FDA Approves Pembrolizumab for Some Patients With PD-L1–Positive Esophageal Cancer

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On July 30, the U.S. Food and Drug Administration (FDA) approved the programmed cell death protein 1 inhibitor pembrolizumab (Keytruda) as monotherapy for the treatment of patients with recurrent locally advanced or metastatic esophageal cancer whose tumors express programmed cell death ligand 1 (PD-L1, at a combined positive score [CPS] ≥ 10, as determined by an FDA-approved test), with disease progression after one or more prior lines of systemic therapy.


The approval was based on data from the KEYNOTE-181 study, a multicenter, randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who had disease progression on or after one prior line of systemic treatment for advanced disease. Patients with HER2-positive esophageal cancer were required to have received treatment with approved HER2-targeted therapy.

All patients were required to have submitted tumor specimens for PD-L1 testing at a central laboratory; PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with a history of noninfectious pneumonitis that required steroids, or current pneumonitis, active autoimmune disease, or a medical condition that required immunosuppression, were ineligible.

Patients were randomly assigned 1:1 to receive either pembrolizumab at 200 mg every 3 weeks or investigator’s choice of any of the following chemotherapy regimens, all given intravenously: paclitaxel at 80 to 100 mg/m2 on days 1, 8, and 15 of every 4-week cycle, docetaxel at 75 mg/m2 every 3 weeks, or irinotecan at 180 mg/m2 every 2 weeks. Randomization was stratified by tumor histology (esophageal squamous cell carcinoma vs esophageal adenocarcinoma/esophagogastric junction cancer) and geographic region (Asia vs not Asia).

Treatment with pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression. Patients randomly assigned to treatment with pembrolizumab were permitted to continue beyond the first Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1)–defined disease progression if clinically stable until the first radiographic evidence of disease progression was confirmed at least 4 weeks later with repeat imaging. Patients treated with pembrolizumab without disease progression could be treated for up to 24 months.

The major efficacy outcome measure was overall survival evaluated in the following co-primary populations: patients with esophageal squamous cell carcinoma, patients with tumors expressing PD-L1 (CPS ≥ 10), and all randomly assigned patients.

The observed hazard ratios (HRs) for overall survival were 0.77 (95% confidence interval [CI] = 0.63–0.96) in patients with esophageal squamous cell carcinoma, 0.70 (95% CI = 0.52–0.94) in patients with tumors expressing PD-L1 CPS ≥ 10, and 0.89 (95% CI = 0.75–1.05) in all randomly assigned patients. On further examination, in patients with esophageal squamous cell carcinoma whose tumors expressed PD-L1 (CPS ≥ 10), an improvement in overall survival was observed among patients assigned to pembrolizumab as compared with chemotherapy.

In patients with esophageal squamous cell carcinoma with PD-L1 expression (CPS ≥ 10), there were 68 events (80%) observed for patients receiving pembrolizumab (n = 85) and 72 events (88%) observed for patients receiving chemotherapy (n = 82). There was a median overall survival of 10.3 months in patients receiving pembrolizumab (95% CI = 7.0–13.5 months) compared with 6.7 months in the chemotherapy arm (95% CI = 4.8–8.6 months).

The median progression-free survival was 3.2 months (range = 2.1–4.4 months) for patients receiving pembrolizumab and 2.3 months (range = 2.1–3.4 months) for patients receiving chemotherapy (HR = 0.66; 95% CI = 0.48–0.92). The objective response rate was 22% (95% CI = 14%–33%) in patients receiving pembrolizumab, with a complete response rate of 5% (n = 4) and a partial response rate of 18% (n = 15). In the chemotherapy arm, the objective response rate was 7% (95% CI = 3%–15%), with a complete response rate of 1% (n = 1) and a partial response rate of 6% (n = 5). The median duration of response was 9.3 months (range = 2.1+ to 18.8+ months) in patients receiving pembrolizumab and 7.7 months (range = 4.3 to 16.8+ months) in the chemotherapy arm.

Among the 314 patients with esophageal cancer enrolled in KEYNOTE-181 treated with pembrolizumab, the median duration of exposure to pembrolizumab was 2.1 months. Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in 2,799 patients with melanoma or non–small cell lung cancer treated with pembrolizumab as a single agent.


This indication was also based on data from KEYNOTE-180, a multicenter, nonrandomized, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who had disease progression on or after at least two prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181.

The major efficacy outcome measures were objective response rate and duration of response according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by blinded independent central review.

The objective response rate in the 35 patients with esophageal squamous cell carcinoma expressing PD-L1 (CPS ≥ 10) was 20% (95% CI = 8%–37%). Among the seven responding patients, the duration of response ranged from 4.2 to 25.1 months or more, with five patients (71%) having responses of 6 months or longer and three patients (57%) having responses of 12 months or longer.