Pembrolizumab in combination with chemotherapy significantly improved overall survival and progression-free survival in the frontline treatment of patients with locally advanced or metastatic esophageal cancer.
Roy Baynes, MD, PhD
Pembrolizumab (Keytruda) in combination with chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) in the frontline treatment of patients with locally advanced or metastatic esophageal cancer, meeting the primary end points of the phase 3 KEYNOTE-590 trial (NCT03189719).1
Moreover, the key secondary end point of objective response rate (ORR) was also met, with the chemoimmunotherapy combination resulting in a significant improvement over chemotherapy alone in this patient population, according to Merck, the developer of the PD-1 inhibitor. The toxicity profile of pembrolizumab proved to be consistent with what has previously been reported in other studies.
The results of the pivotal phase 3 trial will be discussed with global regulatory authorities and the data have been submitted for presentation at the 2020 ESMO Virtual Congress.
“Esophageal cancer is a devastating malignancy with a high mortality rate and few treatment options in the first-line setting beyond chemotherapy,” Roy Baynes, MD, PhD, senior vice president and head of global clinical development, as well as the chief medical officer at Merck Research Laboratories, stated in a press release.
“In this pivotal study, [pembrolizumab] plus chemotherapy resulted in superior OS compared with the current standard of care in the full study population and across all patient groups evaluated,” he added. “These results build upon our research reinforcing the survival benefits of [pembrolizumab], and we look forward to engaging regulatory authorities as quickly as possible.”
In the double-blind, randomized, phase 3 KEYNOTE-590 trial, investigators set out to examine the safety and efficacy of pembrolizumab in combination with the standard chemotherapy regimen comprised of cisplatin and 5-fluorouracil (5-FU) compared with placebo plus the same chemotherapy regimen in the first-line treatment of patients with locally advanced or metastatic esophageal carcinoma.2
Investigators hypothesized that pembrolizumab plus chemotherapy would significantly improve OS specifically in patients with esophageal squamous cell carcinoma (ESCC), those whose tumors had PD-L1 positivity, defined as a combined positive score (CPS) of 10 or more, and in the overall patient population, as well. They also hypothesized that in all 3 of these populations, the chemoimmunotherapy combination would also improve PFS over placebo/chemotherapy.
To be eligible for enrollment, patients had to have a histologically or cytologically confirmed diagnosis of locally advanced or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus or advanced Siewert type 1 adenocarcinoma of the esophagogastric junction (EGJ). Patients had to have an ECOG performance status of 0 to 1, have measurable disease per RECIST v1.1 criteria as determined by the local site investigator or radiology assessment, and be able to provide either a newly collected or archival tissue sample for PD-L1 testing, among other criteria.
Patients with locally advanced esophageal carcinoma that is either resectable or possibly curable with radiation therapy were not permitted to enroll, along with anyone who received previous treatment for advanced/metastatic adenocarcinoma or squamous cell cancer of the esophagus or advanced Siewert type 1 EGJ adenocarcinoma. Moreover, patients who had undergone major surgery, open biopsy, or experienced significant traumatic injury within 28 days prior to randomized could not participate.
The primary end points of the trial included OS in those with ESCC whose tumors had a PD-L1 CPS of 10 or more, OS in all patients with ESCC, OS in all patients whose tumors had a PD-L1 CPS score of 10 or more, and OS in all study participants. Other primary endpoints focused on PFS and included investigator-assessed PFS per RECIST v1.1 criteria in those with ESCC, in those whose tumors had a PD-L1 CPS score of 10 or more, and in all participants.
Key secondary end points of the trial included investigator-assessed ORR per RECIST v1.1 criteria in all study participants, in those with ESCC whose tumors had a PD-L1 CPS score of 10 or more, in those with ESCC, in those whose tumors had a PD-L1 CPS score of 10 or more, as well as duration of response in all participants, and safety, among others.
In the trial, 749 patients were randomized to receive the chemoimmunotherapy or chemotherapy alone. Patients in the experimental arm were given pembrolizumab at a dose of 200 mg intravenously (IV) on day 1 of each 3-week cycle for up to 35 cycles, cisplatin at a dose of 80 mg/m2 on day 1 of each 3-week cycle for up to 6 cycles, and 5-FU at a daily dose of 800 mg/m2 via continuous IV infusion on days 1 to 5 of each 3-week cycle or per the local standard for 5-FU administration, for up to 35 cycles. Those in the placebo arm were given IV placebo every 3 weeks and received cisplatin and 5-FU at the same dose as those in the experimental arm on days 1 to 5.
Pembrolizumab is currently approved in the United States and China for use as a single agent in the second-line treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors are PD-L1 positive.
The FDA approval was based on data from the phase 3 KEYNOTE-181 and phase 2 KEYNOTE-180 trials, in which pembrolizumab resulted in an improvement in median OS versus chemotherapy and elicited promising ORRs in patients with PD-L1–positive esophageal cancer, respectively.3
The PD-1 inhibitor continues to be investigated across multiple settings and stages of gastrointestinal cancer, including in patients with gastric, hepatobiliary, esophageal, pancreatic, colorectal, and anal cancers, according to Merck.