The combination of Keytruda and Lenvima was compared to Lenvima plus everolimus versus Pfizer’s Sutent (sunitinib) for first-line treatment of patients with advanced renal cell carcinoma (RCC).
Merck presented new data from the Phase III CLEAR trial (KEYNOTE-581/Study 307) at the virtual 2021 Genitourinary Cancers Symposium (ASCO GU) of its checkpoint inhibitor Keytruda (pembrolizumab) and Eisai’s tyrosine kinase inhibitor Lenvima (lenvatinib) in renal cell carcinoma. The data was also published in the New England Journal of Medicine.
The combination of Keytruda and Lenvima was compared to Lenvima plus everolimus versus Pfizer’s Sutent (sunitinib) for first-line treatment of patients with advanced renal cell carcinoma (RCC). The combination of Keytruda and Lenvima demonstrated statistically significant and clinically meaningful improvements in progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared to sunitinib. The Lenvima-everolimus combination also demonstrated statistically significant improvements in PFS and ORR compared to sunitinib.
In exploratory analysis, the data for PFS and OS were consistent across prespecified Memorial Sloan Kettering Cancer Center (MSKCC) risk groups, in other words, favorable, intermediate, and poor.
“Continued efforts to improve outcomes in patients with advanced renal cell carcinoma are critical, considering that the number of people diagnosed with the disease has more than doubled over the last 50 years, and almost one-third of these patients are diagnosed at an advanced stage,” said Robert Motzer, Medical Oncologist, Kidney Cancer Section Head, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center.
He went on to say, “Keytruda plus Lenvima demonstrated a median progression-free survival of nearly two years, and seven in 10 patients experienced an objective response. This combination also significantly improved overall survival compared with sunitinib, with a 34% reduction in risk of death. These results suggest that this combination has the potential to impact clinical practice for this type of devastating cancer.”
RCC is the most common form of kidney cancer, with 90% of kidney cancers being RCCs. It is twice as common in men as in women. About 30% of RCC patients will have metastatic disease at diagnosis and up to 40% will develop metastases after primary surgical treatment for localized RCC. Survival rates are very dependent on stage at diagnosis, with a five-year survival rate of 12% for metastatic disease.
The CLEAR study is a Phase III trial with two specific treatment arms, one evaluating Lenvima in combination with Keytruda and the other Lenvima with everolimus, both compared to sunitinib for first-line treatment. The primary endpoint is PFS based on independent review per RECIST v1.1. The key secondary endpoints are OS, ORR and safety. To date, a total of 1,069 patients were randomized in the trial.
The original announcement was made in November 2020, and the two companies have already filed for approval for the combination on the basis of that data. The new data was the first time it was presented before oncologists and the publication also demonstrated PFS of almost two years with the combination, compared to nine months for Sutent, a standard RCC therapy, and also decreased the risk of death by a third.
Keytruda and Pfizer’s TKI Inlyta (axitinib) has already been approved in this setting, as well as Merck KGaA, Darmstadt, Germany’s Bavencio. Bristol Myers Squibb’s combination of Opdivo (nivolumab) and Yervoy (ipilimumab), both checkpoint inhibitors, is approved in the first-line indication, and Bristol Myers Squibb’s Opdivo in combination with Exelixis’ Cabometyx (cabozantinib), another TKI, has been approved for this indication.
The Opdivo/Yervoy combination is typically only used for patients with intermediate or poor risk RCC, while the combination of PD-1 checkpoint inhibitors with TKIs are for all patients, including patients with favorable risk profiles, according to an editorial published with the New England Journal of Medicine study by Alain Ravaud of the University Hospital Centre Bourdeaux in France. Ravaud suggested that this new data and earlier PD-1/TKI combination trials support these as standard first-line treatment unless there are contra-indications. He said there is still a clear role for the Opdivo/Yervoy combination, though.
Merck has a stake in Eisai’s Lenvima as the results of a $5.8 billion deal made in 2018. The two companies are developing and marketing Lenvima together, both as a monotherapy and in combination with Keytruda. Eisai books the sales, and the two companies share profits.
