Merck and Eisai Submit First Application in Japan for Keytruda plus Lenvima as First-Line Treatment for Advanced Renal Cell Carcinoma

April 08, 2021 /BioValleyBIOON/ -- Eisai and its partner Merck & Co. recently announced that they have submitted an application in Japan for the combination of the oral multi-receptor tyrosine kinase inhibitor Lenvima (lenvatinib) and the anti-PD-1 therapy Keytruda (pembrolizumab) for the treatment of patients with advanced renal cell carcinoma (RCC). This marks the first application for this combination therapy in Japan.

This application is based on data from the pivotal Phase 3 CLEAR study (KEYNOTE-581/Study 307). The study results were presented in February this year at the 2021 American ClinicalTumorPresented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO-GU 2021) and simultaneously published in The New England Journal of Medicine. The results demonstrated that, compared with sunitinib, Keytruda plus Lenvima yielded statistically significant improvements across multiple efficacy endpoints.

If approved, the “immunotherapy + targeted therapy” combination regimen of Keytruda plus Lenvima will provide an important new treatment option for patients with first-line advanced renal cell carcinoma (RCC) and has the potential to transform clinical practice in this setting.

Kidney Cancer (Image source: vecteezy.com)

CLEAR (NCT02811861) is a randomized, open-label phase 3Clinical Trial, evaluated Keytruda + Lenvima, Lenvima + everolimus, and sunitinib as first-line treatments for patients with advanced renal cell carcinoma (RCC). The trial enrolled approximately 1,050 patients, who were randomly assigned to three treatment groups receiving: (1) Lenvima (20 mg, orally, once daily) plus Keytruda (200 mg, intravenous infusion, once every 3 weeks); (2) Lenvima (18 mg, orally, once daily) plus everolimus (5 mg, orally, once daily); or (3) sunitinib (50 mg, orally, once daily, administered for 4 weeks followed by a 2-week break). The primary endpoint of the study was progression-free survival (PFS), and key secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety.

The results demonstrated that Keytruda + Lenvima met the primary endpoint (PFS) and key secondary endpoints (OS and ORR): In the intent-to-treat (ITT) study population, compared with the sunitinib group, the Keytruda + Lenvima treatment group showed statistically significant and clinically meaningful improvements in PFS (HR=0.39, p<0.001), OS (HR=0.66, p=0.005), and ORR (RR=1.97, p<0.001). Furthermore, Lenvima + everolimus also met the primary endpoint (PFS) and key secondary endpoint (ORR): In the ITT study population, compared with the sunitinib group, the Lenvima + everolimus group showed statistically significant and clinically meaningful improvements in PFS (HR=0.65, p<0.001) and ORR (RR=1.48, p<0.001). In an exploratory analysis, PFS and OS outcomes were consistent across prespecified Memorial Sloan Kettering Cancer Center (MSKCC) risk groups (favorable, intermediate, and poor). In this study, the safety profiles of Keytruda + Lenvima and Lenvima + everolimus were consistent with those reported in previous studies.

Independent review based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 yielded the following data: (1) For progression-free survival (PFS), the Keytruda + Lenvima group demonstrated a 61% reduction in the risk of disease progression or death compared to the sunitinib group (HR=0.39, p<0.001), with significantly prolonged PFS (median PFS: 23.9 months vs. 9.2 months). (2) For overall survival (OS), the Keytruda + Lenvima group showed a 34% reduction in the risk of death compared to the sunitinib group (HR=0.66, p=0.005); with a median follow-up of 27 months, the median OS was not reached in either group. (3) For objective response rate (ORR), the Keytruda + Lenvima group showed a significant improvement compared to the sunitinib group (71.0% vs. 36.1%; RR=1.97, p<0.001). The complete response (CR) and partial response (PR) rates were 16.1% and 54.9%, respectively, in the Keytruda + Lenvima group, versus 4.2% and 31.9%, respectively, in the sunitinib group. (4) For duration of response (DOR), the median DOR was 25.8 months in the Keytruda + Lenvima group and 14.6 months in the sunitinib group.

In the second experimental treatment arm of this trial, the specific data were as follows: (1) For PFS, the Lenvima plus everolimus group demonstrated a 35% reduction in the risk of disease progression or death compared with the sunitinib group (HR=0.65, p<0.001), with significantly prolonged PFS (median PFS: 14.7 months vs. 9.2 months). (2) For OS, there was no improvement in the Lenvima plus everolimus group compared with the sunitinib group (HR=1.15, p=0.3); with a median follow-up of 27 months, median OS was not reached in either treatment group. (3) For ORR, the Lenvima plus everolimus group showed a significantly higher rate compared with the sunitinib group (53.5% vs. 36.1%, RR=1.48, p<0.001); the CR and PR rates were 9.8% and 43.7%, respectively, in the Lenvima plus everolimus group, versus 4.2% and 31.9%, respectively, in the sunitinib group. (4) For DOR, the median DOR was 16.6 months in the Lenvima plus everolimus group and 14.6 months in the sunitinib group.

It is estimated that in 2020, there were over 430,000 newly diagnosed cases of kidney cancer worldwide, with nearly 180,000 deaths attributed to the disease. In Japan, there were more than 25,000 new diagnoses of kidney cancer in 2020, and over 8,000 deaths. Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for approximately 90% of all cases. Most RCCs are incidentally detected during imaging examinations for other abdominal conditions. Approximately 30% of RCC patients present with metastatic disease at diagnosis, and up to 40% of patients develop metastasis after surgical treatment for localized RCC. The survival rate for this disease is highly dependent onDiagnosisstage, the 5-year survival rate for metastatic disease is 12%, and the prognosis for these patients is very poor.

The Lenvima + Keytruda combination therapy is part of the strategic oncology collaboration between MSD and Eisai. In March 2018, the two companies signed a collaboration agreement worth up to $5.8 billion to develop Lenvima as a monotherapy and in combination with Keytruda for multiple typesTumortreatment.

Lenvima is an oral multi-receptor tyrosine kinase (RTK) inhibitor with a novel binding mode, inhibiting not only those involved in tumor angiogenesis and tumor progression, andTumorIn addition to other pro-angiogenic and oncogenic signaling pathway-related receptor tyrosine kinases (RTKs) involved in immune modulation, including platelet-derived growth factor (PDGF) receptors PDGFRα, KIT, and RET, it can also selectively inhibit the kinase activity of vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, VEGFR3) and fibroblast growth factor (FGF) receptors (FGFR1, FGFR2, FGFR3, FGFR4).

Keytruda is an anti-PD-1 cancer immunotherapy that helps detect and fight tumor cells by enhancing the capability of the human immune system. Keytruda is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activatingTumorT lymphocytes of cells and healthy cells.

Currently, MSD and Eisai are conducting the LEAP (Lenvatinib and Pembrolizumab) clinical development program in 13 different types of tumors (endometrial cancer, hepatocellular carcinoma,Melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, urothelial carcinoma, cholangiocarcinoma, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer, and triple-negativeBreast Cancer) 20 itemsClinical Trialcontinue to study the combination of Keytruda + Lenvima. Data from this project shows that the combination of Keytruda + Lenvima has been used in various typesTumorDemonstrated robust efficacy! (Bioon.com)

Original Source:appLICATION SUBMITTED FOR ADDITIONAL INDICATION OF ANTI CANCER AGENT LENVIMA? IN COMBINATION WITH KEYTRUDA AS A TREATMENT FOR ADVANCED RENAL CELL CARCINOMA IN JAPAN