Pembrolizumab Approved in China for Second-Line PD-L1+ Esophageal Cancer


The National Medical Products Administration in China has approved pembrolizumab for the treatment of patients with locally advanced or metastatic esophageal squamous cell carcinoma whose tumors express PD-L1 as determined by an approved test, following disease progression on 1 prior line of systemic therapy.

Shen Lin, MD

The National Medical Products Administration (NMPA) in China has approved pembrolizumab (Keytruda) for the treatment of patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1 (combined positive score [CPS] 10 or higher) as determined by an approved test, following disease progression on 1 prior line of systemic therapy.1

The approval was based on overall survival (OS) findings from the phase 3 KEYNOTE-181 trial (NCT02564263), as well as results from an extension of the international study in Chinese patients. Results showed that in the overall patient population of PD-L1–positive esophageal cancer, the median OS was 10.3 months for pembrolizumab compared with 6.7 months for chemotherapy, leading to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.46-0.90).2

In the extension study of KEYNOTE-181 in Chinese patients, the findings were consistent with the overall study. Here, the median OS was 12.0 months and 5.4 months for pembrolizumab and chemotherapy, respectively (HR, 0.38; 95% CI, 0.19-0.77).

“In China, more than 90% of esophageal cancers are squamous cell carcinomas, and patients with advanced types of this disease face a poor prognosis and have few treatment options,” said Shen Lin, MD, vice president of Clinical Oncology at Beijing Cancer Hospital and Peking University and deputy director of Beijing Institute for Cancer Research, stated in a press release. “This approval represents an important advancement for certain patients with esophageal squamous cell carcinoma who now have an immunotherapy treatment option.”

In July 2019, the FDA approved pembrolizumab for the same indication, also based on the overall KEYNOTE-181 data.

In the multicenter, randomized, open-label, active-controlled KEYNOTE-181 study, investigators enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after 1 prior line of systemic therapy for advanced disease. Patients with HER2/neu- positive esophageal cancer must have received treatment with approved HER2/neu-targeted therapy.

Patients were randomized 1:1 to receive either pembrolizumab at 200 mg every 3 weeks or investigator’s choice of intravenous chemotherapy: docetaxel at 75 mg/m2 on day 1 of each 21-day cycle; paclitaxel at 80 to 100 mg/m2 on days 1, 8, and 15 of each 28-day cycle; or irinotecan at 80 mg/m2 on day 1 of each 14-day cycle. Randomization was stratified by tumor histology (ESCC vs esophageal adenocarcinoma [EAC]/Siewert type I EAC of the gastroesophageal junction [GEJ]), and geographic region (Asia vs ex-Asia).

Treatment with either pembrolizumab or chemotherapy continued until unacceptable toxicity or disease progression. However, those receiving the PD-1 inhibitor were permitted to continue beyond the first RECIST v1.1-defined disease progression if clinically stable until the first radiographic evidence of progression was confirmed 5 weeks later or longer with repeat imaging. Patients could receive pembrolizumab without disease progression for up to 2 years.

To be eligible for enrollment, all patients were required to have tumor specimens for PD-L1 testing at a central laboratory. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx assay. Patients with a history of non-infectious pneumonitis that required steroids or current pneumonitis, active autoimmune disease, or a condition that required immunosuppression were ineligible.

Assessments occurred every 9 weeks. The primary endpoint was OS in patients with ESCC, patients with tumors expressing PD-L1 CPS 10 or higher, and all randomized patients. Secondary endpoints were progression-free survival (PFS), ORR, and duration of response (DOR), according to RECIST v1.1 as assessed by blinded independent central review (BICR).

Findings demonstrated that pembrolizumab led to a 23% reduction in the risk of death compared with chemotherapy in patients with ESCC (HR, 0.77; 95% CI, 0.63-0.96), and a 30% reduction in those with PD-L1—positive tumors CPS 10 or higher (HR, 0.70; 95% CI, 0.52-0.94), and an 11% reduction in the risk of death in all randomized patients (HR, 0.89; 95% CI, 0.75-1.05). Additional follow-up showed that there was an improvement in OS in patients with ESCC who also had PD-L1–positive tumors (CPS 10 or higher) with pembrolizumab versus chemotherapy.

In the PD-L1 (CPS 10 or higher) cohort, there were 68 events (80%) observed for patients receiving pembrolizumab (n = 85) and 72 events (88%) for those receiving chemotherapy (n = 82). Additional data showed that the median PFS was 3.2 months (range, 2.1-4.4) for those who received pembrolizumab compared with 2.3 months (range, 2.1-3.4) in the chemotherapy arm (HR, 0.66; 95% CI, 0.48-0.92). The ORR with pembrolizumab was 22% (95% CI, 14.0-33.0), which included a 5% complete response (CR) rate and an 18% partial response (PR) rate. With chemotherapy, the ORR was 7% (95% CI, 3.0-15.0), with a 1% CR rate and a 6% PR rate. The median DOR was 9.3 months (range, 2.1+ to 18.8+) in the pembrolizumab arm versus 7.7 months (range, 4.3-16.8+) with those who were treated with chemotherapy.

Also in the pembrolizumab arm, the median duration of exposure was 2.1 months (range, 1 day to 24.4 months). Regarding safety, adverse events associated with pembrolizumab were similar to prior data with the PD-1 inhibitor in patients with melanoma and non—small cell lung cancer.

“In China, there is a high incidence of esophageal cancer, and it is the fourth leading cause of cancer-related death,” Jonathan Cheng, MD, PhD, vice president, oncology clinical research, Merck Research Laboratories, stated in the press release. “This approval for Keytruda provides an important new option for certain patients with esophageal carcinoma in China, where there have been few treatment advances in recent years.”


  1. KEYTRUDA Is Now Approved Across Five indications for Three Different Types of Cancer in China and Is First Anti-PD-1 Therapy Approved for Esophageal Cancer [news release]: Kenilworth, NJ. Merck. Published June 22, 2020. Accessed June 22, 2020.
  2. FDA Approves New Monotherapy Indication for Merck’s KEYTRUDA® (pembrolizumab). FDA. Published July 31, 2019. Accessed July 31, 2019.

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