On October 21, 2016 Merck (NYSE:MRK), known as MSD outside the United States and Canada, reported that the phase 3 KEYNOTE-045 trial investigating the use of KEYTRUDA (pembrolizumab), the company’s anti-PD-1 therapy, in patients with previously treated advanced urothelial cancer, met the primary endpoint of overall survival (OS) (Press release, Merck & Co, OCT 21, 2016, View Source [SID1234515943]). In this trial, KEYTRUDA was superior compared to investigator choice chemotherapy. Based on a pre-specified interim analysis, an independent Data Monitoring Committee (DMC) has recommended that the trial be stopped early.

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"The results of KEYNOTE-045 represent a major breakthrough and will be welcome news for patients dealing with previously treated advanced urothelial cancer," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "We look forward to sharing the findings from this study with the medical community and with regulatory authorities around the world."

The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies involving patients with advanced urothelial cancer. Results from KEYNOTE-045 will be presented at an upcoming medical meeting.

The KEYTRUDA clinical development program includes more than 30 tumor types in more than 360 clinical trials, including nearly 200 trials that combine KEYTRUDA with other cancer treatments. For genitourinary cancers, Merck has the largest immuno-oncology clinical development program in bladder cancer, with 27 trials underway involving KEYTRUDA as monotherapy and in combination, including four registration-enabling studies.

About KEYNOTE-045

KEYNOTE-045 is a randomized, pivotal, phase 3 study (ClinicalTrials.gov, NCT02256436) evaluating KEYTRUDA monotherapy compared to investigator-choice chemotherapy (paclitaxel, docetaxel, vinflunine) in the treatment of patients with metastatic or locally advanced or unresectable (inoperable) urothelial cancer that has recurred or progressed following platinum-based chemotherapy. The co-primary endpoints are overall survival (OS) and progression-free survival (PFS); secondary endpoints are overall response rate (ORR), duration of response (DOR), and safety. The study randomized 542 patients to receive KEYTRUDA (200 mg every three weeks) or investigator-choice of paclitaxel (175 mg/m2 every three weeks), docetaxel (75 mg/m2 every three weeks), or vinflunine (320 mg/m2 every three weeks).

About Bladder Cancer

Bladder cancer begins when cells in the urinary bladder start to grow uncontrollably. As more cancer cells develop, they can form a tumor and spread to other areas of the body. Urothelial carcinoma, the most common type of bladder cancer, starts in the urothelial cells that line the inside of the bladder. In 2012, approximately 430,000 people worldwide were diagnosed with bladder cancer and 165,000 died from the disease. The incidence of bladder cancer is elevated in North America, Europe, North Africa, the Middle East, Australia and New Zealand.

About KEYTRUDA (pembrolizumab)

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

KEYTRUDA is administered as an intravenous infusion over 30 minutes every three weeks for the approved indications. KEYTRUDA for injection is supplied in a 100 mg single use vial.

On October 21, 2016 Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) reported that it will discontinue additional enrollment of the phase 3 ENLIVEN study of the investigational oral CSF-1R inhibitor pexidartinib (PLX3397) in tenosynovial giant cell tumor; however, the study will proceed with currently enrolled patients under a revised protocol (Press release, Daiichi Sankyo, OCT 21, 2016, View Source [SID1234515940]).

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Following review of two recently reported cases of non-fatal, serious liver toxicity, the ENLIVEN data monitoring committee (DMC) recommended that further enrollment into the study be suspended. At the time of enrollment suspension 121 patients had been randomized, five patients short of the 126 planned for full enrollment. The DMC also recommended measures to address these safety concerns while maintaining the blinded nature of the study. As a result, ENLIVEN will continue in order to evaluate its efficacy and safety endpoints.

All regulatory authorities involved in the ENLIVEN study have been notified. All patients currently enrolled in ENLIVEN are being informed about this updated safety information and will be offered the opportunity to re-consent for continued participation in the study.

"Ensuring patient safety is our first obligation and we sincerely thank all of the investigators and patients participating in this study," said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. "Upon completion of the study with currently enrolled patients, Daiichi Sankyo will conduct and report a thorough evaluation of the results and consider any and all appropriate next steps."

ENLIVEN is an ongoing global, multi-center, pivotal two-part phase 3 study evaluating pexidartinib in patients with symptomatic tenosynovial giant cell tumor (TGCT) for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, which is the double-blind phase, is designed to evaluate the efficacy and safety of pexidartinib versus placebo. The second part of the study is a longer-term open-label study of pexidartinib.

About TGCT
Tenosynovial giant cell tumor (TGCT) – also known as pigmented villonodular synovitis (PVNS) or giant cell tumor of the tendon sheath (GCT-TS) – is a rare, usually non-cancerous tumor that affects the synovium-lined joints, bursae, and tendon sheaths, resulting in swelling, pain, stiffness and reduced mobility in the affected joint or limb.1 It is estimated that TGCT has an annual incidence of 11 cases per million.2 Patients are commonly diagnosed in their 20s to 50s,and depending on the type of TGCT, women can be up to twice as likely to develop a tumor as men.3,4

Primary treatment of TGCT includes surgery to remove the tumor, but in patients with a diffuse form where it can wrap around bone, tendons, ligaments and other parts of the joint, the tumor is more difficult to remove and may require multiple surgeries or joint replacement, eventually advancing to the point where surgery is no longer an option and amputation may be considered. It is estimated that the rate of recurrence can be about 15 to 45 percent.5

About Pexidartinib
Pexidartinib is an investigational novel, oral small molecule that potently and selectively inhibits CSF-1R (colony stimulating factor-1 receptor), which is a primary growth driver of abnormal cells in the synovium that cause TGCT.

Pexidartinib has been granted Breakthrough Therapy Designation by the U.S. Food and Drug Administration (FDA) for the treatment of TGCT. Pexidartinib has also been granted Orphan Drug Designation by the FDA for the treatment of PVNS/GCT-TS and received Orphan Designation from the European Commission for the treatment of TGCT. Pexidartinib has not been approved by any regulatory authority for any use.

Pexidartinib is being evaluated in several additional potential clinical indications, including glioblastoma, ovarian, breast, colorectal, pancreatic and prostate cancer, malignant peripheral nerve sheath tumor, and pediatric cancers. It is also being investigated in combination with anti-PD-1 immunotherapy, pembrolizumab, for advanced melanoma or other solid tumors.