FDA Grants Priority Review to Pembrolizumab Plus Lenvatinib in Advanced RCC and Endometrial Cancer

The FDA has granted priority review to 2 supplemental new drug applications for the combination use of pembrolizumab and lenvatinib.

The FDA has granted priority review to 2 supplemental new drug applications (sNDAs) for the combination use of pembrolizumab (Keytruda) and lenvatinib (Lenvima), announced Merck, in a press release.1

FDA approval is being sought for the combination as frontline treatment of patients with advanced renal cell carcinoma (RCC) and as treatment of patients with advanced endometrial carcinoma who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.

“We are pleased that the FDA has granted priority review for Keytruda plus Lenvima—both in advanced renal cell carcinoma and advanced endometrial carcinoma—underscoring the potential significance of the outcomes observed in the CLEAR study (KEYNOTE-581/Study 307) and KEYNOTE-775/Study 309 trials,” said Takashi Owa, PhD, chief medicine creation officer and chief discovery officer, Oncology Business Group at Eisai, in a statement. “Many patients are still in need of new and effective therapies, which fuels our commitment to advancing the development of this combination even more. These milestones reinforce our unwavering dedication to helping the patients we aim to serve.”

Advanced Renal Cell Carcinoma

The sNDA for pembrolizumab/lenvatinib to treat patients with advanced RCC was submitted based on positive progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) results from the pivotal multicenter, open-label, randomized, phase 3 CLEAR study (NCT0281186). Patients in the study were treated with either lenvatinib plus everolimus (Afinitor) or pembrolizumab plus lenvatinib versus sunitinib (Sutent). PFS was the primary end point of the study and OS and ORR were secondary end points along with the number of patients with adverse events (AE), treatment discontinuation rate due to toxicity, time to treatment failure due to toxicity, and health-related quality of life (HRQoL).2

Results from the CLEAR study showed that PFS was prolonged with pembrolizumab/lenvatinib at a median of 23.9 versus 9.2 months with sunitinib (HR, 0.39; 95% CI, 0.32-0.49; P <. 001). The median OS was not reached in any treatment arms, but data showed that OS was significantly longer with pembrolizumab and lenvatinib arm compared to the sunitinib arm (HR, 0.66; 95% CI, 0.49-0.88; P = .005).

In terms of responses, patients who received pembrolizumab plus lenvatinib achieved an ORR of 71% (95% CI, 66.3%-75.7%) which was higher compared with the sunitinib arm ORR of 36.1% (95% CI, 31.2%-41.1%). Responses to the combination of pembrolizumab plus lenvatinib were also more durable than sunitinib at 25.8 months (95% CI, 22.1-27.9 months) versus 14.6 months (95% CI, 9.4-16.7 months).

Treatment-related adverse events (TRAEs) of any grade were observed in 96.9% of the pembrolizumab/lenvatinib arm compared with 92.1% of the sunitinib arm. The combination had more TRAEs leading to dose-reduction (67.3%) compared with the control (49.7%). Moreover, the combination of pembrolizumab and lenvatinib had a 9.7% discontinuation rate.

Advanced Endometrial Carcinoma

The sNDA for pembrolizumab plus lenvatinib as treatment of advanced endometrial carcinoma was supported by data from the phase 3 Study-309/KEYNOTE-775 trial (NCT03517449). Results presented during the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer revealed a response and survival benefit with the combination compared with chemotherapy. The benefit was irrespective of mismatch repair (MMR) status.3

In the study, 827 patients were randomized 1:1 to receive oral lenvatinib at 20 mg daily plus pembrolizumab at 200 mg intravenously (IV) every 3 weeks or doxorubicin at 60 mg/m2 IV every 3 weeks or paclitaxel at 80 mg/m2 IV weekly on a 3-weeks-on and 1-week-off schedule. Treatment was continued until disease progression or unacceptable toxicity. The coprimary end points were PFS and OS, and the secondary end points were ORR, HRQoL, pharmacokinetics, and safety. As an exploratory end point, investigators also evaluated duration of response (DOR).

The median OS observed in patients with MMR-proficient (pMMR) disease was 17.4 months with pembrolizumab plus lenvatinib versus 12.0 months with chemotherapy at a median follow-up of 11.4 months (HR, 0.68; 95% CI, 0.56-0.84; P < .0001). The median OS for all-comers was 18.3 months with pembrolizumab plus lenvatinib compared with 11.4 months with chemotherapy (HR, 0.62; 95% CI, 0.51-0.75; P < .0001).

Treatment with pembrolizumab/lenvatinib achieved a median of 6.6 months in patients with pMMR status compared with 3.8 months win the chemotherapy arm, (HR, 0.60; 95% CI, 0.50-0.72; P <.0001). In all-comers, the median PFS was 7.2 months with pembrolizumab/lenvatinib versus 3.8 months with the control (HR, 0.56; 95% CI, 0.47-0.66; P < .0001).

Patients also had good responses to the experimental combination. In the pMMR group, the ORR observed with pembrolizumab/lenvatinib 30.3% versus 15.1% with chemotherapy (P < .0001). Responses to pembrolizumab/lenvatinib included complete responses (CRs) in 5.2% of patients, partial responses (PRs) in 25.1%, and stable disease (SD) in 48.6%. In comparison, the chemotherapy arm had a 2.6% CR rate, a 12.5% PR rate, and a 15.6% SD rate. Progressive disease was seen in 0.6% of the experimental arm compared with 4.9% of the control arm.

Also, in the pMMR cohort, the median DOR was 9.2 months versus 5.7 months with pembrolizumab/lenvatinib and chemotherapy, respectively. The median time to response was 2.1 months (range, 1.5-9.4 months) with pembrolizumab/lenvatinib and 3.5 months (range, 1.0-7.4 months) with chemotherapy.

In all-comers, pembrolizumab plus lenvatinib achieved an ORR of 31.9% compared with 14.7% in the chemotherapy arm (P < .0001). The CR, PR, and SD rates in the experimental arm were 6.6%, 25.3%, and 47.0%, respectively compared with 2.6%, 12.0%, and 40.1% in the chemotherapy arm. PD was observed in 14.8% of the experimental am versus 29.6% of the chemotherapy arm. The median DOR was 14.4 months with pembrolizumab/lenvatinib compared with 5.7 months with chemotherapy. The median time to response in both treatment arms was 2.1 months.

Any-grade treatment-emergent AEs (TEAEs) leading to dose interruptions were seen in 69.2% of the pembrolizumab/lenvatinib group versus 27.1% of those in the chemotherapy group. Overall, 58.6% of patients discontinued lenvatinib alone, 50.0% discontinued pembrolizumab, and 30.8% of patients discontinued both drugs due to the emergence of any-grade TEAEs.

The most common TEAEs (≥25%) in the overall study population with pembrolizumab/lenvatinib were hypertension (64.0%), hypothyroidism (57.4%), diarrhea (54.2%), nausea (49.5%), and decreased appetite (44.8%). With chemotherapy, the most common TEAEs were anemia (48.7%), nausea (46.1%), and neutropenia (33.8%).

In addition, the grade 3 or higher TEAEs that were most commonly reported with pembrolizumab/lenvatinib were hypertension (37.9%), weight decrease (10.3%), decreased appetite (7.9%), and diarrhea (7.6%).

The FDA has set the Prescription Drug User Fee Act dates of August 25 and 26, 2021 to decide on the approval of pembrolizumab plus lenvatinib for these 2 indications.

“Advanced renal cell carcinoma and advanced endometrial carcinoma are aggressive cancers, and patients urgently need new treatment options that may help improve outcomes,” said Gregory Lubiniecki, MD, vice president, Oncology Clinical Research, Merck Research Laboratories, in the press release. “We appreciate that the FDA has recognized this significant unmet need and the potential for the combination of Keytruda plus Lenvima in these patients by granting priority review for these applications.”


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.

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. 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.