Merck and Eisai's phase 3 trials, LEAP-003 and LEAP-017, investigating the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) have failed to demonstrate a statistically significant improvement in overall survival (OS) for patients with advanced melanoma and metastatic colorectal cancer, respectively. These findings temper hopes for expanding the use of this combination therapy to a broader range of cancers.
The LEAP-003 trial (NCT03820986), a randomized, placebo-controlled study, evaluated pembrolizumab plus lenvatinib versus pembrolizumab alone as a first-line treatment for 674 adults with unresectable or metastatic melanoma. While an earlier interim analysis showed a statistically significant improvement in progression-free survival (PFS), the trial's primary endpoint of OS was not met, leading to the trial's discontinuation.
Similarly, the randomized, open-label, phase 3 LEAP-017 trial (NCT04776148) compared pembrolizumab plus lenvatinib with regorafenib or TAS-102 in 480 patients with unresectable and metastatic colorectal cancer that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H) who had progressed on or after prior treatment. The study showed a trend toward improved survival, but it did not reach statistical significance per the pre-specified statistical analysis plan.
Consistent Safety Profile
Despite the disappointing efficacy results, the safety profile of the pembrolizumab and lenvatinib combination remained consistent with previously reported data in both trials. This is an important consideration as the combination is already approved for other indications.
Ongoing Data Evaluation
Both Merck and Eisai are conducting a full evaluation of the data from these studies, including pre-planned key subgroup analyses. The companies plan to collaborate with investigators to share the detailed results with the scientific community, which may provide insights into potential patient subsets that could benefit from this combination.
Company Statements
Gregory Lubiniecki, MD, vice president, global clinical development, Merck Research Laboratories, stated, "We are grateful to all the investigators, patients, and their families for their participation in these studies, and we will continue to evaluate [pembrolizumab] plus [lenvatinib] across different types of cancer where additional treatment options are needed."
Corina Dutcus, MD, senior vice president, clinical development, oncology at Eisai Inc, added, "While these results are different from our initial expectation, insights from both studies will help contribute to our understanding of [pembrolizumab] plus [lenvatinib]. We remain confident in [lenvatinib] as a pillar of Eisai’s oncology portfolio and will continue to evaluate its potential in ongoing trials within the LEAP program."
Current Approvals
The combination of pembrolizumab plus lenvatinib is currently approved in the United States, Europe, Japan, and other countries for the treatment of advanced renal cell carcinoma (RCC) and some types of advanced endometrial carcinoma. The updated data from the LEAP-003 and LEAP-017 trials do not affect these existing approvals.
Broader LEAP Program
Merck and Eisai are investigating the combination of pembrolizumab and lenvatinib in more than 10 clinical trials across multiple tumor types through the LEAP clinical program. These include studies in endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, RCC, head and neck cancer, colorectal cancer, gastric cancer, and esophageal cancer.
