Merck, known as MSD outside the United States and Canada, and Eisai announced that the Japanese Ministry of Health, Labour and Welfare (MHLW) has approved the combination of Keytruda, Merck’s anti-PD-1 therapy, plus Lenvima, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for radically unresectable or metastatic renal cell carcinoma (RCC).

Keytruda plus Lenvima is also approved in the US and Europe for the first-line treatment of adult patients with advanced RCC. This marks the second approval of this combination in Japan; in December 2021, Keytruda plus Lenvima was approved for unresectable, advanced or recurrent endometrial carcinoma that progressed after chemotherapy.

The approval is based on results from the pivotal phase 3 CLEAR (Study 307)/KEYNOTE-581 trial, in which Keytruda plus Lenvima demonstrated statistically significant improvements versus sunitinib in the primary efficacy outcome of progression-free survival (PFS). Results showed Keytruda plus Lenvima (n=355) reduced the risk of disease progression or death by 61% (HR=0.39 [95% CI, 0.32-0.49]; p<0.0001), with a median PFS of 23.9 months versus 9.2 months for sunitinib (n=357).

“Nearly one in three cases of renal cell carcinoma are diagnosed at an advanced stage, and patients are in need of new treatment options that may improve survival outcomes,” said Dr. Gregory Lubiniecki, vice president, oncology clinical research, Merck Research Laboratories. “In the CLEAR/KEYNOTE-581 trial, Keytruda plus Lenvima reduced the risk of disease progression or death by 61% versus sunitinib, a current standard of care. We are encouraged that patients with certain types of advanced renal cell carcinoma may have the opportunity to benefit from this combination.”

“Today’s milestone for Keytruda plus Lenvima as a treatment for radically unresectable or metastatic renal cell carcinoma is particularly exciting as it marks the second approval for the combination in Japan,” said Terushige Iike, president of Eisai Japan, senior vice president, Eisai. “We are thrilled to be able to provide Japanese patients with a new treatment option, illustrating our shared commitment with Merck to develop therapies with the aim of addressing the unmet needs of those living with difficult-to-treat cancers. We would like to thank the patients, families and healthcare providers who made this approval possible.”

The Japanese package inserts for Keytruda and Lenvima note that in the CLEAR/KEYNOTE-581 trial, adverse reactions were observed in 341 (96.9%) of 352 patients (including 42 of 42 Japanese patients) in the safety analysis set. The most common adverse reactions observed in 20% or more of patients included diarrhoea in 192 patients (54.5%), hypertension in 184 patients (52.3%), hypothyroidism in 150 patients (42.6%), decreased appetite in 123 patients (34.9%), fatigue in 113 patients (32.1%), stomatitis in 113 patients (32.1%), palmar-plantar erythrodysesthesia syndrome in 99 patients (28.1%), proteinuria in 97 patients (27.6%), nausea in 94 patients (26.7%), dysphonia in 87 patients (24.7%), rash in 77 patients (21.9%), and asthenia in 71 patients (20.2%).

Renal cell carcinoma is the most common type of kidney cancer worldwide; about nine out of 10 kidney cancer diagnoses are RCC. In Japan, there were more than 25,000 new cases of kidney cancer diagnosed and more than 8,000 deaths from the disease in 2020. In the US, approximately 30% of patients with RCC will have metastatic disease at diagnosis. Survival is highly dependent on the stage at diagnosis, and with a five-year survival rate in the US of 14% for patients diagnosed with metastatic disease, the prognosis for these patients is poor.

Merck and Eisai continue to study the Keytruda plus LENVIMA combination across several types of cancer with more than 20 clinical trials.

The approval is based on data from CLEAR (Study 307)/KEYNOTE-581 (ClinicalTrials.gov, NCT02811861), a phase 3, multicenter, open-label, randomized trial conducted in 1,069 patients with advanced RCC in the first-line setting. The primary efficacy outcome was PFS as assessed by blinded independent central review (BICR) according to RECIST v1.1. Key secondary efficacy outcome measures were overall survival and objective response rate.

Patients were randomized 1:1:1 to receive Keytruda (200 mg intravenously every three weeks for up to 24 months) plus Lenvima (20 mg orally once daily), or LENVIMA (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily for four weeks on treatment, followed by two weeks off treatment). Treatment continued until unacceptable toxicity or disease progression as determined by investigator and confirmed by BICR using RECIST v1.1. If disease progression was observed by imaging evaluation, clinically stable patients with no symptoms indicating disease progression were allowed to continue on study treatment until disease progression was observed in a subsequent imaging evaluation.

Keytruda is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumour 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 tumour cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,700 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.

Keytruda is indicated for the treatment of patients with unresectable or metastatic melanoma.