FDA Grants Priority Review to Pembrolizumab/Lenvatinib for Advanced RCC and Endometrial Carcinoma

The FDA has granted priority review to applications that are seeking 2 approvals of pembrolizumab in combination with lenvatinib in advanced renal cell carcinoma and advanced endometrial carcinoma.

The FDA has granted priority review to applications that are seeking 2 approvals of pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) in advanced renal cell carcinoma (RCC) and advanced endometrial carcinoma, according to an announcement from Merck.1

A supplemental biologics license application (sBLA) for pembrolizumab and a supplemental new drug application (sNDA) for lenvatinib are for the frontline treatment of patients with advanced RCC; these applications are supported by findings from the phase 3 CLEAR trial (KEYNOTE-581/Study 307; NCT02811861).

Data demonstrated that the doublet resulted in a longer progression-free survival compared with sunitinib (Sutent), at a median of 23.9 months and 9.2 months, respectively (HR, 0.39; 95% CI, 0.32-0.49; P <.001).2 The combination also resulted in a longer overall survival (OS) vs sunitinib (HR, 0.66; 95% CI, 0.49-0.88; P = .005), and a higher confirmed objective response rate (ORR), at 71.0% vs 36.1%, respectively.

The second set of applications are for the treatment of patients with advanced endometrial carcinoma who experience progressive disease after previous systemic therapy in any setting and who are not eligible for curative surgery or radiation based on data from the phase 3 KEYNOTE-775/Study 309 trial (NCT03517449).

Results presented during the 2021 SGO Virtual Annual Meeting on Women’s Cancer indicated that in all comers, the median OS with the combination was 18.3 months vs 11.4 months with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P <.0001).3 Moreover, the median PFS in this group was 7.2 months and 3.8 months in the investigative and control arms, respectively (HR, 0.56; 95% CI, 0.47-0.66; P <.0001). Pembrolizumab plus lenvatinib also elicited an ORR of 31.9% vs 14.7% with chemotherapy (P <.0001).

Under the Prescription Drug User Fee Act, the FDA will make a decision on the advanced RCC sNDA and sBLA on August 25, 2021 and August 26, 2021, respectively. The target action date for the endometrial carcinoma applications is September 3, 2021.

“Advanced RCC and advanced endometrial carcinoma are aggressive cancers, and patients urgently need new treatment options that may help improve outcomes,” Gregory Lubiniecki, vice president of Oncology Clinical Research at Merck Research Laboratories, stated in a press release. “We appreciate that the FDA has recognized this significant unmet need and the potential for the combination of [pembrolizumab] plus [lenvatinib] in these patients by granting priority review for these applications.”

In the phase 3 CLEAR trial, investigators set out to compare the safety and efficacy of pembrolizumab plus lenvatinib or lenvatinib plus everolimus (Afinitor) with sunitinib in the frontline treatment of patients with advanced RCC.

To be eligible for enrollment, patients had to have advanced clear-cell disease, be treatment naïve, have a Karnofsky performance status of at least 70, have measurable disease, and acceptable organ function. Patients were stratified based on geographic region (Western Europe and North America vs rest of the world) and Memorial Sloan Kettering Cancer Center risk category (favorable, intermediate, or poor).

A total of 1069 study participants were randomized 1:1:1 to receive oral lenvatinib at 20 mg once daily plus 200 mg of intravenous (IV) pembrolizumab every 3 weeks (n = 352); oral lenvatinib at 18 mg once daily plus 5 mg of oral everolimus once daily (n = 355); or 50 mg of oral sunitinib once day for 4-weeks-on and 2-weeks-off (n = 340).

The primary end point of the trial was PFS per independent review committee (IRC) and RECIST v1.1 criteria, while secondary end points comprised OS, ORR per IRC and RECIST v1.1 criteria, safety, and health-related quality of life (HRQoL). Duration of response (DOR) and biomarkers served as other exploratory end points.

The toxicity profile of pembrolizumab plus lenvatinib proved to be consistent with the known profile of each agent and the regimen was determined to be manageable with dose modifications, if required.

The objective of the KEYNOTE-775/Study 309 was to evaluate the safety and efficacy of pembrolizumab plus lenvatinib vs physician’s choice of doxorubicin or paclitaxel in patients with advanced endometrial carcinoma had previously received at least 1 platinum-based chemotherapy regimen in any setting, including the neoadjuvant and adjuvant settings.

Eligibility criteria called for patients to have advanced, metastatic, or recurrent endometrial cancer, measurable disease per blinded independent central review (BICR), previously received 1 platinum-based chemotherapy, an ECOG performance status of 0 to 1, and available tissue for mismatch repair (MMR) testing.

Stratification factors included MMR status and further stratification within proficient MMR by region (European, United States, Canada, Australia, New Zealand, and Israel vs the rest of the world), ECOG performance status (0 vs 1), and previous history of pelvic radiation (yes vs no).

In total, 827 participants were randomized 1:1 to either oral lenvatinib at a daily dose of 20 mg plus IV pembrolizumab at 200 mg every 3 weeks (n = 411) or IV doxorubicin at 60 mg/m2 every 3 weeks or IV paclitaxel given weekly at a dose of 80 mg/m2 on a 3-weeks-on/1-week-off schedule (n = 416).

The primary end points of the trial were PFS per BICR and OS, while secondary end points included ORR, HRQoL, pharmacokinetics, and safety. DOR was an important exploratory end point for the study.

The most frequent treatment-emergent adverse effects (TEAEs) reported in the all-comer population who received the doublet were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), and decreased appetite (44.8%). Grade 3 or higher TEAEs experienced with the combination included hypertension (37.9%), weight decrease (10.3%), decreased appetite (7.9%), and diarrhea (7.6%). Grade 5 toxicities occurred in 5.7% of those on the investigative arm and 21% of these were associated with gastrointestinal disorders.


  1. Merck and Eisai receive priority review from FDA for KEYTRUDA (pembrolizumab) plus LENVIMA (lenvatinib) applications for advanced renal cell carcinoma and for advanced endometrial carcinoma. News release. Merck. May 6, 2021. Accessed May 6, 2021. https://bit.ly/2PYnqtM
  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. 20201;39(suppl 6):269. doi:10.1200/JCO.2021.39.6_suppl.269
  3. Makker V, Colombo N, Herráez AC, et al. A multicenter, open-label, randomized, phase 3 sdtudy to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: Study 309/KEYNOTE-775. Presented at: 2021 SGO Virtual Annual Meeting on Women’s Cancer; March 19-26, 2021; Virtual.