Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced first-time data from the pivotal Phase 3 KEYNOTE-590 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, in combination with platinum-based chemotherapy (cisplatin plus 5-fluorouracil [5-FU]) for the first-line treatment of patients with locally advanced or metastatic esophageal and gastroesophageal junction (GEJ) cancer. In the study, KEYTRUDA in combination with chemotherapy significantly improved overall survival (OS), reducing the risk of death by 27% [HR=0.73 [95% CI, 0.62-0.86]; p<0.0001], versus chemotherapy in all randomized patients. KEYTRUDA in combination with chemotherapy also significantly improved progression-free survival (PFS), reducing the risk of disease progression or death by 35% or more than a third [HR=0.65 [95% CI, 0.55-0.76]; p<0.0001] in all randomized patients. With these results, KEYTRUDA is the first anti-PD-1 therapy in combination with chemotherapy to show superior OS, PFS and objective response rates (ORR) versus chemotherapy, the current standard of care, for these patients regardless of histology or PD-L1 expression status.

“Esophageal cancer is an aggressive disease that is associated with very poor survival, and there is an urgent need for advances for newly diagnosed, previously untreated patients,” said Dr. Ken Kato, chief, department of Head and Neck Medical Oncology, National Cancer Center Hospital, Tokyo, Japan. “In KEYNOTE-590, with a 27% reduction in the risk of death, the results show KEYTRUDA has the potential to change the current treatment paradigm for the first-line treatment of patients with locally advanced and unresectable or metastatic esophageal or esophagogastric junction cancer. Results also showed a median overall survival of 12.4 months for KEYTRUDA versus 9.8 months for chemotherapy.”

“These findings for KEYTRUDA in combination with chemotherapy are particularly impressive considering improvement in overall survival was observed across all patient populations – including those patients with esophageal squamous cell carcinoma, adenocarcinoma and gastroesophageal junction tumors – and regardless of PD-L1 expression,” said Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories. “Our goal is to extend the lives of people living with cancer, and these important findings add to a growing body of survival data for KEYTRUDA in a wide range of cancers.”

These late-breaking data were presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 on Monday, Sept. 21 (Abstract #LBA51). As announced, data spanning more than 15 types of cancer will be presented from Merck’s broad oncology portfolio and investigational pipeline at the congress. A compendium of presentations and posters of Merck-led studies is available here. Follow Merck on Twitter via @Merck and keep up to date with ESMO news and updates by using the hashtag #ESMO20.

Merck will be sharing these data with regulatory authorities worldwide. KEYTRUDA is currently approved in the U.S., China and Japan 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 [CPS] ≥10). Merck is continuing to study KEYTRUDA across multiple settings and stages of gastrointestinal cancer – including gastric, hepatobiliary, esophageal, pancreatic, colorectal and anal cancers – through its broad clinical program.

KEYNOTE-590 Trial Design and Additional Data (Abstract #LBA8)

KEYNOTE-590 is a Phase 3, randomized, double-blind trial (ClinicalTrials.gov, NCT03189719) that enrolled 749 patients and is evaluating KEYTRUDA in combination with chemotherapy, versus placebo plus chemotherapy (cisplatin plus 5-FU), for the first-line treatment of patients with locally advanced or metastatic esophageal carcinoma (including esophageal squamous cell carcinoma [ESCC] and adenocarcinoma of the esophagus) or Siewert type 1 GEJ. The primary endpoints are OS in patients with ESCC whose tumors expressed PD-L1 (CPS ≥10) and OS and PFS in patients with ESCC, in all randomized patients whose tumors expressed PD-L1 (CPS ≥10), and in all randomized patients. Secondary endpoints include ORR (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 by investigator review) in all patients, duration of response (DOR) and safety. OS and PFS were tested using a hierarchical strategy, such that testing was first performed in patients with ESCC whose tumors expressed PD-L1 (CPS ≥10), with partial alpha passing from a successful test of the hypothesis, then in all patients with ESCC, then in all patients whose tumors expressed PD-L1 (CPS ≥10), and finally in all participants.

At the first interim analysis, after a median follow-up of 10.8 months, KEYTRUDA in combination with chemotherapy demonstrated superior OS versus chemotherapy in all randomized patients in the study (HR=0.73 [95% CI, 0.62-0.86]; p<0.0001), in patients with ESCC whose tumors expressed PD-L1 (CPS ≥10) (HR=0.57 [95% CI, 0.43-0.75]; p<0.0001), in patients with ESCC (HR=0.72 [95% CI, 0.60-0.88]; p=0.0006), and in patients whose tumors expressed PD-L1 (CPS ≥10) (HR=0.62 [95% CI, 0.49-0.78]; p<0.0001). In all randomized patients in the study, the median OS was 12.4 months (95% CI, 10.5-14.0) in the KEYTRUDA combination arm versus 9.8 months (95% CI, 8.8-10.8) in the chemotherapy arm. In patients with ESCC whose tumors expressed PD-L1 (CPS ≥10), the median OS was 13.9 months (95% CI, 11.1-17.7) in the KEYTRUDA combination arm versus 8.8 months (95% CI, 7.8-10.5) in the chemotherapy arm. In patients with ESCC, the median OS was 12.6 months (95% CI, 10.2-14.3) in the KEYTRUDA combination arm versus 9.8 months (95% CI, 8.6-11.1) in the chemotherapy arm. In patients whose tumors expressed PD-L1 (CPS ≥10), the median OS was 13.5 months (95% CI, 11.1-15.6) in the KEYTRUDA combination arm versus 9.4 months (95% CI, 8.0-10.7) in the chemotherapy arm.

KEYTRUDA in combination with chemotherapy demonstrated superior PFS versus chemotherapy in all randomized patients in the study (HR=0.65 [95% CI, 0.55-0.76]; p<0.0001), in patients with ESCC (HR=0.65 [95% CI, 0.54-0.78]; p<0.0001), and in patients whose tumors expressed PD-L1 (CPS ≥10) (HR=0.51 [95% CI, 0.41-0.65]; p<0.0001). In all randomized patients in the study, the median PFS was 6.3 months (95% CI, 6.2-6.9) in the KEYTRUDA combination arm versus 5.8 months (95% CI, 5.0-6.0) in the chemotherapy arm. In patients with ESCC, the median PFS was 6.3 months (95% CI, 6.2-6.9) in the KEYTRUDA combination arm versus 5.8 months (95% CI, 5.0-6.1) in the chemotherapy arm. In patients whose tumors expressed PD-L1 (CPS ≥10), the median PFS was 7.5 months (95% CI, 6.2-8.2) in the KEYTRUDA combination arm versus 5.5 months (95% CI, 4.3-6.0) in the chemotherapy arm.

KEYTRUDA in combination with chemotherapy demonstrated superior ORR versus chemotherapy in all randomized patients in the study. The ORR was 45.0% (95% CI, 39.9-50.2) in the KEYTRUDA combination arm versus 29.3% (95% CI, 24.7-34.1) in the chemotherapy arm (p<0.0001). Additionally, the median DOR was 8.3 months (range, 1.2+ to 31.0+) in the KEYTRUDA combination arm versus 6.0 months (range, 1.5+ to 25.0+) in the chemotherapy arm.

Treatment-related adverse events (TRAEs) led to discontinuation in 19.5% of patients in the KEYTRUDA combination arm and 11.6% of patients in the chemotherapy arm. Grade 3-5 TRAEs occurred in 71.9% of patients in the KEYTRUDA combination arm and 67.6% of patients in the chemotherapy arm. There were nine treatment-related deaths in the KEYTRUDA combination arm and five treatment-related deaths in the chemotherapy arm. Immune-mediated adverse events of any grade occurred in 25.7% of patients in the KEYTRUDA combination arm and 11.6% of patients in the chemotherapy arm.