Merck's Keytruda Combo Fails to Meet Overall Survival Endpoint in Phase III Gastroesophageal Cancer Trial

Merck's blockbuster cancer drug Keytruda (pembrolizumab) has encountered a setback in its latest Phase III clinical trial, raising questions about the limits of its widespread use in oncology. The LEAP-015 study, which evaluated Keytruda in combination with Eisai's tyrosine kinase inhibitor Lenvima (lenvatinib), failed to meet one of its primary endpoints in patients with advanced gastroesophageal adenocarcinoma.

Trial Results and Implications

The LEAP-015 trial investigated the efficacy of Keytruda plus Lenvima in patients with locally advanced unresectable or metastatic HER2-negative gastroesophageal adenocarcinoma. While the combination showed a statistically significant improvement in progression-free survival (PFS) compared to placebo, it did not demonstrate an improvement in overall survival (OS), which was the other primary endpoint of the study.

The trial did report positive results for some secondary endpoints, including an improvement in objective response rate (ORR). However, the failure to meet the OS endpoint is a significant disappointment for Merck and Eisai, as overall survival is generally considered the gold standard for efficacy in oncology trials.

Gregory Lubiniecki, Vice President of Global Clinical Development at Merck Research Laboratories, acknowledged the challenges of treating advanced gastroesophageal adenocarcinoma, stating that the results "add to our understanding of this combination in this difficult-to-treat cancer type."

Keytruda's Broader Context

This setback for Keytruda comes amid a series of recent challenges for the PD-1 inhibitor, which has been a cornerstone of Merck's oncology portfolio since its first FDA approval in September 2014. The drug has accumulated around 50 approvals across various cancer types, often as part of combination therapies.

However, recent events suggest that Keytruda may be approaching the limits of its expandable indications:

1. In August 2024, Merck halted a Phase III trial of Keytruda in combination with anti-TIGIT antibody vibostolimab and chemotherapy for extensive-stage small cell lung cancer due to failure to meet the primary endpoint of overall survival.

2. In late 2024, an FDA committee recommended limiting the use of Keytruda and Bristol Myers Squibb's rival drug Opdivo in stomach and esophageal cancers based on PD-L1 expression levels.

These developments, along with the latest LEAP-015 results, indicate that while Keytruda remains a critical player in the immuno-oncology space, its growth trajectory may be slowing as it encounters more resistant cancer types and treatment scenarios.

Future Directions

Despite this setback, Merck and Eisai plan to conduct a full analysis of the LEAP-015 data and present the results at an upcoming medical meeting. The companies are also continuing to study the Keytruda-Lenvima combination in other cancer types, including hepatocellular carcinoma and esophageal cancer, as part of the broader LEAP clinical program.

The combination is already approved for use in advanced renal cell carcinoma and certain types of endometrial carcinoma, highlighting the importance of continued research to identify the most effective applications for these therapies.

As the landscape of cancer treatment evolves, the pharmaceutical industry will be closely watching how Merck navigates the challenges facing Keytruda and whether the company can maintain its dominant position in the immuno-oncology market.