KEYNOTE-590 Demonstrates OS Benefit With Pembrolizumab Plus Chemotherapy in Advanced Esophageal Cancer

The primary end point of the phase 3 KEYNOTE-590 trial was met when the combination of pembrolizumab (Keytruda) and chemotherapy improved overall survival (OS) and progression-free survival (PFS) as initial treatment of patients with locally advanced or metastatic esophageal cancer during an interim analysis of the study, Merck announced in a press release.¹

According to the independent Data Monitoring Committee, the results were both statistically significant and clinically meaningful. In addition, a key secondary end point, objective response rate (ORR), was also met with the combination of pembrolizumab and chemotherapy. The safety profile observed in the study was consistent with a prior analysis of KEYNOTE-590.

As of result of the positive data, the results have been submitted for presentation at the upcoming European Society for Medical Oncology (ESMO) Virtual Congress 2020.

“Esophageal cancer is a devastating malignancy with a high mortality rate and few treatment options in the first-line setting beyond chemotherapy,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “In this pivotal study, Keytruda plus chemotherapy resulted in superior overall survival compared with the current standard of care in the full study population and across all patient groups evaluated. These results build upon our research reinforcing the survival benefits of Keytruda, and we look forward to engaging regulatory authorities as quickly as possible.”

KEYNOTE-590 is a randomized, double-blind, phase 3 clinical trial which is investigating the efficacy and safety of pembrolizumab in combination with the chemotherapy regimen of cisplatin plus 5-fluorouracil (5-FU) compared with placebo plus chemotherapy in 749 patients with locally advanced or metastatic esophageal carcinoma (NCT03189719). Duration of response and safety are 2 additional secondary end point of the study.

Patients in the pembrolizumab arm receive the drug at 200 mg on day 1 of each 3-week cycle, for up to 35 cycles. Cisplatin in both study arms is administered at a dose level of 50 mg/m2 on day 1 of each 3-week cycle for up to 6 cycles, and 5-FU was administered at 800 mg/m2 per day on day 1 to day 5 of each 3-week cycle for up to 35 cycles. All agents in the study were administered intravenously.

Pembrolizumab in combination with chemotherapy previously demonstrated an OS benefit in patients with advanced or metastatic esophageal cancer with who had positive PD-L1 expression in the phase 3 KEYNOTE-181 clinical trial. It was the first time a PD-1 inhibitor demonstrated survival improvement in this patient population.²

Results presented during the 2019 Gastrointestinal Cancers Symposium for KEYNOTE-181 showed that in 628 patients who were followed for a median of 7.1 months in the pembrolizumab arm and 6.9 months in the chemotherapy-only arm, the median OS was 9.3 months (95% CI, 6.6-12.5) versus 6.7 months (95% CI, 5.1-8.2), respectively (HR, 0.69; 95% CI, 0.52-0.93; P = .0074). The 1-year OS observed in the pembrolizumab arm was calculated as 43% compared with 20% with chemotherapy alone.

Notably, in the cohort of patients with squamous cell carcinoma, the OS improvement was clinically meaning at 8.2 months (95% CI, 6.7-10.3) in the pembrolizumab plus chemotherapy arm versus 7.1 months (95% CI, 6.1-8.2) in the chemotherapy alone arm, but the OS benefit did not meet the requirement for statistical significance (HR, 0.89; 95% CI, 0.75-1.05; P = .0560).

No statistical significance was observed in terms of OS in the intent-to-treat population, in which the median OS was 7.1 months in both treatment arms (HR, 0.89; 95% CI, 0.75-1.05; P = .0560).

In terms of safety, treatment-related adverse events (TRAEs) were reported in 64.3% of patients in the pembrolizumab arm versus 86.1 of those in the chemotherapy-only arm. The most common in the pembrolizumab arm included fatigue (11.8%), hypothyroidism (10.5%), decreased appetite (8.6%), asthenia (7.0%), nausea (7.0%) and diarrhea (5.4%). There were also grade 3 to 5 TRAEs observed in 18.2% of patients who received pembrolizumab and 40.9% of those who received chemotherapy alone. Death from TRAEs occurred in 5 patients overall.

KEYNOTE-590 expands on the KEYNOTE-181 data by bringing the active combination to the frontline setting. KEYNOTE-590 is expected to complete in April of 2021.¹

Pembrolizumab is an anti-PD1 therapy that has FDA indications across multiple solid tumors. In esophagus cancer, pembrolizumab is approved by the FDA and in China as monotherapy for the second-line treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (Combined Positive Score ≥10).

_References:

_{1. Merck’s Keytruda® (pembrolizumab) in combination with chemotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in locally advanced or first-line metastatic esophageal cancer. News release. Merck. August 19, 2020. Accessed August 19, 2020. https://bit.ly/3kXyFNC}

_{2. Kojima T, Muro K, Francois E, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study. J Clin Oncol. 2019;37 (suppl 4; abstr 2).}