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MSD Announces Positive Study Investigating the Use of Pembrolizumab Compared to Chemotherapy in Patients with Ipilimumab-Refractory Advanced Melanoma

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MSD, known as Merck in the United States and Canada, announced today that a pre-specified analysis of investigational data from a pivotal Phase 2 study (KEYNOTE-002) showed pembrolizumab, the company’s anti-PD-1 therapy, substantially improved the primary endpoint of progression-free survival (PFS, as assessed by RECIST 1.1, independent central review) (HR 0.57 and 0.50 for 2 mg/kg and 10 mg/kg every three week doses, respectively), compared to chemotherapy (P<0.0001 for both comparisons) in patients with ipilimumab-refractory advanced melanoma (n=540).1 At six months, the PFS rates for pembrolizumab were 34 percent at the 2 mg/kg dose (95% CI, 27-41) (n=180) and 38 percent at the 10 mg/kg dose (95% CI, 31-45) (n=181), compared to 16 percent for chemotherapy (95% CI, 10-22) (n=179). The median duration of follow-up at the interim analysis was 10 months.1

These findings, including pre-specified analyses of overall response rate (ORR), duration of response, safety and health-related quality of life (HRQoL), were presented today in an oral session by Dr. Antoni Ribas, professor, Hematology/Oncology and Surgery, and director of the Tumor Immunology Program at the Jonsson Comprehensive Cancer Center, University of California, Los Angeles at the Society of Melanoma Research (SMR) 2014 International Congress in Zurich, Switzerland.

“These findings demonstrate pembrolizumab was superior to chemotherapy in helping more patients with ipilimumab-refractory advanced melanoma achieve progression-free survival,” said Dr. Eric Rubin, vice president, global clinical development for oncology, Merck Research Laboratories. “The comparative efficacy and safety data from the pivotal KEYNOTE-002 study validate and extend the findings from our earlier study in these difficult-to-treat patients, and we look forward to sharing data on overall survival at a future congress.”

For the pre-specified analysis of PFS, no significant differences were observed between pembrolizumab doses (HR 0.91, range 0.71-1.16) (P<0.44). An assessment of PFS by investigator review was shown to be consistent with the central review findings. In addition, the PFS effect in favour of pembrolizumab was consistent across all pre-specified sub-groups.1

The objective of the pre-specified analysis was to evaluate the superiority of either dose of KEYTRUDA over chemotherapy for PFS (conducted after >= 270 PFS events at a 0.25% significance level) (one-sided) (estimated HR, 0.66). The study was designed with co-primary endpoints of PFS and overall survival. An evaluation of overall survival is planned at the pre-specified final analysis in 2015.

Additional Efficacy Data and Safety from the KEYNOTE-002 Study

Overall response rates (confirmed) for pembrolizumab were five to six times higher compared to chemotherapy. For pembrolizumab, ORR was 21 percent at 2 mg/kg dose (95% CI, 15-28) and 25 percent at 10 mg/kg dose (95% CI, 19-32), compared to 4 percent for chemotherapy (95% CI, 2-9) (P<0.0001 for both comparisons). At the time of pre-specified analysis, the median duration of response for pembrolizumab was not reached, and confirmed responses were ongoing in 92 percent of patients receiving 2 mg/kg dose (range 6+ to 50+) and 87 percent receiving 10 mg/kg dose (range 5+ to 48+), respectively. The median duration of response was 37 weeks for chemotherapy arm and 63 percent of responses were ongoing (range 7+ to 41). There was no significant difference in ORR or duration of response between the doses of pembrolizumab (P=0.21).

In a pre-specified exploratory analysis for HRQoL, patients treated with pembrolizumab reported a significantly smaller decrement in health status/quality of life score compared to those treated with chemotherapy (based on European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire or “EORTC QLQ-C30″). The mean change from baseline at week 12 (difference in least squares) for pembrolizumab compared to chemotherapy was 6.52 (P=0.011) at 2 mg/kg dose and 6.57 (p=0.009) at the 10 mg/kg dose, respectively.

The incidence of adverse events was consistent with previously reported data for pembrolizumab. Despite longer median treatment duration, the incidence of treatment-related, grade 3-5 adverse events was lower with pembrolizumab at 2 mg/kg dose (11%) and at 10 mg/kg dose (14%), compared to chemotherapy (26%). Serious treatment-related adverse events were observed for pembrolizumab at 2 mg/kg dose (8%) and 10 mg/kg dose (11%), and for chemotherapy (10%). Immune-related grade 3 adverse events observed for pembrolizumab across doses included hepatitis (n=3), colitis (n=2), pneumonitis (n=3), hypophysitis (n=1) and iritis or uveitis (n=1). No grade 4/5 immune-related adverse events were reported. Three percent of patients receiving pembrolizumab at 2 mg/kg dose and 7 percent at the 10 mg/kg dose, as well as 6 percent receiving chemotherapy discontinued treatment due to investigator assessed, treatment-related adverse events. One treatment-related death was reported for pembrolizumab and none in the chemotherapy arm.

About the KEYNOTE-002 Study

KEYNOTE-002 is a global, randomized pivotal Phase 2 study (n=540) evaluating pembrolizumab at doses of 2 mg/kg every three weeks (n=180) and 10mg/kg every three weeks (n=181) compared to investigator’s choice chemotherapy (n=179) (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or temozolomide) in patients with ipilimumab-refractory advanced melanoma. In the study, 83 percent of patients had the most advanced stage of disease (M1c) and 73 percent of patients had received at least two prior systemic therapies including ipilimumab. Co-primary endpoints were PFS and OS; secondary endpoints were ORR, duration of response and safety; and HRQoL as a pre-specified exploratory endpoint. Tumour response was assessed at week 12, then every 6 weeks through week 48, followed by every 12 weeks thereafter by independent, central, blinded radiographic review per RECIST 1.1 (Response Evaluation Criteria in Solid Tumours). Patients on chemotherapy with progressive disease as assessed by blinded central review were able to cross over to pembrolizumab arms after three months.

About Pembrolizumab

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, pembrolizumab releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumour immune response.

Our Focus on Cancer

Our goal is to translate breakthrough science into biomedical innovations to help people with cancer worldwide. For MSD 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 MSD

Today’s MSD is a global healthcare leader working to help the world be well. MSD is known as Merck in 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.

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 MSD’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; MSD’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 MSD’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

MSD 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).

Reference
1. A Randomized Controlled Comparison of Pembrolizumab and Chemotherapy in Patients With Ipilimumab-Refractory Melanoma. Ribas, A, Puzanov, I, Dummer, R et al. Presented at Society for Melanoma Research 2014 International Congress, 13-16 November 2014, Zurich, Switzerland.

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