The FDA has approved pembrolizumab, an 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 III KEYNOTE-590 trial, which demonstrated significant improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) for PEMBROLIZUMAB plus fluorouracil (FU) and cisplatin versus FU and cisplatin alone, regardless of histology or PD-L1 expression status. For OS and PFS, pembrolizumab plus FU and cisplatin reduced the risk of death by 27 percent (HR=0.73 [95% CI, 0.62-0.86]; p<0.0001) and reduced the risk of disease progression or death by 35 percent (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 percent (95% CI, 40-50) for patients who received pembrolizumab plus FU and cisplatin and 29 percent (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 pembrolizumab, 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 pembrolizumab. Based on the severity of the adverse reaction, pembrolizumab should be withheld or permanently discontinued and corticosteroids administered if appropriate. Pembrolizumab can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, pembrolizumab 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 Peter Enzinger, MD, Director, Center for Esophageal and Gastric Cancer, Dana-Farber/Brigham and Women's Cancer Center. “Today's approval of this indication for [pembrolizumab] 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."
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.
Data Supporting the Approval
The approval was based on data from KEYNOTE-590 (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 pembrolizumab (200 mg on Day 1 every 3 weeks) or placebo (on Day 1 every 3 weeks) in combination with cisplatin (80 mg/m2 on Day 1 every 3 weeks for up to six cycles) plus FU (800 mg/m2 per day on Days 1 to 5 every 3 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 pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression. Patients could be treated with pembrolizumab 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 percent male; 37 percent white, 53 percent Asian and 1 percent Black; 40 percent had an ECOG PS of 0, and 60 percent had an ECOG PS of 1. Ninety-one percent had M1 disease, and 9percent had M0 disease. Seventy-three percent had a tumor histology of squamous cell carcinoma, and 27 percent had adenocarcinoma.
The trial demonstrated statistically significant improvements in OS and PFS for patients randomized to pembrolizumab in combination with chemotherapy compared to chemotherapy alone
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 pembrolizumab 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 pembrolizumab 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 pembrolizumab combination arm and 5.1 months (range: 3 days to 27 months) in the chemotherapy arm. Pembrolizumab was discontinued for adverse reactions in 15% of patients. The most common adverse reactions resulting in permanent discontinuation of pembrolizumab (≥1%) were pneumonitis (1.6%), acute kidney injury (1.1%) and pneumonia (1.1%). Adverse reactions leading to interruption of pembrolizumab occurred in 67 percent of patients. The most common adverse reactions leading to interruption of pembrolizumab (≥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 pembrolizumab plus chemotherapy were nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%) and weight loss (24%).