The FDA has approved pembrolizumab for patients with recurrent, locally advanced, or metastatic squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 with a combined positive score (CPS) of 10 or higher, as determined by an FDA-approved test, following disease progression after one or more prior lines of systemic therapy.
The approval represents a significant advancement for patients with advanced esophageal squamous cell cancer, a challenging malignancy with limited treatment options. Concurrent with the drug approval, the FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting appropriate patients for this indication.
Clinical Evidence Supporting Approval
The efficacy of pembrolizumab was demonstrated through two pivotal clinical trials: KEYNOTE-181 (NCT02564263) and KEYNOTE-180 (NCT02559687).
KEYNOTE-181 Trial Results
KEYNOTE-181 was a randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who had progressed on or after one prior line of systemic treatment for advanced or metastatic disease. Patients were randomized 1:1 to receive either pembrolizumab 200 mg intravenously every 3 weeks or investigator's choice of control therapy, including paclitaxel, docetaxel, or irinotecan.
The primary efficacy outcome was overall survival (OS) in patients with ESCC, patients with tumors expressing PD-L1 CPS ≥10, and all randomized patients. The trial demonstrated a clinically meaningful survival benefit for the target population. The hazard ratio for OS in patients with ESCC whose tumors expressed PD-L1 CPS ≥10 was 0.64 (95% CI: 0.46, 0.90). Median OS was 10.3 months (95% CI: 7.0, 13.5) in the pembrolizumab arm compared to 6.7 months (95% CI: 4.8, 8.6) in the control arm.
KEYNOTE-180 Supporting Data
KEYNOTE-180 was a single-arm, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who had progressed on or after at least 2 prior systemic treatments for advanced disease. The study used identical dosing to KEYNOTE-181 but required patients to have received more prior treatments.
In the 35 patients with ESCC expressing PD-L1 CPS ≥10, the overall response rate (ORR) was 20 percent (95% CI: 8, 37). Response durations ranged from 4.2 to 25.1+ months, with 71 percent of responders (five patients) having responses of 6 months or longer and 57 percent (three patients) having responses of 12 months or longer.
Safety Profile and Dosing
Adverse reactions in patients with esophageal cancer were consistent with those observed in 2,799 patients with melanoma or non-small cell lung cancer treated with single-agent pembrolizumab. Common adverse reactions reported in at least 20 percent of patients receiving pembrolizumab include fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.
The recommended pembrolizumab dose for esophageal cancer is 200 mg administered intravenously every 3 weeks. Treatment should continue until disease progression or unacceptable toxicity occurs.
Companion Diagnostic Requirement
The approval specifically requires PD-L1 testing using the FDA-approved PD-L1 IHC 22C3 pharmDx kit to identify patients whose tumors express PD-L1 with a CPS ≥10. This biomarker-driven approach ensures that treatment is targeted to patients most likely to benefit from pembrolizumab therapy.
The approval provides a new treatment option for patients with advanced esophageal squamous cell cancer, a population with significant unmet medical need following progression on standard systemic therapies.
