Keytruda Wins Big in China, Now Approved for Esophageal Squamous Cell Carcinomas

by Sangeeta Chakraborty
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By Sangeeta Chakraborty, Ph.D.

China’s National Medical Products Administration (NMPA) approved Keytruda (pembrolizumab), Merck’s blockbuster anti-PD1 drug, as monotherapy on 22nd June 2020 for the treatment of patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). Only those patients whose tumors express PD-L1 with a combined positive score of 10 or higher, as determined using the PD-L1 IHC 22C3 pharmDx assay, and for whom a prior line of systemic therapy has failed, are eligible to receive the treatment.

Esophageal cancer is the sixth leading cause of death in the world. It can be classified into two types: squamous cell carcinoma (SCC) and adenocarcinoma (ACC). The classification is based on the type of cell in the esophagus where cancer originates. SCC begins in the flat squamous epithelial lining of the esophagus and gradually grows outward of the esophageal wall. ACC, on the other hand, starts in the mucus-secreting glandular cells in the gastro-esophageal junction. In China, 90% of all esophageal cancers are SCC and remains the fourth leading cause of death from cancer.

This approval represents a significant advancement for certain patients with esophageal squamous carcinoma who now have an immunotherapy treatment option”, said Dr. Shen Lin, vice president of Clinical Oncology at Beijing Cancer Hospital and Peking University and deputy director of Beijing Institute for Cancer Research.



Keytruda’s approval comes in light of the findings from the global Phase 3 KEYNOTE-181 trial as well as results from an extension of the trial in Chinese patients. Earlier in July 2019, the FDA had approved Keytruda for the same indication, based on data from both the Phase 3 and Phase 2 KEYNOTE-180 trials.

  • KEYNOTE-181 is a multicenter, randomized, open-label trial that enrolled 628 patients with either metastatic squamous cell carcinoma (SCC) or adenocarcinoma (ACC) of the esophagus. The trial compared Keytruda vs. chemotherapy as second-line therapy in patients who relapsed with locally advanced or metastatic form of the cancer following failure of their first-line systemic treatment.
  • Patients were randomized 1:1 to receive either Keytruda or investigator’s choice of intravenous chemotherapy: docetaxel, paclitaxel, or irinotecan. Tumor samples from all patients were checked for PD-L1 expression using the PD-L1 IHC 22C3 pharmDx assay and were also histologically stratified as SCC vs. ACC.
  • The primary outcome measure of overall survival (OS) was determined in three groups:
    1. Patients with esophageal squamous cell carcinoma (SCC)
    2. Patients whose tumors express PD-L1 protein with a CPS≥10
    3. All randomly assigned patients (intent to treat group)

Although the drug did not improve overall survival in the whole patient population who received treatment, it did benefit patients whose tumors expressed higher amounts of PD-L1 protein (CPS≥10). Compared with chemotherapy alone, Keytruda was found to be superior in prolonging the overall survival in high PD-L1 expressing patients (median OS 9.3 vs. 6.7 months) regardless of the cancer type. However, the results were far more impressive for SCC patients with CPS ≥10 PD-L1 vs. ACC patients with CPS ≥10, and this is what signaled the green light for Keytruda’s approval.

In SCC CPS ≥10, the median OS was 10.3 months for Keytruda compared with 6.7 months for chemotherapy, and the immunotherapy led to a 36% reduction in the risk of death. The results from the Chinese counterpart of the global trial also showed similar trends with SCC patients; Keytruda receivers had an overall survival median of 12 months while those on chemotherapy had an OS of 5.4 months.

Adverse events were similar to prior data with the drug in patients with melanoma and NSCLC. In patients with PD-L1 CPS ≥10, 68 events (80%) were observed in the Keytruda arm vs. 72 events (88%) in the chemotherapy arm. Fewer patients had drug-related adverse events of any grade (64% vs. 86%) in the Keytruda cohort.

Keytruda is now approved across five indications for three different types of cancer in China, including advanced NSCLC and advanced melanoma, and is the first anti-PD-1 therapy approved in the country for esophageal cancer.

“The approval for patients with second-line esophageal squamous cell carcinoma marks the fifth indication for KEYTRUDA across three different types of cancer in China,” said Joseph Romanelli, president of MSD (Merck) in China. “With each approval, we’ve made steady progress to ensure patients have access to KEYTRUDA, and we will ensure the same for patients who are impacted by esophageal squamous cell carcinoma.”




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