KENILWORTH, NJ, USA I November 12, 2016 I Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced results from the pivotal KEYNOTE-045 study investigating the use of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, in patients with advanced bladder (urothelial) cancer previously treated with platinum-containing chemotherapy. As previously announced, KEYTRUDA was superior to investigator-choice chemotherapy for the primary endpoint of overall survival (OS) in this phase 3 study, and was stopped early. Specifically, there was a 27 percent reduction in the risk of death in patients treated with KEYTRUDA compared to chemotherapy (OS, HR = 0.73, p-value: 0.0022). Data presented at the Society for Immunotherapy of Cancer’s (SITC) 31st Annual Meeting are the first publicly presented findings from this study.
“The improved overall survival for patients receiving KEYTRUDA in this trial are clinically significant and could impact how physicians consider treating patients with previously treated advanced urothelial cancer,” said Dr. Roger Dansey, senior vice president, oncology late-stage development, Merck Research Laboratories. “These data add to the growing body of evidence from our clinical development program for KEYTRUDA in a range of cancers, including advanced urothelial cancer.”
Study findings are being presented by Dr. Joaquim Bellmunt from Dana-Farber Cancer Institute on Saturday, Nov. 12th from 11:45 a.m. – 12:00 p.m. ET (Abstract #470).
“There have been few advancements in the treatment of bladder cancer in the past several decades, with chemotherapy being the only option,” said Dr. Dean F. Bajorin, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center. “These data demonstrate the potential for pembrolizumab to provide a meaningful improvement in overall survival for patients with advanced urothelial cancer who previously have received platinum-containing chemotherapy.”
The KEYTRUDA (pembrolizumab) 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. Currently, 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.
Findings from KEYNOTE-045
KEYNOTE-045 is a randomized, pivotal, phase 3 study evaluating KEYTRUDA monotherapy compared to investigator-choice chemotherapy (paclitaxel, docetaxel, vinflunine) in the treatment of patients with metastatic or locally advanced, unresectable (inoperable) urothelial cancer (urothelial carcinoma of the renal pelvis, ureter, bladder, or urethra) that has recurred or progressed following platinum-based chemotherapy. The co-primary endpoints are OS and progression-free survival (PFS); secondary endpoints are overall response rate (ORR), duration of response, and safety. The study randomized 542 patients to receive KEYTRUDA (200 mg every three weeks) (n=270) or investigator-choice chemotherapy (n=272) – either paclitaxel (175 mg/m2 every three weeks), docetaxel (75 mg/m2 every three weeks), or vinflunine (320 mg/m2 every three weeks). The study was designed to assess key endpoints in patients with or without PD-L1 expression (the total study population, n=542), as well as in patients with PD-L1 expressing tumors (expression of 10% or more) (n=74/270 in the KEYTRUDA arm; n=90/272 in the chemotherapy arm).
Findings presented at SITC from the total study population showed a significant improvement in OS with KEYTRUDA compared to chemotherapy, with a 27 percent reduction in the risk of death (HR: 0.73 [95% CI, 0.59 – 0.91], p-value: 0.0022). Median OS was 10.3 months (95% CI, 8.0 – 11.8) with KEYTRUDA, compared to 7.4 months (95% CI, 6.1 – 8.3) in the chemotherapy arm. The estimated one-year OS rate was 43.9 percent with KEYTRUDA, compared to 30.7 percent in the chemotherapy arm.
In the OS analysis of patients with PD-L1 expression, there was a 43 percent reduction in the risk of death with KEYTRUDA, compared to chemotherapy (HR: 0.57 [95% CI, 0.37 – 0.88], p-value: 0.0048). Median OS was 8.0 months (95% CI, 5.0 – 12.3) with KEYTRUDA, compared to 5.2 months (95% CI, 4.0 – 7.4) in the chemotherapy arm. The estimated one-year OS rate was 39.8 percent with KEYTRUDA, compared to 26.9 percent in the chemotherapy arm.
An analysis of the study’s second primary endpoint, PFS, in the total study population showed a median PFS of 2.1 months (95% CI, 2.0 – 2.2) with KEYTRUDA, compared to 3.3 months (95% CI, 2.3 – 3.5) in the chemotherapy arm (HR: 0.98 [95% CI, 0.81 – 1.19], p-value: 0.42). The six-month PFS rate was 28.8 percent with KEYTRUDA, compared to 26.8 in the chemotherapy arm; the one-year PFS rate was 16.8 percent with KEYTRUDA, compared to 6.2 percent in the chemotherapy arm.
The difference in response rates between the two arms was 9.6 percentage points (p-value: .0011), which was statistically significant and in favor of KEYTRUDA. The ORR was 21.1 percent with KEYTRUDA (7.0% were complete responses), compared to 11.4 percent in the chemotherapy arm (3.3% were complete responses). In patients with PD-L1 expression, ORR was 21.6 percent with KEYTRUDA (6.8% were complete responses), compared to 6.7 percent in the chemotherapy arm (2.2% were complete responses).
The median duration of response for patients treated with KEYTRUDA had not yet been reached at the time of analysis (range: 1.6+ to 15.6+ months) – with 68 percent of responses estimated to last for 12 months or more. In the chemotherapy arm, the median duration of response was 4.3 months (range: 1.4+ to 15.4+ months) – with 35 percent of responses estimated to last for 12 months or more.
The safety profile of KEYTRUDA in this trial was consistent with that observed in previously reported studies involving patients with advanced urothelial cancer. The treatment-related adverse events observed in this trial (any grade occurring in 10 percent or more) were pruritus (19.5% with KEYTRUDA; 2.7% with chemotherapy), fatigue (13.9% with KEYTRUDA; 27.8% with chemotherapy), nausea (10.9% with KEYTRUDA; 24.3% with chemotherapy), diarrhea (9.0% with KEYTRUDA; 12.9% with chemotherapy), decreased appetite (8.6% with KEYTRUDA; 16.1% with chemotherapy), asthenia (5.6% with KEYTRUDA; 14.1% with chemotherapy), anemia (3.4% with KEYTRUDA; 24.7% with chemotherapy), constipation (2.3% with KEYTRUDA; 20.4% with chemotherapy), peripheral sensory neuropathy (0.8% with KEYTRUDA; 11.0% with chemotherapy), peripheral neuropathy (0.4% with KEYTRUDA; 10.6% with chemotherapy), neutrophil count decreased (0.4% with KEYTRUDA (pembrolizumab); 14.1% with chemotherapy), alopecia (37.6% with chemotherapy) and neutropenia (15.3% with chemotherapy). Immune-mediated adverse events were thyroid abnormalities (9.4% with KEYTRUDA (pembrolizumab); 1.6% with chemotherapy), pneumonitis (4.1% with KEYTRUDA; 0.4% with chemotherapy), colitis (2.3% with KEYTRUDA; 0.4% with chemotherapy), infusion reactions (0.8% with KEYTRUDA; 3.9% with chemotherapy), severe skin toxicity (0.8% with KEYTRUDA; 1.2% with chemotherapy), nephritis (0.8% with KEYTRUDA), adrenal insufficiency (0.4% with KEYTRUDA) and myositis (0.4% with chemotherapy). Fifteen patients in the KEYTRUDA arm and 28 patients in the chemotherapy arm discontinued treatment due to a treatment-related adverse event; there were four treatment-related deaths in each arm.
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.
KEYTRUDA Indications and Dosing
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a dose of 2 mg/kg every three weeks until disease progression or unacceptable toxicity.
Lung Cancer
KEYTRUDA 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 (pembrolizumab) is also 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.
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.
Our Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, helping people fight cancer is our passion and supporting accessibility to our cancer medicines is our commitment. Our focus is on pursuing research in immuno-oncology and we are accelerating every step in the journey – from lab to clinic – to potentially bring new hope to people with cancer.
As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the fastest-growing development programs in the industry. We are currently executing an expansive research program that includes more than 360 clinical trials evaluating our anti-PD-1 therapy across more than 30 tumor types. We also continue to strengthen our immuno-oncology portfolio through strategic acquisitions and are prioritizing the development of several promising immunotherapeutic 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 125 years, Merck has been a global health care 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 health care through far-reaching policies, programs and partnerships. For more information, visit www.merck.com and connect with us on Twitter, Facebook, YouTube and LinkedIn.
SOURCE: Merck
