Merck and Eisai Report Failure of 'Keylen' Combination to Meet OS Endpoints in Phase III Trials for Melanoma and Colorectal Cancer

On April 7, MSD/Eisai announced that two Phase III studies of Keytruda (pembrolizumab) in combination with Lenvima (lenvatinib) did not meet their primary endpoints. Firstly, the Phase III LEAP-003 study evaluating first-line treatment in adult patients with unresectable or metastatic advanced melanoma did not meet one of the co-primary endpoints of overall survival (OS). Additionally, the Phase III LEAP-017 study investigating pembrolizumab in combination with lenvatinib for patients with microsatellite stable/mismatch repair proficient (MSS/pMMR) unresectable or metastatic colorectal cancer also did not meet the primary endpoint of OS.

LEAP-003 is a randomized, placebo-controlled Phase III study designed to evaluate the efficacy and safety of pembrolizumab in combination with lenvatinib compared to pembrolizumab monotherapy as a first-line treatment for adult patients with unresectable or metastatic advanced melanoma. The primary endpoints include overall survival (OS) and progression-free survival (PFS), while key secondary endpoints encompass objective response rate (ORR), duration of response (DOR), and safety.

The study enrolled a total of 674 patients, who were randomly assigned in a 1:1 ratio to receive either pembrolizumab (200 mg intravenous infusion every 3 weeks) plus lenvatinib (20 mg orally daily) or pembrolizumab (200 mg intravenous infusion every 3 weeks) plus placebo. Early interim analysis showed that the study met its primary endpoint of significantly improving PFS in patients. However, recent analysis indicated that, compared with pembrolizumab alone, the combination therapy of pembrolizumab and lenvatinib did not significantly improve OS in patients. As a result, the two companies decided to terminate this study.

LEAP-017 is a randomized, open-label Phase III study designed to evaluate the efficacy of pembrolizumab in combination with lenvatinib versus regorafenib or TAS-102 (trifluridine/tipiracil) in patients with previously treated, disease-progressed MSS/pMMR unresectable or metastatic colorectal cancer. The primary endpoint is OS, with key secondary endpoints including PFS, ORR, and DOR. A total of 480 patients are enrolled. Patients in the two groups receive either pembrolizumab (400 mg intravenous infusion every 6 weeks) plus lenvatinib (20 mg orally daily), or regorafenib (160 mg orally daily on days 1–21 of each 4-week cycle) or TAS-102 (35 mg/m² orally twice daily on days 1–5 and days 8–12 of each 4-week cycle).

The study results showed that although OS, PFS, ORR, and DOR in the treatment group improved compared to the control group, the trend was not significant and did not demonstrate a statistically significant difference. However, the two companies have not decided whether to terminate the LEAP-017 study.

Dr. Corina Dutcus, Senior Vice President of Eisai's Oncology Clinical Research and Development, said, "Although the results were not as expected, these two studies will help deepen our understanding of the two drugs. At the same time, we are very confident in this portfolio and will continue to evaluate its development potential in the LEAP program."

So far, the "K cola combination" of Pembrolizumab and Lenvatinib has been approved for two indications. In September 2019, this combination received accelerated FDA approval for the treatment of endometrial cancer, and in July 2021, it received full approval. In August 2021, Pembrolizumab + Lenvatinib was again approved by the FDA for first-line treatment of patients with advanced renal cell carcinoma. The pivotal Phase III KEYNOTE-581 study showed that the combination therapy reduced the risk of disease progression or death by 61%, with a median progression-free survival (mPFS) of approximately 2 years, compared to 9 months for Sunitinib.

However, from December 2021 to the end of 2022, the "Keytruda-Lenvima combination" failed in three Phase III studies: first-line treatment of advanced NSCLC, first-line treatment of advanced urothelial carcinoma unsuitable for platinum-based chemotherapy, and first-line treatment of unresectable hepatocellular carcinoma. Now, the "Keytruda-Lenvima combination" has again fallen short in first-line treatment of unresectable or metastatic melanoma and in treating MSS/pMMR unresectable or metastatic colorectal cancer with disease progression after treatment. The repeated setbacks of the Keytruda-Lenvima combination have inevitably raised doubts within the industry about whether it can withstand future tests.

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