Frontline Pembrolizumab/Lenvatinib Significantly Improves Survival, Responses in Advanced RCC

November 10, 2020 - The combination of pembrolizumab plus lenvatinib significantly improved progression-free survival, overall survival, and the objective response rate compared with sunitinib, when used in the frontline treatment of patients with advanced renal cell carcinoma.

The combination of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) significantly improved progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR) compared with sunitinib (Sutent), when used in the frontline treatment of patients with advanced renal cell carcinoma (RCC), meeting the primary end points of the phase 3 KEYNOTE-581/CLEAR trial (NCT02811861).1

Moreover, the combination of lenvatinib plus everolimus (Afinitor) was also found to significantly improve PFS and ORR versus sunitinib in the intent-to-treat patient population, which included those who fell into all different Memorial Sloan Kettering Cancer Center (MSKCC) risk groups.

The toxicity profiles of pembrolizumab/lenvatinib and lenvatinib/everolimus proved to be consistent with what has previously been observed in prior trials.

Merck and Eisai announced plans to share these data with regulatory agencies on a global scale. The pharmaceutical companies have also shared their intention to submit marketing authorization applications based on findings from this trial. Data will be presented at an upcoming medical conference.

“The results for [pembrolizumab] plus [lenvatinib] versus sunitinib, which showed a statistically significant improvement in PFS, OS, and ORR, build on the growing scientific evidence that supports the investigation of [pembrolizumab]-based combinations for the first-line treatment of advanced RCC,” Gregory Lubiniecki, MD, associate vice president of Oncology Clinical Research at Merck Research Laboratories, stated in a press release. “Merck and Eisai are committed to working together to continue to explore the potential of the [pembrolizumab] plus [lenvatinib] combination, particularly in areas of great unmet need, such as RCC.”

In the multicenter, randomized, open-label phase 3 trial, investigators are comparing the safety and efficacy of lenvatinib in combination with everolimus (arm A), or pembrolizumab (arm B), versus sunitinib (arm C) as frontline treatment in patients with advanced RCC.

To be eligible for inclusion, patients had to have histological or cytological confirmation of RCC with a clear cell component, at least 1 measurable target lesion per RECIST v1.1 criteria, a Karnofsky Performance status of 70 or higher, adequately controlled blood pressure, and acceptable organ function.2 If they received prior systemic anticancer agent for RCC, had central nervous system metastases, an active malignancy within the past 24 months, received radiation therapy within 21 days before study start, or a live vaccine within 30 days of study treatment start, then they could not participate.

The primary end point of the trial was PFS by independent review in accordance with RECIST v1.1 criteria, while key secondary end points included OS, ORR, and safety.

Around 1050 patients were enrolled to the trial and they were randomized to 1 of 3 treatment arms. In arm A, patients received oral lenvatinib at a daily dose of 18 mg plus oral everolimus given at a daily dose of 5 mg. In arm B, participants were given oral lenvatinib at a daily dose of 20 mg with 200 mg of intravenous pembrolizumab every 3 weeks. Arm C received oral sunitinib at a daily dose of 50 mg for 4 weeks on treatment, followed by 2 weeks off treatment.

“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 and Chief Medicine Creation and Chief Discovery Officer of the Oncology Business Group at Eisai, added in the 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.”

Pembrolizumab/lenvatinib also showcased early antitumor activity and tolerability in previously treated patients with advanced solid tumors, according to interim data from the phase 2 LEAP-005 trial(NCT03797326).3

Results presented during the 2020 ESMO Virtual Congress demonstrated that the combination elicited an ORR of 29.0% (95% CI, 14.2%-48.0%) by blinded independent central review and RECIST v1.1 criteria in 31 patients with triple-negative breast cancer (TNBC) who received the regimen in the second- or third-line setting. Moreover, the ORR was even higher in 21 patients with ovarian cancer who received pembrolizumab/lenvatinib in the fourth-line setting, at 32.2% (95% CI, 16.7%-51.4%).

The combination continues to be examined in the LEAP clinical program across 19 trials spanning 13 different tumors, including endometrial carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, RCC, squamous head and neck carcinoma, urothelial cancer, biliary tract cancer, colorectal cancer, gastric cancer, ovarian cancer, glioblastoma, and TNBC.


  1. 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 with advanced renal cell carcinoma. News release. Merck. November 10, 2020. Accessed November 10, 2020.
  2. Lenvatinib/everolimus or lenvatinib/pembrolizumab versus sunitinib alone as treatment of advanced renal cell carcinoma (CLEAR). Updated July 31, 2020. Accessed November 10, 2020.
  3. Lwin Z, Gomez-Roca C, Saada-Bouzid E, et al. LEAP-005: phase II study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumors. Ann Oncol. 2020;31(suppl 4):LBA41. doi:10.1016/j.annonc.2020
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