Eisai Co., Ltd. and Merck, known as MSD outside the United States and Canada, announced that the companies have agreed upon a strategic collaboration for the worldwide co-development and co-commercialization of Lenvima (lenvatinib mesylate), an orally available tyrosine kinase inhibitor discovered by Eisai.
Under the agreement, Eisai and Merck will develop and commercialize Lenvima jointly, both as monotherapy and in combination with Merck’s anti-PD-1 therapy, Keytruda (pembrolizumab).
Eisai will book Lenvima product sales globally, as monotherapy and in combination, and Merck and Eisai will share gross profits equally. Lenvima is currently approved as monotherapy for use in the treatment of thyroid cancer, as well as in combination with everolimus for the treatment of patients with renal cell carcinoma (RCC) who have failed previous therapy. Applications for regulatory approval of Lenvima monotherapy for the treatment of hepatocellular carcinoma have been submitted in Japan, the United States, Europe, China and other countries.
A phase 3 study (Study 307), sponsored by Eisai, is ongoing to evaluate separate combinations of Lenvima with Keytruda (pembrolizumab) or Lenvima with everolimus versus chemotherapy alone for the treatment of RCC. In January 2018, the companies announced that the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for the Lenvima/Keytruda combination in advanced and/or metastatic RCC. This was based on interim results from an ongoing Phase 1b/2 trial (Study 111/KEYNOTE-146), evaluating the combination in select solid tumors (including RCC and endometrial cancer), which provided evidence for synergistic effects on the observed overall response rate, regardless of treatment experience or PD-L1 tumour expression.
Per the agreement, the companies will also jointly initiate new clinical studies evaluating the Lenvima/Keytruda combination to support 11 potential indications in 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 cancer types.
“Aiming to maximize the potential of Lenvima and expedite the creation of innovative treatments in this age of "Cancer Evolution," we have entered into this collaboration with Merck who developed the anti-PD-1 antibody Keytruda,” commented Haruo Naito, representative corporate officer and CEO of Eisai Co., Ltd. “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.”
“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,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “There is strong scientific evidence supporting synergistic effects of Keytruda when used in combination with Lenvima, and the companies have already received Breakthrough Therapy Designation from the US FDA for the Keytruda/Lenvima combination in renal cell carcinoma. Through this collaboration, we will both broaden our oncology portfolio and have the opportunity to help even more cancer patients around the world.”
Gross profits from Lenvima product sales globally will be shared equally by Eisai and Merck. Expenses incurred during co-development, including for studies evaluating Lenvima as monotherapy, will be shared equally by the two companies.
Under the agreement, Merck will pay Eisai an upfront payment of $300 million US dollars and up to $650 million US dollars for certain option rights through 2020 (Eisai’s financial year: fiscal year ended March 2021), as well as $450 million US dollars as reimbursement for research and development expenses. In addition, Eisai is eligible to receive up to $385 million US dollars associated with the achievement of certain clinical and regulatory milestones and a maximum of up to $3.97 billion US dollars for the achievement of milestones associated with sales of Lenvima. Assuming the achievement of all development and commercial goals for all indications, the total amount of upfront, option and regulatory and sales milestone payments has the potential to reach up to $5.76 billion US dollars.
The impact of this collaboration on Eisai's consolidated financial results has been incorporated into the Notification Regarding Revision of Consolidated Financial Results Forecasts (IFRS) for the Fiscal Year Ending March 31, 2018 announced on March 8 (Japan).
Study 111/KEYNOTE-146 is a multicenter, open-label, phase 1b/2 clinical study being carried out in the United States and the European Union to evaluate the efficacy and safety of Lenvima in combination with Keytruda (pembrolizumab). The primary objective of the phase 1b portion of the study was to determine the maximum tolerated dose in patients with unresectable solid tumours (endometrial cancer, melanoma, non-small cell lung cancer, RCC, squamous cell carcinoma of the head and neck, and urothelial cancer) who had progressed after treatment with approved therapies or for which there are no standard effective therapies available. The initial part of phase 2 enrolled patients with select solid tumours after previous treatment with 0-2 lines of systemic therapy (unless discussed with the sponsor) with a recommended dosage based on the results of the phase 1b part. The primary endpoint of the initial part of phase 2 was objective response rate (ORR) after 24 weeks of treatment, with select secondary endpoints including ORR, disease control rate, progression-free survival, and duration of response. The expansion part of phase 2 is ongoing, and enrollment of patients is continuing in the endometrial cancer cohort.
From the results of the analysis (investigator review) of the RCC cohort 1 (n=30) in Study 111/KEYNOTE-146 as of March 1, 2017, the primary endpoint of the phase 2 portion, ORR after 24 weeks of treatment (ORR Week 24) was 63 per cent (95% CI, 44-80), with tumour regression observed in 93 per cent (28/30) of patients since the initiation of treatment (baseline). A tumour response was observed regardless of previous treatment experience or tumour PD-L1 expression. In this cohort, the most frequently observed adverse events (top six) were diarrhoea, fatigue, hypothyroidism, stomatitis, hypertension, and nausea.
The results of the interim analysis (n=23) of the endometrial cancer cohort in Study 111/KEYNOTE-146 as of December 1, 2016, indicated ORR Week 24 of 52.2 per cent (95% CI, 30.6-73.2) based on independent radiologic review and 47.8 per cent (95% CI, 26.8-69.4) based on investigator review. Additionally, tumor regression was observed regardless of the state of microsatellite instability (MSI). Anti-PD-1 antibodies are generally less effective in patients with low frequency of MSI, which is a biomarker for the inability to repair errors in the base sequence of DNA, or who are MSI negative. In this cohort, the most frequently observed adverse events (top five) were hypertension, fatigue, arthralgia, diarrhoea, and nausea.
Meanwhile, a similar phase 1b clinical study (Study 115/KEYNOTE-523) in Japanese patients with unresectable solid tumours and a phase 1b clinical study (Study 116/KEYNOTE-524) of the combination therapy in hepatocellular carcinoma in Japan and the United States are both underway.
Discovered and developed in-house by Eisai, Lenvima is an orally administered multiple receptor tyrosine kinase (RTK) inhibitor with a novel binding mode that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2 and VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3 and FGFR4) in addition to other pathway-related RTKs (including the platelet-derived growth factor (PDGF) receptor PDGFRa; KIT; and RET) involved in tumour angiogenesis, tumour progression and modification of tumour immunity.
Currently, Eisai has obtained approval for Lenvima as a treatment for refractory thyroid cancer in over 50 countries, including the United States, Japan, in Europe and Asia. Additionally, Eisai has obtained approval for the agent in combination with everolimus as a second-line treatment for RCC in over 40 countries, including the United States and in Europe. In Europe, the agent was launched under the brand name Kisplyx for RCC.
Furthermore, Eisai has submitted applications for an indication covering hepatocellular carcinoma in Japan (June 2017), the United States and Europe (July 2017), China (October 2017), Taiwan (December 2017) and other countries.