Eisai Co., Ltd. and Merck announced that the U.S. Food and Drug Administration has granted Breakthrough Therapy Designation 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).
This designation represents the second Breakthrough Therapy Designation for Lenvima and the twelfth for Keytruda. The FDA's Breakthrough Therapy Designation program is intended to expedite development and review of drugs for serious or life-threatening conditions, requiring preliminary clinical evidence demonstrating substantial improvement over currently available therapy on at least one clinically significant endpoint.
Clinical Evidence Supporting the Designation
The Breakthrough Therapy Designation was based on results from the RCC cohort in Study 111, a multicenter, open-label Phase 1b/2 clinical study being conducted in the United States and European Union to evaluate the efficacy and safety of Lenvima in combination with Keytruda in subjects with selected solid tumors.
Study 111's Phase 1b portion determined the maximum tolerated dose in patients with unresectable solid tumors, including renal cell carcinoma, endometrial cancer, non-small cell lung cancer, urothelial cancer, squamous cell head and neck cancer, and melanoma. Patients who had progressed after treatment with approved therapies or for whom no standard effective therapies were available received 24 mg of Lenvima orally daily and 200 mg of Keytruda intravenously every three weeks.
The Phase 2 portion is being conducted with patients who have select solid tumors with 0-2 prior lines of systemic therapy, using a recommended dosage of 20 mg of Lenvima daily and 200 mg of Keytruda every three weeks. The primary endpoint is objective response rate at 24 weeks after treatment began, with secondary endpoints including objective response rate, disease control rate, progression-free survival, and duration of response.
Strategic Collaboration Framework
The combination therapy development is part of a broader strategic collaboration between Merck and Eisai worth up to $5.76 billion. Under this agreement, Merck is paying Eisai $300 million upfront and up to $650 million for specific option rights through 2020, plus reimbursing $450 million in research and development expenses. Eisai is eligible for up to $385 million in clinical and regulatory milestones and up to $3.97 billion in various sales milestones.
Eisai will handle Lenvima product sales worldwide as both a monotherapy and in combination, with the two companies sharing gross profits equally. The collaboration aims to develop treatments for endometrial cancer, non-small cell lung cancer, hepatocellular carcinoma, head and neck cancer, bladder cancer, melanoma, and other cancer types.
Regulatory Benefits and Development Timeline
The Breakthrough Therapy Designation provides several advantages including more intensive guidance on efficient drug development programs, access to a regulatory liaison to help accelerate review time, and eligibility for rolling review as well as priority review.
"We are encouraged that the FDA has recognized the potential of Lenvima plus Keytruda for patients with advanced and/or metastatic renal cell carcinoma with the Breakthrough Therapy Designation," said Dr. Takashi Owa, vice president and chief medicine creation officer of Eisai's oncology business group. "We are committed to working closely with Merck and the FDA to expedite this clinical program with the hope that we may offer another important option for patients in need."
Disease Context and Unmet Medical Need
In 2012, approximately 338,000 patients worldwide had renal cancer, including approximately 58,000 in the United States, 115,000 in Europe, and 17,000 in Japan. In the United States, approximately 63,990 new cases were estimated to occur in 2017. Approximately 25-30 percent of patients present with metastatic disease at time of diagnosis.
Renal cell carcinoma comprises approximately 90 percent of all kidney malignancies and originates from malignant cells in the lining of the kidney tubules. The average age at diagnosis is 64, and the disease is more likely to affect men than women. For advanced or metastatic renal cell carcinoma that is difficult to treat surgically, the standard treatment is molecular targeted drug therapy, though significant unmet medical need remains.
Mechanism of Action and Scientific Rationale
Lenvima is a receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor receptors VEGFR1, VEGFR2, and VEGFR3. It also inhibits other receptor tyrosine kinases implicated in pathogenic angiogenesis, tumor growth, and cancer progression, including fibroblast growth factor receptors FGFR1-4, platelet-derived growth factor receptor alpha, KIT, and RET.
Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells. The combination of Lenvima and everolimus has shown increased anti-angiogenic and anti-tumor activity compared to each drug alone in preclinical studies.
"There is strong scientific evidence supporting synergistic effects of Keytruda when used in combination with Lenvima," said Dr. Roger Perlmutter, president of Merck Research Laboratories. "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."
The combination of Lenvima and Keytruda remains investigational, and its efficacy and safety have not been established. Eisai currently has Lenvima in a Phase III clinical trial evaluating separate combinations of Lenvima with Keytruda or Lenvima with everolimus versus chemotherapy alone for RCC treatment.
