Merck, known as MSD outside the United States and Canada, announced that the US Food and Drug Administration (FDA) has approved Keytruda, Merck’s anti-PD-1 therapy, for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation in combination with platinum- and fluoropyrimidine-based chemotherapy.
The approval is based on results from the phase 3 KEYNOTE-590 trial, which demonstrated significant improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for Keytruda plus fluorouracil (FU) and cisplatin versus FU and cisplatin alone, regardless of histology or PD-L1 expression status. For OS and PFS, Keytruda plus FU and cisplatin reduced the risk of death by 27% (HR=0.73 [95% CI, 0.62-0.86]; p<0.0001) and reduced the risk of disease progression or death by 35% (HR=0.65 [95% CI, 0.55-0.76]; p<0.0001) versus FU and cisplatin alone. The ORR, an additional efficacy outcome measure, was 45% (95% CI, 40-50) for patients who received Keytruda plus FU and cisplatin and 29% (95% CI, 25-34) for those who received FU and cisplatin alone (p<0.0001).
Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with Keytruda, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of Keytruda. Based on the severity of the adverse reaction, Keytruda should be withheld or permanently discontinued and corticosteroids administered if appropriate. Keytruda can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, Keytruda can cause fetal harm when administered to a pregnant woman.
“Because esophageal cancer generally has poor survival rates, new first-line therapies are urgently needed for these patients,” said Dr. Peter Enzinger, director, Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women’s Cancer Center. “Today’s approval of this indication for Keytruda introduces a new option, which has shown a superior survival benefit compared to FU and cisplatin alone, for newly diagnosed patients with locally advanced or metastatic esophageal or GEJ carcinoma that is not amenable to surgical resection or definitive chemoradiation, regardless of PD-L1 expression status and tumor histology.”
“There have been few advances in improving survival outcomes in the first-line treatment setting for esophageal cancer over the last three decades,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “We are committed to putting patients first and continuing our research to help advance new approaches to potentially extend the lives of people with cancer. We thank all of the patients, their caregivers and healthcare professionals who participated in the study.”
This approval was reviewed under the FDA’s Real-Time Oncology Review (RTOR) pilot program and the FDA’s Project Orbis, an initiative of the Oncology Center of Excellence that provides a framework for concurrent review of oncology drugs among its international partners. Under this project, the FDA, Australian Therapeutic Goods Administration, Health Canada and Swissmedic collaboratively reviewed the KEYNOTE-590 application. The application is still under review in Australia, Canada and Switzerland.
The approval was based on data from KEYNOTE-590 (ClinicalTrials.gov, NCT03189719), a multicenter, randomized, placebo-controlled trial that enrolled 749 patients with metastatic or locally advanced esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma who were not candidates for surgical resection or definitive chemoradiation. Patients were randomized (1:1) to receive either Keytruda (200 mg on Day 1 every three weeks) or placebo (on Day 1 every three weeks) in combination with cisplatin (80 mg/m2 on Day 1 every three weeks for up to six cycles) plus FU (800 mg/m2 per day on Days 1 to 5 every three weeks, or per local standard for FU administration, for up to 24 months); all study medications were administered via intravenous infusion.
Randomization was stratified by tumor histology (squamous cell carcinoma vs. adenocarcinoma), geographic region (Asia vs. ex-Asia) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (0 vs. 1).
Treatment with Keytruda or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with Keytruda for up to 24 months in the absence of disease progression. The major efficacy outcome measures were OS and PFS, as assessed by the investigator according to RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ). The study pre-specified analyses of OS and PFS based on squamous cell histology, Combined Positive Score (CPS) =10, and in all patients. Additional efficacy outcome measures were ORR and duration of response (DOR), according to modified RECIST v1.1, as assessed by the investigator.
The study population characteristics were median age of 63 years (range: 27 to 94), 43% age 65 or older; 83% male; 37% white, 53% Asian and 1% Black; 40% had an ECOG PS of 0, and 60% had an ECOG PS of 1. Ninety-one percent had M1 disease, and 9% had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27% had adenocarcinoma.
In a pre-specified formal test of OS in patients with PD-L1 (CPS =10) (n=383), the median was 13.5 months (95% CI, 11.1-15.6) for the Keytruda arm and 9.4 months (95% CI, 8.0-10.7) for the placebo arm, with a HR of 0.62 (95% CI, 0.49-0.78; p<0.0001). In an exploratory analysis, in patients with PD-L1 (CPS <10) (n=347), the median OS was 10.5 months (95% CI, 9.7-13.5) for the Keytruda arm and 10.6 months (95% CI, 8.8-12.0) for the placebo arm, with a HR of 0.86 (95% CI, 0.68-1.10).
In the study, the median duration of exposure was 5.7 months (range: 1 day to 26 months) in the Keytruda combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. Keytruda was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of Keytruda (=1%) were pneumonitis (1.6%), acute kidney injury (1.1%) and pneumonia (1.1%). Adverse reactions leading to interruption of Keytruda occurred in 67% of patients. The most common adverse reactions leading to interruption of Keytruda (=2%) were neutropenia (19%), fatigue/asthenia (8%), decreased white blood cell count (5%), pneumonia (5%), decreased appetite (4.3%), anemia (3.2%), increased blood creatinine (3.2%), stomatitis (3.2%), malaise (3.0%), thrombocytopenia (3%), pneumonitis (2.7%), diarrhea (2.4%), dysphagia (2.2%) and nausea (2.2%). The most common adverse reactions (all grades =20%) for Keytruda plus chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%) and weight loss (24%).
Esophageal cancer begins in the inner layer (mucosa) of the esophagus and grows outward. Esophageal cancer is the eighth most commonly diagnosed cancer and the sixth leading cause of death from cancer worldwide. In the US, about 67% of newly diagnosed esophageal cancer cases were adenocarcinoma, and 33% were squamous cell carcinoma. It is estimated there will be approximately 19,260 new cases of esophageal cancer diagnosed and about 15,530 deaths resulting from the disease in the US in 2021.
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 1,400 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 benefitting from treatment with Keytruda, including exploring several different biomarkers.