Second-Line Pembrolizumab Therapy Conveys Survival Benefit in Patients with Advanced Esophageal Cancer

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Esophageal and esophagogastric junction cancer is the seventh most frequently diagnosed cancer globally, accounting for 572,000 cancer cases in 2018.1 There are 2 main types of esophageal cancer: adenocarcinoma and squamous-cell carcinoma (SCC).1 SCC can develop throughout the esophagus while adenocarcinoma generally develops in the lower portion of the esophagus.2 In Asia and Eastern Europe, SCC is the most common type of esophageal cancer, and patients with this cancer type have a poor prognosis.1 Tobacco and alcohol use are primary risk factors for SCC.1 In North America and Western Europe, adenocarcinoma is the most common type of esophageal cancer, and it is strongly associated with obesity.1 Minimally invasive esophageal cancer can often be treated with surgical resection.2 Locally advanced resectable esophageal cancer is treated with multimodal therapy that may include surgery, chemotherapy, radiation therapy, and/or immunotherapy.2 Unresectable, advanced, and metastatic esophageal cancer management is palliative, with either local or systemic therapies.3 In Japan, the first-line therapy standard of care for patients with advanced or metastatic esophageal cancer is chemotherapy consisting of cisplatin and 5-fluorouracil.4 If the disease progresses after first-line treatment, there are limited therapy options available.4

The KEYNOTE-181 trial enrolled patients with advanced or metastatic esophageal cancer who failed first-line therapy and evaluated the use of 200 mg of pembrolizumab every 3 weeks versus either paclitaxel, docetaxel, or irinotecan as a second-line therapy.4 Patients were randomized 1:1 to receive either pembrolizumab or chemotherapy of the investigator’s choice. Muro and colleagues analyzed a subgroup of 152 Japanese patients enrolled in this trial. Of these patients, 150 had SCC and 79 had a programmed death-ligand 1 combined positive score (CPS) ≥10. Overall survival (OS) for the group receiving pembrolizumab was 12.4 months.4 For the group receiving chemotherapy, OS was 8.2 months. When the CPS ≥10 group was analyzed, the patients receiving pembrolizumab had a median OS of 12.6 months and patients receiving chemotherapy had a median OS of 8.4 months. Objective response was found in 20.8% of patients who received pembrolizumab and 10.7% in patients receiving chemotherapy.4

Most patients experienced ≥1 adverse events. In patients receiving chemotherapy, 95.9% reported treatment-related adverse events (TRAEs) with 50% reporting grade 3-5 adverse events. In patients who received pembrolizumab, 74.0% reported TRAEs with 16.9% reporting grade 3-5 adverse events. One patient in each treatment group died of TRAEs. When immune-mediated adverse events were analyzed, 31.2% of patients receiving pembrolizumab reported experiencing these while 5.4% of the chemotherapy group reported immune-mediated adverse events.4


  1. Ajani JA, D’Amico TA, Bentrem DJ, et al. Esophageal and esophagogastric junction cancers, version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17:855-883.
  2. National Cancer Institute. Esophageal cancer treatment (adult) (PDQ®)-health professional version. Updated July 15, 2021. Accessed October 3, 2021.
  3. Yoon HH. Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: approach to later lines of systemic therapy. UpToDate; 2020. Accessed October 2, 2021.
  4. Muro K, Kojima T, Moriwaki T, et al. Second-line pembrolizumab versus chemotherapy in Japanese patients with advanced esophageal cancer: subgroup analysis from KEYNOTE-181 [published online ahead of print September 30, 2021]. Esophagus. doi: 10.1007/s10388-021-00877-3.

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