Eisai Co., Ltd. and Merck announced that they received Therapy Designation from the U.S. Food and Drug Administration (FDA) for Eisai's multiple receptor tyrosine kinase inhibitor LENVIMA® (lenvatinib) in combination with Merck's anti-PD-1 therapy KEYTRUDA® (pembrolizumab) for the potential treatment of patients with advanced and/or metastatic renal cell carcinoma (RCC). The LENVIMA and KEYTRUDA combination therapy is being jointly developed by Eisai and Merck. This is the second Breakthrough Therapy Designation for LENVIMA and the twelfth Breakthrough Therapy Designation granted to KEYTRUDA.

The Breakthrough Therapy Designation is an FDA program intended to expedite development and review of drugs for serious or life-threatening conditions. In order to qualify for this designation, preliminary clinical evidence must demonstrate that the drug may provide substantial improvement over currently available therapy on at least one clinically significant endpoint. The benefits of this Breakthrough Therapy Designation include more intensive guidance on an efficient drug development program, access to a regulatory liaison to help accelerate review time and eligibility for rolling review as well as priority review.

This Breakthrough Therapy Designation was based on the results of the RCC cohort in Study 111, a multicenter, open-label phase 1b/2 clinical study being carried out in the U.S. and the European Union (EU) to evaluate the efficacy and safety of LENVIMA in combination with KEYTRUDA in subjects with selected solid tumors. Study 111 is a multicenter, open-label phase 1b/2 clinical study being carried out in the U.S. and EU to evaluate the efficacy and safety of LENVIMA in combination with KEYTRUDA. The primary objective of the phase 1b part was to determine the maximum tolerated dose.

Patients with unresectable solid tumors (renal cell carcinoma, endometrial cancer, non-small cell lung cancer, urothelial cancer, squamous cell head and neck cancer and melanoma) who had progressed after treatment with approved therapies or for which there are no standard effective therapies available were administered 24 mg of LENVIMA orally daily, as well as 200 mg of KEYTRUDA intravenously every three weeks. Dose reductions of LENVIMA were permitted based on observed toxicity. The phase 2 part was conducted with patients who had select solid tumors with 0-2 prior lines of systemic therapy (unless discussed with the sponsor), with a recommended dosage of 20 mg of LENVIMA daily and 200 mg of KEYTRUDA every three weeks as determined based on the results of the phase 1b part.

The primary endpoint of the phase 2 part was objective response rate at 24 weeks after treatment began, with select secondary endpoints including objective response rate, disease control rate, progression-free survival and duration of response. Currently, the phase 2 part is underway, with enrollment expanded for the endometrial cancer cohort. 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.; and Renal Cell Cancer (RCC): in combination with everolimus for patients with advanced RCC following one prior anti-angiogenic therapy.

LENVIMA, discovered and developed by Eisai, is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). LENVIMA also inhibits other RTKs that have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors FGFR1-4; the platelet derived growth factor receptor alpha (PDGFRa), KIT, and RET. The combination of LENVIMA and everolimus showed increased anti-angiogenic and anti-tumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.

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, 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. 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%). 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.