Merck’s KEYTRUDA® (pembrolizumab) Reduced Risk of Death by 31 Percent Compared to Chemotherapy in Previously Treated Patients with Advanced Esophageal or Esophagogastric Junction Carcinoma Whose Tumors Expressed PD-L1 (CPS ≥10)

Results from Phase 3 KEYNOTE-181 Trial to be Presented at 2019 Gastrointestinal Cancers Symposium (ASCO GI)

KENILWORTH, NJ, USA I January 14, 2019 I Merck (NYSE:MRK), known as MSD outside the United States and Canada, today announced the first presentation of results from KEYNOTE-181, a Phase 3 trial investigating KEYTRUDA, Merck’s anti-PD-1 therapy, as monotherapy for the second-line treatment of advanced or metastatic esophageal or esophagogastric junction carcinoma. In this pivotal study, KEYTRUDA met a primary endpoint by significantly improving overall survival (OS) in patients with squamous cell carcinoma or adenocarcinoma who progressed after standard therapy and whose tumors expressed PD-L1 (Combined Positive Score [CPS] ≥10), with a 31 percent reduction in the risk of death compared to chemotherapy (paclitaxel, docetaxel or irinotecan) (HR=0.69 [95% CI, 0.52-0.93]; p=0.0074). This represents the first time an anti-PD-1 therapy has demonstrated a survival benefit for this patient population. The primary endpoint of OS was also evaluated in patients with squamous cell histology and in the entire intention-to-treat (ITT) study population. While directionally favorable, statistical significance for OS was not met in these two patient groups. These results, as well as other study findings, are being presented at the 2019 Gastrointestinal Cancers Symposium (ASCO GI) in San Francisco in an oral presentation on Thursday, Jan. 17 (Abstract #2).

“The prognosis for patients diagnosed with esophageal cancer is poor, and for those who experience disease progression, there is no established standard of care, underscoring the need for improved therapies in the second-line setting,” said Dr. Takashi Kojima, professor at the Department of Gastroenterology and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan. “The significant improvement in overall survival observed with KEYTRUDA in patients with squamous cell carcinoma or adenocarcinoma whose tumors expressed PD-L1 with a CPS of 10 or greater represents an important scientific advancement and has the potential to benefit patients who currently have limited treatment options.”

“Esophageal cancer often progresses aggressively, so we are encouraged to see these overall survival results for KEYTRUDA as monotherapy in previously treated patients,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Merck is committed to understanding the clinical benefit of KEYTRUDA across a range of gastrointestinal cancers, including esophageal cancer. Along with other new data for KEYTRUDA and from our broad oncology portfolio, we are pleased to share our latest clinical research in gastrointestinal cancers at ASCO GI.”

As previously announced, data from KEYNOTE-181 will be submitted to the U.S. Food and Drug Administration (FDA) and other regulatory authorities for review.

Merck is continuing to study KEYTRUDA across multiple settings and stages of gastrointestinal cancer – including gastric, hepatocellular carcinoma and esophageal – through a broad clinical program comprised of more than 9,000 patients in 65 studies involving KEYTRUDA, including 7,000 patients in 35 Merck-affiliated studies. In esophageal cancer, the Phase 3 trial KEYNOTE-590, evaluating KEYTRUDA in combination with chemotherapy as a first-line treatment, is ongoing.

Study Design and Additional Data from KEYNOTE-181 (Abstract #2)

KEYNOTE-181 is a randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT02564263) investigating KEYTRUDA monotherapy compared to chemotherapy in more than 600 patients with advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or Siewert type I adenocarcinoma of the esophagogastric junction that has progressed after first-line standard therapy. The primary endpoint is OS (evaluated in all patients as well as in patients with PD-L1 CPS ≥10 and in patients with squamous cell carcinoma). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR) and safety/tolerability.

In the study, a total of 628 patients were randomized 1:1 to receive either KEYTRUDA (200 mg fixed dose every three weeks) or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: docetaxel (75 mg/m2 on Day 1 of each 21-day cycle), paclitaxel (80-100 mg/m2 on Days 1, 8, and 15 of each 28-day cycle), or irinotecan (80 mg/m2 on Day 1 of each 14-day cycle). Of these 628 patients, 401 had squamous cell carcinoma, and 222 had a PD-L1 CPS ≥10. Median follow-up for the study was 7.1 months for KEYTRUDA and 6.9 months for chemotherapy.

Among patients in the study whose tumors expressed PD-L1 (CPS ≥10) (n=222/628), the median OS in the KEYTRUDA group was 9.3 months (95% CI, 6.6-12.5) compared to a median OS of 6.7 months for patients in the chemotherapy group (95% CI, 5.1-8.2). In addition, the estimated 12-month OS rate in these patients was 43 percent for KEYTRUDA compared with 20 percent for chemotherapy.

In patients with squamous cell carcinoma (n=401/628), there was a clinically meaningful improvement in OS with KEYTRUDA compared to chemotherapy, which did not meet statistical significance per the pre-specified statistical plan (HR=0.78 [95% CI, 0.63-0.96]; p=0.0095). Among these 401 patients, median OS was 8.2 months in the KEYTRUDA group (95% CI, 6.7-10.3) compared with 7.1 months in the chemotherapy group (95% CI, 6.1-8.2).

In the entire ITT study population (n=628), while also directionally favorable, the difference in OS was not statistically significant (HR=0.89 [95% CI, 0.75-1.05]; p=0.0560), with a median OS of 7.1 months for both treatment groups. Per the pre-specified statistical analysis plan, the secondary endpoints of PFS and ORR were not formally tested, as OS was not reached in the full ITT study population.

The safety of KEYTRUDA in KEYNOTE-181 was consistent with what has been seen in previous trials among patients treated with KEYTRUDA monotherapy. Treatment-related adverse events (TRAEs) occurred in 64.3 percent of patients taking KEYTRUDA compared with 86.1 percent for chemotherapy. The most common TRAEs in the KEYTRUDA group with an incidence of 5 percent or more were fatigue (11.8%), hypothyroidism (10.5%), decreased appetite (8.6%), asthenia (7.0%), nausea (7.0%) and diarrhea (5.4%). Grade 3-5 TRAEs occurred in 57 patients (18.2%) taking KEYTRUDA compared with 121 (40.9%) on chemotherapy. There were five treatment-related deaths in each of the groups.

About Esophageal Cancer

Esophageal cancer, a type of cancer that is particularly difficult to treat, begins in the inner layer (mucosa) of the esophagus and grows outward. There are two main types of esophageal cancer: squamous cell carcinoma and adenocarcinoma. Globally, esophageal cancer is the seventh most commonly diagnosed cancer. This year, an estimated 17,650 adults in the United States will be diagnosed with esophageal cancer, and 16,080 deaths from this disease will occur. Worldwide, there were estimated to be over 572,000 new cases of esophageal cancer and approximately 508,000 deaths resulting from this disease in 2018 alone.

About KEYTRUDA® (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that 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.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 900 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefiting from treatment with KEYTRUDA, including exploring several different biomarkers.

KEYTRUDA® (pembrolizumab) Indications and Dosing

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity.

Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic 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, as a single agent, is 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.

When administering KEYTRUDA in combination with chemotherapy, KEYTRUDA should be administered prior to chemotherapy when given on the same day. See also the Prescribing Information for the chemotherapy agents administered in combination with KEYTRUDA, as appropriate.

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.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. 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 adults with cHL, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression. In pediatric patients with cHL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. 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 confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

In adults with PMBCL, 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. In pediatric patients with PMBCL, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In locally advanced or metastatic urothelial carcinoma, KEYTRUDA is administered at a fixed dose of 200 mg every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

  • solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
  • colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.

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. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

In adult patients with MSI-H cancer, 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. In children with MSI-H cancer, KEYTRUDA is administered at a dose of 2 mg/kg (up to a maximum of 200 mg) every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 [Combined Positive Score (CPS) ≥1] as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. 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. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. 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. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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. The recommended dose of KEYTRUDA is a fixed dose of 200 mg every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. 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. The recommended dose of KEYTRUDA in adults is 200 mg administered as an intravenous infusion over 30 minutes every three weeks until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression. The recommended dose of KEYTRUDA in pediatric patients is 2 mg/kg (up to a maximum of 200 mg), administered as an intravenous infusion over 30 minutes every three weeks until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology 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 more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. 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. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube and LinkedIn.

SOURCE: Merck

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