Merck & Co. will partner with Eisai to codevelop its marketed cancer treatment Lenvima® (lenvatinib mesylate) for additional oncology indications, both alone and in combination with Merck’s Keytruda® (pembrolizumab), through a collaboration that could generate up to $5.76 billion for Eisai, the companies said today.

The value of the collaboration represents potentially the second most valuable immuno-onocology partnership ever launched—the second time in as many months that has occurred.

The announcement comes two months after the companies won the FDA’s Breakthrough Therapy designation for a Lenvima/Keytruda combination in advanced and/or metastatic renal cell carcinoma (RCC).

That decision followed positive interim results in an ongoing Phase Ib/II trial (Study 111/KEYNOTE-146), evaluating the combination in six types of solid tumors—RCC, endometrial cancer, non-small-cell lung cancer, urothelial cancer, squamous cell carcinoma of the head and neck, and melanoma—in the U.S. and Europe. Study 111/KEYNOTE-146 yielded an overall response rate after 24 weeks of treatment of 63%, with tumor regression observed in 93% of patients (28 of 30) since the start of combination treatment with Lenvima and Keytruda.

The companies also have ongoing an Eisai-sponsored Phase III trial in the U.S., Europe, and Japan (Study 307) designed to assess separate combinations of Lenvima and Keytruda, as well as Lenvima and Novartis’ Afinitor® (everolimus), versus chemotherapy alone in RCC.

Study 307 and Study 111 are two of eight clinical studies in progress that are evaluating Lenvima as monotherapy or in combo with Keytruda.

“Together with Eisai, we aim to maximize the value of Lenvima for its current indications while jointly pursuing additional approvals in combination with Keytruda across a wide range of cancers,” Merck Research Laboratories president Roger M. Perlmutter, M.D., Ph.D., said in a statement. “Through this collaboration, we will both broaden our oncology portfolio and have the opportunity to help even more cancer patients around the world.”

Second-Largest I/O Partnership

The partnership surpasses the potential second most valuable immuno-oncology partnership announced just last month, when Bristol-Myers Squibb (BMS) and Nektar Therapeutics launched an up-to-$3.6 billion-plus combination cancer immunotherapy collaboration.

The top immuno-onocology collaboration, as ranked by GEN last year, remains the €5.78 billion ($7.1 billion) partnership by Merck & Co. and Ablynx, launched in 2014 and expanded in 2015 to include discovery and development of up to 12 additional cancer drugs based on single-domain antibody fragments, or Nanobodies®

Beyond immunotherapy, Merck has an even larger up to $8.5 billion cancer partnership with AstraZeneca to codevelop and cocommercialize the latter’s ovarian cancer poly(ADP-ribose) polymerase (PARP) inhibitor Lynparza™ (olaparib) and late-stage investigational MAPK/ERK kinase 1/2 (MEK 1/2) inhibitor selumetinib for multiple cancer indications.

Eisai and Merck have agreed to jointly launch new clinical studies evaluating the Lenvima/Keytruda combination in 11 potential indications covering six types of cancer—endometrial cancer, non-small-cell lung cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, and melanoma—as well as a “basket” trial targeting multiple unspecified cancer types.

Lenvima is an oral multiple receptor tyrosine kinase (RTK) inhibitor whose binding mode is designed to selectively inhibit the kinase activities of vascular endothelial growth factor (VEGF) receptors 1,2, and 3; and fibroblast growth factor (FGF) receptors 1, 2, 3, and 4, in addition to other pathway-related RTKs that include three platelet-derived growth factor (PDGF) receptors involved in tumor angiogenesis, tumor progression and modification of tumor immunity, PDGFRα, KIT, and RET.

Lenvima is approved as a single agent for refractory thyroid cancer in the U.S. and more than 50 countries, including in Europe and Asia. The U.S. indication includes locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC).

Lenvima is also approved in combination with Afinitor as a second-line treatment for RCC in the U.S. and more than 40 countries, including in Europe—where the drug was launched in that indication under the name Kisplyx®. The U.S. indication covers patients with advanced RCC following one prior antiangiogenic therapy.

Additional Applications Pending

Last year, Eisai submitted applications to market Lenvima for hepatocellular carcinoma in the U.S. as well as Japan, Europe, China, Taiwan, and other countries.

Merck agreed to pay Eisai $300 million upfront and up to $650 million for certain option rights through Eisai’s 2020 fiscal year, which ends March 31, 2021.

Merck also agreed to pay Eisai $450 million U.S. dollars for R&D expenses, up to $385 million tied to achieving clinical and regulatory milestones—and up to $3.97 billion tied to achieving sales milestones for Lenvima.

The two companies said they plan to share equally the gross profits from global Lenvima product sales, as well as expenses incurred during codevelopment, including for studies evaluating Lenvima as monotherapy.

Added Haruo Naito, Eisai representative corporate officer and CEO: “By providing new treatment options including for refractory cancers with no hopes for a cure to date, we are striving to further contribute to increasing the benefits provided to patients and their families.”

In addition to Study 307 and Study 111, the other six ongoing clinical trials of Lenvima include:

  • Study 308—A Phase III study (Study 308) in thyroid cancer being conducted in China.
  • Study 215—A Phase II study in biliary tract cancer being conducted in Japan.
  • Study 209—A Phase II study in non-small-cell lung cancer with RET translocations being conducted in Japan, the U.S., Europe, and Asia.
  • Study 115/KEYNOTE-523—A Phase Ib study of the Lenvima/Keytruda combo in RCC, endometrial cancer, non-small-cell lung cancer, urothelial cancer, squamous cell carcinoma of the head and neck, and melanoma, being conducted in Japan.
  • Study 116/KEYNOTE-524—A Phase Ib study of Lenvima/Keytruda in hepatocellular carcinoma being conducted in Japan and the U.S.
  • A Phase Ib study of Lenvima and Bristol-Myers Squibb’s Opdivo® (nivolumab) in hepatocellular carcinoma being conducted in Japan.
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