Merck's Keytruda-Lenvima Combo Faces Setback in GI Cancer Trial

Merck & Co. and Eisai have encountered a significant challenge in their ongoing clinical trials for the combination therapy of Keytruda (pembrolizumab) and Lenvima (lenvatinib). The latest results from the Phase III LEAP-015 trial in gastroesophageal adenocarcinoma have yielded mixed outcomes, raising questions about the future of this combination in certain cancer indications.

Trial Results and Implications

The LEAP-015 trial, which evaluated Keytruda and Lenvima in combination with chemotherapy for patients with newly diagnosed, advanced HER2-negative gastroesophageal adenocarcinoma, failed to meet one of its primary endpoints. While the combination showed a statistically significant improvement in progression-free survival (PFS) and objective response rate (ORR), it did not demonstrate a significant benefit in overall survival compared to chemotherapy alone.

This outcome adds to a growing list of challenges for the Keytruda-Lenvima combination. Previous trials in the LEAP program, including studies in non-small cell lung cancer, liver cancer, and head and neck cancer, have also faced setbacks. The repeated failures have led to scrutiny of Merck's aggressive clinical development strategy, particularly in cases where late-stage testing was initiated without robust mid-stage validation.

Keytruda's Evolving Landscape

Keytruda, Merck's blockbuster cancer drug, has been a cornerstone of the company's oncology portfolio since its first FDA approval in September 2014. With approximately 50 approvals across various cancer types, often as part of combination therapies, Keytruda has been a dominant force in the immuno-oncology space.

However, recent developments suggest that Keytruda may be approaching its limits in terms of widespread use. In addition to the LEAP-015 results, other recent setbacks include:

• The halting of a Phase III trial of Keytruda plus anti-TIGIT antibody vibostolimab and chemotherapy in extensive-stage small cell lung cancer in August 2024.
• An FDA committee recommendation to limit the use of Keytruda and Bristol Myers Squibb's Opdivo in stomach and esophageal cancers based on PD-L1 expression levels.

Future Directions and Pipeline Focus

Despite these challenges, Merck and Eisai remain committed to further analysis of the LEAP-015 data. Gregory Lubiniecki, VP of global clinical development at Merck Research Laboratories, stated that the results would inform future research efforts to improve patient outcomes.

As Keytruda faces headwinds, attention is shifting to other promising assets in Merck's pipeline. Notable among these are:

1. Sac-TMT: A TROP2 antibody-drug conjugate partnered with Kelun Biotech, currently in multiple global Phase III trials.
2. mRNA-4157 (V940): A personalized cancer vaccine developed in collaboration with Moderna, advancing into pivotal studies for early-stage non-small cell lung cancer.

These pipeline candidates represent Merck's efforts to diversify beyond Keytruda and address upcoming patent cliffs. The company's aggressive development strategies for these assets underscore its commitment to maintaining its position in oncology, even as its flagship product faces new challenges.