On March 22, 2021, pembrolizumab was approved for use in combination with platinum- and fluoropyrimidine-based chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal junction (tumors with epicenter 1 to 5 cm above the gastroesophageal junction) carcinoma who are not candidates for surgical resection or definitive chemoradiation.1,2
Supporting Efficacy Data
Approval was based on findings in the phase III, placebo-controlled, double-blind KEYNOTE-590 trial (ClinicalTrials.gov identifier NCT03189719).2 In the trial, 749 patients were randomly assigned to first-line treatment with pembrolizumab at 200 mg (n = 373) or placebo (n = 376) every 3 weeks for up to 35 cycles, both in combination with chemotherapy. Chemotherapy consisted of cisplatin at 80 mg/m2 on day 1 of each 3-week cycle for up to six cycles and fluorouracil (5-FU) at 800 mg/m2/d on days 1 to 5 of each 3-week cycle (or per local standard for 5-FU administration) for up to 24 months.
The main efficacy outcome measures were overall survival and investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Median overall survival was 12.4 months (95% confidence interval [CI] = 10.5–14.0 months) in the pembrolizumab group vs 9.8 months (95% CI = 8.8–10.8 months) in the chemotherapy group (hazard ratio [HR] = 0.73, 95% CI = 0.62–0.86, P < .0001). Median progression-free survival was 6.3 months (95% CI = 6.2–6.9 months) in the pembrolizumab group vs 5.8 months (95% CI = 5.0–6.0 months) in the chemotherapy group (HR = 0.65, 95% CI = 0.55–0.76, P < .0001).
An objective response was observed in 45% vs 29% of patients (P < .0001), with a complete response in 6% vs 2.4%. Median response durations were 8.3 months vs 6.0 months.
How It Works
Binding of PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Pembrolizumab is an anti–PD-1 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2 ligands, thereby releasing PD-1 pathway–mediated inhibition of the immune response, including antitumor immune response.
How It Is Used
In the current indication, the recommended dose of pembrolizumab is 200 mg every 3 weeks or 400 mg every 6 weeks, in combination with platinum- and fluoropyrimidine-based chemotherapy, with pembrolizumab treatment continuing until disease progression, unacceptable toxicity, or for up to 24 months. Pembrolizumab should be given prior to chemotherapy when given on the same day.
No dose reductions of pembrolizumab are recommended. In general, pembrolizumab should be withheld for grade 3 immune-mediated adverse reactions and permanently discontinued for grade 4 immune-mediated adverse reactions, recurrent grade 3 immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the corticosteroid dose to ≤ 10 mg of prednisone or equivalent per day within 12 weeks of initiating steroids. Pembrolizumab infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions and permanently discontinued for grade 3 or 4 reactions. Specific management guidelines for immune-mediated adverse events are provided in the warnings/precautions section of product labeling.
In theKEYNOTE-590 trial, the median duration of exposure to study treatment was 5.7 months (range = 1 day to 26 months) in the pembrolizumab group and 5.1 months (range = 3 days to 27 months) in the chemotherapy group.
In the trial, the most common adverse events of any grade among patients receiving pembrolizumab/chemotherapy were nausea (67% vs 63% in the chemotherapy group), fatigue/asthenia (57% vs 46%), decreased appetite (44% vs 38%), constipation (40% vs 40%), diarrhea (36% vs 33%), vomiting (34% vs 32%), stomatitis (27% vs 26%), and weight loss (24% vs 24%). The most common grade 3 or 4 adverse events included fatigue/asthenia, nausea, vomiting, and stomatitis. The most common grade 3 or 4 laboratory abnormalities were neutropenia (43% vs 41%), lymphopenia (22% vs 18%), anemia (21% vs 24%), leukopenia (21% vs 17%), hyponatremia (19% vs 19%), and hypokalemia (12% vs 15%).
Pembrolizumab treatment was interrupted due to adverse events in 67% of patients, the most common causes being neutropenia, fatigue/asthenia, decreased white blood cell count, pneumonia, decreased appetite, anemia, increased blood creatinine, stomatitis, malaise, thrombocytopenia, pneumonitis, diarrhea, dysphagia, and nausea. Pembrolizumab was permanently discontinued due to adverse events in 15% of patients, with the most common causes being pneumonitis, acute kidney injury, and pneumonia.
Pembrolizumab has warnings/precautions for immune-mediated adverse reactions. These reactions, which may be severe or fatal and can occur in any organ system or tissue, include immune-mediated pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and dermatologic adverse reactions, as well as solid organ transplant rejection. Pembrolizumab also has warnings/precautions for infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation before and after pembrolizumab treatment, including fatal or serious complications; and embryofetal toxicity.
Patients should be monitored for early identification and management of immune-mediated adverse reactions, including evaluation of liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. Patients should be advised not to breastfeed while receiving pembrolizumab.
1. U.S. Food and Drug Administration: FDA approves pembrolizumab for esophageal or GEJ carcinoma. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-esophageal-or-gej-carcinoma. Accessed April 7, 2021.
2. Keytruda (pembrolizumab) injection for intravenous use prescribing information, Merck & Co, Inc, March 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s096lbl.pdf. Accessed April 7, 2021.