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KEYNOTE-181: Improved OS in Patients with Advanced Esophageal Cancer Treated with Second-Line Pembrolizumab

2021 Year in Review - Gastrointestinal Cancer

KEYNOTE-181 results show improved overall survival in patients with advanced esophageal cancer treated with second-line pembrolizumab compared with chemotherapy.

Esophageal cancer is the sixth leading cause of cancer-related mortality globally, having caused 508,000 deaths in 2018.1 Adenocarcinoma and squamous-cell carcinoma (SCC) are the 2 major histological types of esophageal cancer.1 Adenocarcinoma usually develops in the lower part of the esophagus, whereas SCC can develop throughout the esophagus.2 SCC is more likely to develop near the tracheal bifurcation and has a tendency for earlier lymphatic spread.1 SCC is associated with a poor prognosis.1 Although minimally invasive esophageal cancer can often be treated with surgical resection, locally advanced resectable esophageal cancer needs treatment with multimodal therapy, including surgery, chemotherapy, radiation therapy, and/or immunotherapy.2 Patients with advanced and metastatic esophageal cancer that cannot be removed by surgery are managed with palliative local or systemic therapy.3

The KEYNOTE-181 trial enrolled patients with advanced or metastatic esophageal cancer who had failed first-line therapy. The study evaluated the use of 200 mg of pembrolizumab every 3 weeks versus either paclitaxel, docetaxel, or irinotecan as a second-line therapy. Subgroup analysis of 152 Japanese patients, 150 with SCC and 79 with a PD-L1 combined positive score (CPS) ≥10, was performed. The overall survival (OS) for the patients who were treated with pembrolizumab was 12.4 months, whereas the OS for the group receiving chemotherapy was 8.2 months. The CPS ≥10 group analysis found that the patients who received pembrolizumab had a median OS of 12.6 months and the chemotherapy group had a median OS of 8.4 months. The objective response rate for patients receiving pembrolizumab was 20.8% and 10.7% in patients receiving chemotherapy.

A majority of patients experienced ≥1 adverse events (AEs), with 95.9% of patients receiving chemotherapy reporting treatment-related AEs (TRAEs) and 50% of these patients reporting grade 3 to 5 AEs. Of the patients who received pembrolizumab, 74.0% reported TRAEs and 16.9% reported grade 3 to 5 AEs. One patient in each treatment group died of TRAEs. Immune-mediated AEs were experienced by 31.2% of patients in the pembrolizumab group and 5.4% of the chemotherapy group reported this type of AE.

Second-line pembrolizumab improved OS in patients with advanced esophageal cancer compared with chemotherapy in the KEYNOTE-181 patient population.

Source: 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. Esophagus. 2021 Sep 30. doi: 10.1007/s10388-021-00877-3. Online ahead of print.


  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 13, 2021.
  3. UpToDate. Progressive, locally advanced unresectable, and metastatic esophageal and gastric cancer: approach to later lines of systemic therapy. Accessed October 12, 2021.
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