a Phase 3 study this year to better understand the potential of KEYTRUDA in advanced bladder cancer.”

Early findings for investigational use of KEYTRUDA in advanced bladder cancer

Data from a cohort of the ongoing Phase 1b KEYNOTE-012 study evaluated KEYTRUDA monotherapy at 10 mg/kg every two weeks in patients with advanced bladder cancer whose tumors were determined to be positive for PD-L1 expression (n=29). As measured by Merck’s proprietary immunohistochemistry (IHC) clinical trial assay, tumors were classified as PD-L1 positive based on greater than or equal to one percent of tumor cells demonstrating expression of the PD-L1 marker, or any positive staining with the same reagent in tumor stroma. The majority of patients had received one or more prior lines of therapy.

Antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1*

Patients Evaluable for Response (n=29)
n Percentage 95% CI
Overall Response Rate (ORR) 7 24.1 10.3 – 43.5
Best overall response
  • Complete response
3 10.3 2.2 – 27.4
  • Partial response
4 13.8 3.9 – 31.7
  • Stable disease
4 13.8 3.9 – 31.7
  • Progressive disease
14 48.3 29.4 – 67.5
  • No assessment
4 13.8 3.9 – 31.7

*Analysis cut-off date: August 6, 2014

At six months, 58 percent of patients were alive and median overall survival was 9.3 months (95% CI, 3.6-NR). Additionally, tumor shrinkage was achieved in 64 percent of evaluable patients with one post-baseline treatment scan. Analysis of the relationship between PD-L1 expression and clinical outcomes is ongoing.

Adverse events were consistent with previously reported safety data for KEYTRUDA. The most common investigator-assessed, treatment-related adverse events (occurring in greater than or equal to two patients) included fatigue (18%), peripheral edema (12%), and nausea (9%). Grade 3-5 investigator-assessed, treatment-related adverse events occurred in a total of four patients. One infusion-related reaction was observed and one patient discontinued KEYTRUDA due to a treatment-related adverse reaction. There were no treatment-related deaths.

About the KEYNOTE-012 Study

KEYNOTE-012 is an ongoing multi-center, non-randomized Phase 1b trial evaluating the safety, tolerability, and anti-tumor activity of KEYTRUDA monotherapy in patients with advanced triple negative breast cancer (TNBC), advanced head and neck cancer, advanced urothelial (bladder) cancer, or advanced gastric cancer. The primary endpoints of the study include overall safety, tolerability and anti-tumor activity (as measured by RECIST v1.1) in PD-L1 positive tumors; secondary endpoints include progression-free survival (PFS), overall survival (OS) and duration of response.

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.

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.

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.

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 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 Bladder (Urothelial Tract) Cancer

Bladder cancer is the most common form of urothelial cancer, a cancer that forms in the layer of tissue (also called the urothelium) that lines the urethra, bladder, ureters, prostate and renal pelvis.1 Among others, risk factors for bladder cancer include smoking, exposure to certain industrial chemicals in the workplace, race, ethnicity, age, and gender.2 The incidence of bladder cancer is elevated in North America, Europe, North Africa, the Middle East, Australia and New Zealand.3 In 2012, there were an estimated 430,000 new cases of bladder cancer and 165,000 bladder cancer deaths worldwide.3

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 consumer care 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

This news release includes “forward-looking statements” within the meaning of the safe harbor provisions of the United States Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of Merck’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include, but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and healthcare legislation in the United States and internationally; global trends toward healthcare cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; Merck’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of Merck’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in Merck’s 2013 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see Prescribing Information for KEYTRUDA (pembrolizumab) at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf and the Medication Guide for KEYTRUDA at http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_mg.pdf.

KEYTRUDA(R) is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

1 National Cancer Institute. General Information About Bladder and Other Urothelial Cancers. http://www.cancer.gov/cancertopics/pdq/screening/bladder/Patient/page2. Accessed September 23, 2014.

2 American Cancer Society. What are the risk factors for bladder cancer? http://www.cancer.org/cancer/bladdercancer/detailedguide/bladder-cancer-risk-factors. Accessed September 23, 2014.

3 WHO. 5.10 Bladder Cancer. In: Stewart BW, Wild CP, eds. World Cancer Report 2014. Lyon, France: WHO Press; 2014: 681-695.

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