Eisai Co., Ltd. and Merck Enter Global Strategic Oncology Collaboration for LENVIMA® (lenvatinib mesylate)

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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 U.S. 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 tumor 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 U.S. 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.”

Financial Considerations

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 U.S. dollars and up to $650 million U.S. dollars for certain option rights through 2020 (Eisai’s financial year: fiscal year ended March 2021), as well as $450 million U.S. dollars as reimbursement for research and development expenses. In addition, Eisai is eligible to receive up to $385 million U.S. dollars associated with the achievement of certain clinical and regulatory milestones and a maximum of up to $3.97 billion U.S. 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 U.S. 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).

About the Phase 1b/2 Study (Study 111/KEYNOTE-146) that Supported Breakthrough Therapy Designation for the LENVIMA/KEYTRUDA Combination

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 tumors (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 tumors 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 percent (95% CI, 44-80), with tumor regression observed in 93 percent (28/30) of patients since the initiation of treatment (baseline). A tumor response was observed regardless of previous treatment experience or tumor PD-L1 expression. In this cohort, the most frequently observed adverse events (top six) were diarrhea, 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 percent (95% CI, 30.6-73.2) based on independent radiologic review and 47.8 percent (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, diarrhea, and nausea.

Meanwhile, a similar Phase 1b clinical study (Study 115/KEYNOTE-523) in Japanese patients with unresectable solid tumors 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.

About LENVIMA^® (lenvatinib mesylate)

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 PDGFRα; KIT; and RET) involved in tumor angiogenesis, tumor progression and modification of tumor 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.

The eight major clinical studies in progress on LENVIMA are as follows:

• A Phase 3 clinical study (Study 307) of separate combinations of LENVIMA with KEYTRUDA (pembrolizumab) or LENVIMA with everolimus versus chemotherapy alone in RCC (first-line) conducted in Japan, the United States and Europe.
• A Phase 3 clinical study (Study 308) of LENVIMA in thyroid cancer being conducted in China.
• A Phase 2 clinical study (Study 215) of LENVIMA in biliary tract cancer being conducted in Japan.
• A Phase 2 clinical study (Study 209) of LENVIMA in non-small cell lung cancer with RET translocations being conducted in Japan, the United States, Europe and Asia.
• A Phase 1b/2 clinical study (Study 111/KEYNOTE-146) of LENVIMA in combination with KEYTRUDA in select solid tumors (RCC, endometrial cancer, non-small cell lung cancer, urothelial cancer, squamous cell carcinoma of the head and neck, and melanoma) being conducted in the United States and European Union. Based on interim results, the combination treatment has been granted Breakthrough Therapy Designation by the U.S. FDA for the potential treatment of patients with advanced and/or metastatic RCC.
• A Phase 1b clinical study (Study 115/KEYNOTE-523) of LENVIMA in combination with KEYTRUDA in select solid tumors (RCC, endometrial cancer, non-small cell lung cancer, urothelial cancer, squamous cell carcinoma of the head and neck, and melanoma) being conducted in Japan.
• A Phase 1b clinical study (Study 116/KEYNOTE-524) of LENVIMA in combination with KEYTRUDA in hepatocellular carcinoma being conducted in Japan and the United States.
• A Phase 1b clinical study of LENVIMA in combination with nivolumab in hepatocellular carcinoma being conducted in Japan.

LENVIMA^® (lenvatinib) Indications in the U.S.

LENVIMA^® (lenvatinib) is a kinase inhibitor that is indicated for:

• Differentiated Thyroid Cancer (DTC): single agent for patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
• Renal Cell Cancer (RCC): in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy.

Important Safety Information

Warnings and Precautions

• In DTC, hypertension was reported in 73% of patients on LENVIMA (lenvatinib) vs 16% with placebo (44% vs 4% grade ≥3). In RCC, hypertension was reported in 42% of patients on LENVIMA + everolimus vs 10% with everolimus alone (13% vs 2% grade 3). Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. Systolic blood pressure ≥160 mmHg occurred in 29% of patients, and 21% of patients had a diastolic blood pressure ≥100 mmHg in the LENVIMA + everolimus–treated group. Blood pressure should be controlled prior to treatment and monitored throughout. Withhold dose for grade 3 hypertension despite optimal antihypertensive therapy; resume at reduced dose when controlled at grade ≤2. Discontinue for life-threatening hypertension
• In DTC, cardiac dysfunction was reported in 7% of patients on LENVIMA vs 2% with placebo (2% vs 0% grade ≥3). In RCC, decreased ejection fraction and cardiac failure were reported in 10% of patients on LENVIMA + everolimus vs 6% with everolimus alone (3% vs 2% grade 3). Monitor for signs/symptoms of cardiac decompensation. Withhold LENVIMA for development of grade 3 cardiac dysfunction until improvement to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity and persistence of cardiac dysfunction. Discontinue for grade 4 cardiac dysfunction
• In DTC, arterial thromboembolic events were reported in 5% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, arterial thromboembolic events were reported in 2% of patients on LENVIMA + everolimus vs 6% with everolimus alone (2% vs 4% grade ≥3). Discontinue following an arterial thrombotic event. The safety of resuming LENVIMA after an arterial thromboembolic event has not been established, and LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis in 1 patient. In DTC, ALT and AST increases (grade ≥3) occurred in 4% and 5% of patients on LENVIMA, respectively, vs 0% with placebo. In RCC, ALT and AST increases (grade ≥3) occurred in 3% of patients on LENVIMA + everolimus vs 2% and 0% with everolimus alone, respectively. Monitor liver function before initiation, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold dose for liver impairment grade ≥3 until resolved to grade 0, 1, or baseline. Resume at reduced dose or discontinue based on severity/persistence of hepatotoxicity. Discontinue for hepatic failure
• In DTC, proteinuria was reported in 34% of patients on LENVIMA vs 3% with placebo (11% vs 0% grade 3). In RCC, proteinuria was reported in 31% of patients on LENVIMA + everolimus vs 14% with everolimus alone (8% vs 2% grade 3). Monitor for proteinuria before and during treatment. Withhold dose for proteinuria ≥2 g/24 h. Resume at reduced dose when proteinuria is <2 g/24 h. Discontinue for nephrotic syndrome
• In RCC, diarrhea was reported in 81% of patients on LENVIMA + everolimus vs 34% with everolimus alone (19% vs 2% grade ≥3). Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Withhold dose for diarrhea grade ≥3. Resume at a reduced dose when diarrhea resolves to grade 1 or baseline. Permanently discontinue LENVIMA for grade 4 diarrhea despite medical management
• In DTC, events of renal impairment were reported in 14% of patients on LENVIMA vs 2% with placebo (3% vs 1% grade ≥3). In RCC, events of renal impairment were reported in 18% of patients on LENVIMA + everolimus vs 12% with everolimus alone (10% vs 2% grade ≥3). Withhold LENVIMA for grade 3 or 4 renal failure/impairment. Resume at reduced dose or discontinue, depending on severity/persistence of renal impairment. Active management of diarrhea and any other gastrointestinal (GI) symptoms should be initiated for grade 1 events
• In DTC, events of GI perforation or fistula were reported in 2% of patients on LENVIMA vs 0.8% with placebo. In RCC, events of GI perforation, abscess, or fistula (grade ≥3) were reported in 2% of patients on LENVIMA (lenvatinib) + everolimus vs 0% with everolimus alone. Discontinue in patients who develop GI perforation or life-threatening fistula
• In DTC, QT/QTc interval prolongation was reported in 9% of patients on LENVIMA vs 2% with placebo (2% vs 0% >500 ms). In RCC, QTc interval increases >60 ms were reported in 11% of patients on LENVIMA + everolimus (6% >500 ms) vs 0% with everolimus alone. Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold dose for QTc interval prolongation >500 ms. Resume at reduced dose when QTc prolongation resolves to baseline
• In DTC, hypocalcemia (grade ≥3) was reported in 9% of patients on LENVIMA vs 2% with placebo. In RCC, hypocalcemia (grade ≥3) was reported in 6% of patients on LENVIMA + everolimus vs 2% with everolimus alone. Monitor blood calcium levels at least monthly and replace calcium as necessary. Interrupt and adjust LENVIMA as necessary
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 4 patients. Withhold LENVIMA for RPLS until fully resolved. Resume at reduced dose or discontinue based on the severity and persistence of neurologic symptoms
• Across clinical studies in which 1,160 patients received LENVIMA monotherapy, hemorrhage (grade ≥3) was reported in 2% of patients. In DTC, hemorrhagic events occurred in 35% of patients on LENVIMA vs 18% with placebo (2% vs 3% grade ≥3). There was 1 fatal intracranial hemorrhage case among 16 patients who received LENVIMA and had central nervous system metastases at baseline. The most frequently reported hemorrhagic event was epistaxis (11% grade 1, 1% grade 2). Discontinuation due to hemorrhagic events occurred in 1% of patients on LENVIMA. In RCC, hemorrhagic events occurred in 34% of patients on LENVIMA + everolimus vs 26% with everolimus alone (8% vs 2% grade ≥3). The most frequently reported hemorrhagic event was epistaxis (23% for LENVIMA + everolimus vs 24% with everolimus alone). There was 1 fatal cerebral hemorrhage case. Discontinuation due to hemorrhagic events occurred in 3% of patients on LENVIMA + everolimus. Consider the risk of severe or fatal hemorrhage associated with tumor invasion/infiltration of major blood vessels (eg, carotid artery). Withhold LENVIMA for the development of grade 3 hemorrhage until resolved to grade 0 or 1. Resume at reduced dose or discontinue based on severity/persistence of hemorrhage. Discontinue for grade 4 hemorrhage
• In DTC patients with normal baseline thyroid-stimulating hormone (TSH), elevation of TSH level above 0.5 mU/L was observed postbaseline in 57% of patients on LENVIMA vs 14% with placebo. In RCC, grade 1 or 2 hypothyroidism occurred in 24% of patients on LENVIMA + everolimus vs 2% with everolimus alone. In RCC patients with normal or low TSH at baseline, elevation of TSH was observed postbaseline in 60% of patients on LENVIMA + everolimus vs 3% with everolimus alone. Monitor thyroid function before initiation of and at least monthly throughout treatment. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state
• Impaired wound healing, including fistula formation, has been reported in patients receiving LENVIMA. Temporary interruption of LENVIMA therapy should be considered in patients undergoing major surgical procedures
• LENVIMA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy

Adverse Reactions

• In DTC, the most common adverse reactions (≥30%) observed in LENVIMA-treated patients vs placebo-treated patients were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decrease (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%)
• In DTC, adverse reactions led to dose reductions in 68% of patients receiving LENVIMA (lenvatinib) and in 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo for adverse reactions. The most common adverse reactions (≥10%) resulting in dose reductions of LENVIMA were hypertension (13%), proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse reactions (≥1%) resulting in discontinuation of LENVIMA were hypertension (1%) and asthenia (1%)
• In RCC, the most common adverse reactions (>30%) observed in patients treated with LENVIMA + everolimus vs everolimus alone were diarrhea (81% vs 34%), fatigue (73% vs 40%), arthralgia/myalgia (55% vs 32%), decreased appetite (53% vs 18%), vomiting (48% vs 12%), nausea (45% vs 16%), stomatitis/oral inflammation (44% vs 50%), hypertension/increased blood pressure (42% vs 10%), peripheral edema (42% vs 20%), cough (37% vs 30%), abdominal pain (37% vs 8%), dyspnea/exertional dyspnea (35% vs 28%), rash (35% vs 40%), weight decreased (34% vs 8%), hemorrhagic events (32% vs 26%), and proteinuria/urine protein present (31% vs 14%). The most common serious adverse reactions (≥5%) were renal failure (11%), dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%), and dyspnea (5%)
• In RCC, adverse reactions led to dose reductions or interruption in 89% of patients receiving LENVIMA + everolimus and in 54% of patients receiving everolimus alone. The most common adverse reactions (≥5%) resulting in dose reductions in the LENVIMA + everolimus–treated group were diarrhea (21%), fatigue (8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%). Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the LENVIMA + everolimus–treated group and in 12% of patients in the everolimus-treated group

Use in Specific Populations

• Because of the potential for serious adverse reactions in nursing infants, advise women to discontinue breastfeeding during treatment
• LENVIMA may result in reduced fertility in females of reproductive potential and may result in damage to male reproductive tissues, leading to reduced fertility of unknown duration

For more information about LENVIMA, click here for the full Prescribing Information.