Merck, known as MSD outside the United States and Canada, and Eisai Inc. announced that the US Food and Drug Administration (FDA) has accepted and granted priority review for applications seeking two new approvals for the combination of Keytruda, Merck’s anti-PD-1 therapy, plus Lenvima, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai.
The first set of applications (a supplemental Biologics License Application [sBLA] for Keytruda and a supplemental New Drug Application [sNDA] for Lenvima) are for the first-line treatment of patients with advanced renal cell carcinoma (RCC), based on progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) data from the pivotal phase 3 CLEAR study (KEYNOTE-581/Study 307).
The second set of applications are for the treatment of patients with advanced endometrial carcinoma who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation, based on PFS, OS and ORR data from the pivotal phase 3 KEYNOTE-775/Study 309 trial. These are the first applications to be submitted in the US for this combination therapy based on phase 3 clinical data. The FDA has set Prescription Drug User Fee Act (PDUFA) dates, or target action dates, of August 25 and 26, 2021, for the advanced RCC sNDA and sBLA applications, respectively, and September 3, 2021, for the advanced endometrial carcinoma applications.
“Advanced renal cell carcinoma and advanced endometrial carcinoma are aggressive cancers, and patients urgently need new treatment options that may help improve outcomes,” said Dr. Gregory Lubiniecki, vice president, oncology clinical research, Merck Research Laboratories. “We appreciate that the FDA has recognized this significant unmet need and the potential for the combination of Keytruda plus Lenvima in these patients by granting priority review for these applications.”
“We are pleased that the FDA has granted priority review for Keytruda plus Lenvima—both in advanced renal cell carcinoma and advanced endometrial carcinoma—underscoring the potential significance of the outcomes observed in the CLEAR study (KEYNOTE-581/Study 307) and KEYNOTE-775/Study 309 trials,” said Dr. Takashi Owa, chief medicine creation officer and chief discovery officer, oncology business group at Eisai. “Many patients are still in need of new and effective therapies, which fuels our commitment to advancing the development of this combination even more. These milestones reinforce our unwavering dedication to helping the patients we aim to serve.”
The applications in advanced RCC are based on results from the CLEAR study (KEYNOTE-581/Study 307), in which Keytruda plus Lenvima demonstrated statistically significant improvements in PFS, OS and ORR versus sunitinib. These data were presented in February at the virtual 2021 Genitourinary Cancers Symposium (ASCO GU) and simultaneously published in the New England Journal of Medicine.
The applications in advanced endometrial carcinoma are based on results from KEYNOTE-775/Study 309, in which Keytruda plus Lenvima demonstrated statistically significant improvements in PFS, OS and ORR versus chemotherapy (investigator’s choice of doxorubicin or paclitaxel), regardless of mismatch repair (MMR) status. These data were presented in March at the virtual Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer. KEYNOTE-775/Study 309 is the confirmatory trial for KEYNOTE-146/Study 111, which supported the 2019 accelerated approval of the combination for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation. This indication was an accelerated approval based on tumor response and durability of response and reviewed under the FDA’s Real-Time Oncology Review pilot program and the FDA’s Project Orbis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.
Merck and Eisai are studying the Keytruda plus Lenvima combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program in 14 different tumor types (endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, renal cell carcinoma, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer, pancreatic cancer and triple-negative breast cancer) across more than 20 clinical trials.
The CLEAR study (KEYNOTE-581/Study 307) is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT02811861) evaluating Lenvima in combination with Keytruda or in combination with everolimus versus sunitinib for the first-line treatment of patients with advanced RCC. The primary endpoint is PFS, as assessed by independent review per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Key secondary endpoints include OS, ORR and safety. A total of 1,069 patients were randomized (1:1:1) to receive:
Lenvima (20 mg orally once daily) in combination with Keytruda (200 mg intravenously [IV] every three weeks for up to 24 months; or Lenvima (18 mg orally once daily) in combination with everolimus (5 mg orally once daily); or Sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks off treatment).
KEYNOTE-775/Study 309 is a multicenter, randomized, open-label, Phase 3 trial (ClinicalTrials.gov, NCT03517449) evaluating Keytruda in combination with Lenvima in patients with advanced endometrial carcinoma who had been previously treated with at least one prior platinum-based chemotherapy regimen in any setting, including in the neoadjuvant and adjuvant settings. The dual primary endpoints are PFS, as assessed by blinded independent central review (BICR) per RECIST v1.1, and OS. Select secondary endpoints include ORR and duration of response (DOR), as assessed by BICR. A total of 827 patients were randomized (1:1) to receive: Keytruda (200 mg IV every three weeks) in combination with Lenvima (20 mg orally once daily); or Investigator’s choice of either doxorubicin (60 mg/m2 IV every three weeks) or paclitaxel (80 mg/m2 IV given weekly, three weeks of receiving weekly paclitaxel and one week of not receiving paclitaxel).
Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In the U.S. alone, it is estimated there will be nearly 76,000 new cases of kidney cancer diagnosed and almost 14,000 deaths from the disease in 2021. Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancers are RCCs. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 30% of patients with RCC will have metastatic disease at diagnosis, and as many as 40% will develop metastases after primary surgical treatment for localized RCC. Survival is highly dependent on the stage at diagnosis, and the five-year survival rate is 13% for patients with metastatic disease.
Endometrial carcinoma begins in the inner lining of the uterus, which is known as the endometrium, and is the most common type of cancer in the uterus. In 2020, it was estimated there were more than 417,000 new cases and more than 97,000 deaths from uterine body cancers worldwide (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In the U.S., it is estimated there will be more than 66,000 new cases of uterine body cancer and nearly 13,000 deaths from the disease in 2021. The five-year survival rate for metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.
Keytruda is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. 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.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying Keytruda across a wide variety of cancers and treatment settings. The Keytruda clinical program seeks to understand the role of Keytruda across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with Keytruda, including exploring several different biomarkers.