FDA approves frontline pembrolizumab plus lenvatinib for kidney cancer


The FDA has approved pembrolizumab (Keytruda) plus lenvatinib (Lenvima) for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).1

The approval is based on findings from the phase 3 KEYNOTE-581/CLEAR trial (Study 307), which showed that frontline therapy with the combination reduced the risk of death by 34% versus sunitinib (Sutent) in patients with advanced RCC.

The combination of the anti–PD-1 immunotherapy and the multikinase inhibitor also improved progression-free survival (PFS) and response compared with sunitinib. The results of the trial, which were presented at the 2021 Genitourinary Cancers Symposium and simultaneously published in the New England Journal of Medicine, also showed that combining lenvatinib with the mTOR inhibitor everolimus (Afinitor) improved PFS and objective response rate (ORR) but not OS versus sunitinib in this setting.2,3

“This approval is based in part on data demonstrating that Keytruda plus Lenvima significantly reduced the risk of disease progression or death versus sunitinib,” Robert J. Motzer, MD, Jack and Dorothy Byrne Chair in Clinical Oncology, Kidney Cancer Section Head, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center stated in a press release. “This is a significant milestone for newly diagnosed patients with advanced renal cell carcinoma and introduces a promising combination option in the first-line setting.”

Patients were eligible to enroll onto the KEYNOTE trial if they were treatment-naïve, had adequate organ function, measurable disease and presented with advanced clear-cell RCC. Patients were then stratified into 2 geographic regions—Western Europe and North America vs. rest of the world—and stratified by favorable, intermediate or poor disease risk.

The trial comprised 1069 patients who were then randomized in a 1:1:1 fashion to receive lenvatinib 20 mg oral QD plus pembrolizumab 200 mg IV Q3W (n = 355), lenvatinib 18 mg oral QD plus everolimus 5 mg oral QD (n = 357), or sunitinib 50 mg oral QD for 4 weeks on and 2 weeks off (n = 357).

PFS by IRC per RECIST v1.1 was the primary endpoint, and secondary endpoints included OS, ORR by IRC per RECIST v1.1, safety and health-related quality of life (HRQoL).

The median PFS with lenvatinib and pembrolizumab was 23.9 months (95% CI, 20.8-27.7) compared to 9.2 months (95% CI, 6-11) with single-agent sunitinib (HR, 0.39; 95% CI, 0.32-0.49; P < .001). The lenvatinib plus everolimus treatment arm achieved a median PFS of 14.7 months (95% CI, 11.1-16.7) compared to the 9.2 months in the sunitinib arm (HR, 0.65; 95% CI, 0.53-0.8; P < .001).

The PFS benefit extended across all patient subgroups in both the lenvatinib and pembrolizumab and lenvatinib and everolimus treatment arms.

A median OS was not reached in any of the three treatment arms; however, the data indicated the endpoint was significantly longer in the lenvatinib and pembrolizumab arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; P = .005). There was no observed OS benefit in the lenvatinib and everolimus treatment arm over sunitinib alone (HR, 1.15; 95% CI, 0.88-1.5; P = .3).

ORR was higher in both the lenvatinib plus pembrolizumab (71%; 95% CI, 66.3-75.7) and lenvatinib plus everolimus (53.5%; 95% CI, 48.3-58.7) treatment arms compared to sunitinib (36.1%; 95% CI, 31.2-41.1).

Patients in the lenvatinib plus pembrolizumab arm achieved the longest median DOR at 25.8 months (95% CI, 22.1-27.9), compared to 16.6 months (95% CI, 14.6-20.6) in the lenvatinib plus everolimus arm and 14.6 months (95% CI, 9.4-16.7) in the sunitinib arm.

Nearly all patients in each treatment arm – lenvatinib plus pembrolizumab (96.9%), lenvatinib plus everolimus (97.7%) and sunitinib (92.1%) – experienced any treatment-related adverse event (TRAE). Patients in the lenvatinib plus pembrolizumab (67.3%) and lenvatinib plus everolimus (69.3%) treatment arms were more likely than the sunitinib arm (49.7%) to experience TRAEs that led to dose reductions. Of note, the number of patients needing to have lenvatinib discontinued in either treatment arm was 18.5% and 16.1%, respectively. Moreover, the discontinuation rate of both drugs in the lenvatinib plus pembrolizumab arm was 9.7%.


1. FDA Approves KEYTRUDA® (pembrolizumab) Plus LENVIMA® (lenvatinib) Combination for First-Line Treatment of Adult Patients With Advanced Renal Cell Carcinoma (RCC). Published online August 12, 2021. Accessed August 12, 2021. https://bit.ly/3jHFJxW.

2. Motzer RJ, Porta C, Eto M, et al. Phase 3 trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) monotherapy as a first-line treatment for patients (pts) with advanced renal cell carcinoma (RCC) (CLEAR study). J Clin Oncol. 2021; 39(suppl6):269. doi: 10.1200/JCO.2021.39.6_suppl.269.

3. Motzer RJ, Alekseev B, Rha S.-Y., et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Published online February 13, 2021. N Engl J Med. doi: 10.1056/NEJMoa2035716

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