Lenvatinib in Combination with Pembrolizumab or Everolimus Shows Promise for Advanced RCC

The phase 3 KEYNOTE-581/CLEAR trial (Study 307) demonstrated that both combinations saw meaningful improvements in the study’s primary end point of progression-free survival for patients with advanced renal cell carcinoma.

New investigational data from the pivotal phase 3 KEYNOTE-581/CLEAR trial (Study 307) demonstrated that the combination of pembrolizumab (Keytruda) and lenvatinib (Lenvima) in patients with advanced renal cell carcinoma (RCC) met the study’s primary end point of progression-free survival (PFS) and its key secondary end points of overall survival (OS) and objective response rate (ORR).

The results, announced by Merck, demonstrated a statistically significant and clinically meaningful improvement in PFS, OS, and ORR versus lenvatinib combined with sunitinib (Sutent) in the intention-to-treat (ITT) study population. Additionally, lenvatinib plus everolimus also met the trial’s primary end point of PFS and a key secondary end point of ORR, demonstrating a statistically significant and clinically meaningful improvement in PFS and ORR versus the sunitinib combination in the ITT study population.

Regarding safety, the safety profiles of both pembrolizumab plus lenvatinib and lenvatinib plus everolimus were found to be consistent with previously reported studies.

“The results from KEYNOTE-581/CLEAR (Study 307) support the potential use of [pembrolizumab] plus [lenvatinib] for the first-line treatment of advanced RCC. These data also support the potential first-line use of [lenvatinib] plus everolimus, which is already approved in advanced RCC following prior antiangiogenic therapy,” Takashi Owa, PhD, vice president, chief of Medicine Creation and chief discovery officer of the Oncology Business Group at Eisai, said in a press release. “These findings energize our efforts as we continue to advance our understanding and address the unmet needs of patients with difficult-to-treat cancers.”

The multicenter, randomized, open-label, phase 3 trial is evaluating lenvatinib in combination with pembrolizumab or in combination with everolimus versus sunitinib for the first-line treatment of patients with advanced RCC. The primary end point is PFS by independent review per RECIST v1.1 criteria and key secondary end points include OS, ORR, and safety.

The study enrolled approximately 1050 patients who were randomized to 1 of 3 treatment arms to receive either:

  • 18 mg of lenvatinib orally once daily in combination with 5 mg orally once daily of everolimus; or
  • 20 mg of lenvatinib orally once daily in combination with 200 mg of pembrolizumab intravenously every 3 weeks; or
  • 50 mg of sunitinib orally once daily for 4 weeks on treatment, followed by 2 weeks off treatment

The ITT population included patients across all Memorial Sloan Kettering Cancer Center risk groups, including favorable, intermediate and poor.

Merck and Eisai indicated they will discuss these data with regulatory authorities worldwide, with the intent to submit marketing authorization applications based on these results. In addition, they will be submitting these results to be presented at an upcoming medical meeting.

Of note, the companies are continuing to study the pembrolizumab plus lenvatinib combination through the LEAP (LEnvatinib And Pembrolizumab) clinical program across 19 trials in 13 different tumor types, including in endometrial carcinoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer, RCC, squamous cell carcinoma of the head and neck, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, glioblastoma, ovarian cancer and triple-negative breast cancer.


KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Demonstrated Statistically Significant Improvement in Progression-Free Survival (PFS), Overall Survival (OS) and Objective Response Rate (ORR) Versus Sunitinib as First-Line Treatment for Patients… [news release]. Kenilworth, NJ & Woodcliff Lake, NJ. Published November 10, 2020. Accessed November 10, 2020. https://www.merck.com/news/keytruda-pembrolizumab-plus-lenvima-lenvatinib-demonstrated-statistically-significant-improvement-in-progression-free-survival-pfs-overall-survival-os-and-objective-response-rate/