Esophageal cancer includes esophageal squamous-cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), both of which carry a poor prognosis and are among the leading causes of cancer-related mortality worldwide.1 ESCC occurs in the upper or middle part of the esophagus, usually arising from the esophageal squamous epithelium lining which, after being exposed to carcinogens or damage, abnormally proliferates into invasive cancer.1 ESCC is more common in Africa and Southeast Asia.1 EAC occurs in the lower middle of the esophagus, beginning in glandular cells near the stomach, which proliferate typically after damage from gastroesophageal reflux disease.1 It is the primary type of esophageal cancer in North America and Europe.1 Despite the development and approval of various treatments for esophageal cancer in the past decade, little improvement in patient survival has been realized.1 However, various treatment regimens and avenues of approach are still being evaluated. The current first-line treatment recommendation is fluoropyrimidine plus platinum-based chemotherapy.
The KEYNOTE-590 phase 3 clinical trial investigated the use of pembrolizumab, a monoclonal antibody, plus chemotherapy versus chemotherapy alone as a first-line treatment for patients with advanced esophageal cancer or Siewert type-1 gastroesophageal junction cancer. The investigators enrolled 749 adult patients in 168 medical centers in 26 countries in this trial. Patients were randomly assigned 1:1 to 1 of 2 treatment groups. Group 1 received 200 mg of pembrolizumab intravenously plus 5-fluorouracil and cisplatin once every 3 weeks for up to 35 cycles. Group 2 received 200 mg of placebo intravenously plus 5-fluorouracil and cisplatin once every 3 weeks for up to 35 cycles. The study’s primary end points were overall survival (OS) and progression-free survival (PFS).
At first analysis, pembrolizumab plus chemotherapy demonstrated a superior OS in patients. Group 1 patients with ESCC and a PD-L1 combined positive score (CPS) ≥10 had an OS of 13.9 months compared with 8.8 months for group 2 patients with ESCC and CPS ≥10. Group 1 patients with ESCC had an OS of 12.6 months, and group 2 patients with ESCC had an OS of 9.8 months. Group 1 patients with PD-L1 CPS ≥10 had an OS of 13.5 months compared with an OS of 9.4 months for group 2 patients with PD-L1 CPS ≥10. When all randomized patients were evaluated, group 1 had an OS of 12.4 months and group 2 had an OS of 9.8 months.
PFS evaluation found pembrolizumab plus chemotherapy was superior to chemotherapy alone. PFS in group 1 patients with ESCC was 6.3 months and 5.8 months in group 2 patients with ESCC. Group 1 patients with PD-L1 CPS ≥10 had a PFS of 7.5 months, and group 2 patients with PD-L1 CPS ≥10 had a PFS of 5.5 months. In all randomized patients, PFS was 6.3 months for group 1 patients and 5.8 months for group 2 patients. Treatment-related adverse events grade ≥3 occurred in 72% of group 1 patients and 68% of group 2 patients.
Pembrolizumab plus chemotherapy improved OS and PFS in treatment-naïve patients with advanced esophageal cancer.
Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398:759-771.
- Yang YM, Hong P, Xu WW, et al. Advances in targeted therapy for esophageal cancer. Signal Transduct Target Ther. 2020;5:229.