Merck's Keytruda Receives Fifth Indication Approval in China for PD-L1-Positive Esophageal Squamous Cell Carcinoma

On June 19, 2020, the information on drug approval documents pending collection indicated that Merck & Co.’s blockbuster PD-1 inhibitor Keytruda (pembrolizumab) received approval for an additional new indication. It is indicated for the treatment of locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) that is PD-L1 positive (Combined Positive Score [CPS] ≥10) and has progressed following prior first-line systemic therapy.

In July 2018, Keytruda was first approved in China for the first-line treatment of metastatic melanoma. In 2019, Keytruda sequentially gained three lung cancer indications in China: first-line treatment of EGFR-negative and ALK-negative metastatic non-squamous NSCLC; first-line treatment of locally advanced or metastatic NSCLC with PD-L1 positive expression and no specific genetic mutations; and first-line treatment of metastatic squamous NSCLC. This approval marks the fifth indication for Keytruda in China and the first gastrointestinal indication approved for this drug in the country.

Esophageal cancer is one of the malignancies with distinct characteristics in China. In China, squamous cell carcinoma accounts for the majority (97%) of esophageal cancer cases, whereas adenocarcinoma predominates in Western populations (80%). Although many clinicians have observed differences in the treatment outcomes between these two histological subtypes, large-scale Phase III clinical trials confirming such disparities have been lacking. Furthermore, most patients are diagnosed at an advanced stage when curative surgical resection is no longer feasible; thus, the standard of care is chemoradiotherapy, which often yields suboptimal results and is associated with a high risk of recurrence. Recurrence/metastasis and resistance to chemoradiotherapy are the two major challenges contributing to the high mortality rate of esophageal cancer.

In 2019, the global data from the KEYNOTE-181 study were released, leading to FDA approval and establishing it as the first immunotherapy for esophageal cancer worldwide. Subsequently, data from the Chinese subgroup were progressively disclosed, demonstrating that the efficacy of immunotherapy in Chinese patients with esophageal squamous cell carcinoma was superior to the global results. This marked the first time in a large-scale Phase III trial that significant therapeutic differences between Eastern and Western esophageal cancer populations were confirmed. Among Chinese patients with PD-L1-positive esophageal cancer, Keytruda extended median overall survival (OS) from 5.3 months to 12 months, reducing the risk of disease-related death by 66%. Importantly, these findings were observed in patients with recurrent or metastatic disease, showing outcomes even superior to those of certain first-line chemotherapy regimens for esophageal cancer.

As the PD-1 monoclonal antibody with the most approved indications, Keytruda has gained new indications annually outside of China, covering more than ten cancer types, including head and neck squamous cell carcinoma and invasive bladder cancer. Recently, it received its second “tumor-agnostic” indication in the United States, for the monotherapy treatment of patients with unresectable or metastatic solid tumors who have high tumor mutational burden (TMB-H) and whose disease has progressed following prior treatments, regardless of cancer type.