Pembrolizumab (Keytruda®, Merck) has been approved by the FDA for patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus (ESCC) with tumors expressing a programmed death ligand-1 (PD-L1) combined positive score (CPS) of at least 10 and with disease progression following one or more previous systemic treatments.
The approval was based on the Keynote-181 (NCT02559687) and Keynote-180 (NCT02564263) clinical trials. Keynote-181 enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who experienced disease progression on or after one previous systemic therapy for advanced or metastatic disease. Patients were randomized in a 1:1 ratio to receive pembrolizumab 200 mg every three weeks for up to two years or the investigator's choice of paclitaxel, docetaxel, or irinotecan, for a primary end point of overall survival. Keynote-180, a single-arm trial, enrolled 121 patients with locally advanced or metastatic esophageal cancer who experienced disease progression on or after at least two prior lines of systemic therapy for primary end points of overall response rate and response duration.
In Keynote-181, pembrolizumab increased median overall survival compared with the control arm (10.3 months vs 6.7 months). In Keynote-180, in 35 patients whose cancer expressed PD-L1 CPS ≥10, pembrolizumab achieved an overall response rate of 20% and response durations ranging from 4.2 to 25.1 months or more, with 71% of patients experiencing responses of at least 6 months and 57% of patients experiencing responses of at least 12 months.
Adverse reactions occurring in at least 20% of patients receiving pembrolizumab included fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
In addition to the approval of pembrolizumab, the FDA has approved the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients with ESCC who are eligible for pembrolizumab.
"Where effective treatment options are an unmet need," conclude the researchers, led by first author Manish Shah, MD, of the Division of Hematology and Medical Oncology at Weill Cornell Medical College, in their publication of the KEYNOTE-180 results in JAMA Oncology, "pembrolizumab provided durable antitumor activity with manageable safety in patients with heavily pretreated esophageal cancer."
The recommended dosage of pembrolizumab is 200 mg every three weeks.
For More Information
Clinicaltrials.gov (2019). Study of pembrolizumab (MK-3475) in previously-treated participants with advanced carcinoma of the esophagus or esophagogastric junction (MK-3475-180/Keynote-180). NLM identifier: NCT02559687.
Clinicaltrials.gov (2019). Study of pembrolizumab (MK-3475) versus investigator's choice standard therapy for participants with advanced esophageal/esophagogastric junction carcinoma that progressed after first line therapy (MK-3475-181/Keynote-181). NLM identifier: NCT02564263.
Kojima T, Muro K, Francois E, et al (2019). Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. J Clin Oncol. [Epub ahead of print] DOI:10.1200/JCO.2019.37.4_suppl.2
Shah M, Kojima T, Hochhauser D, et al (2018). Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncology. [Epub ahead of print] DOI:10.1001/jamaoncol.2018.5441
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