Pembrolizumab Plus Lenvatinib Earns Priority Review in 2 Disease Indications


In the advanced treatment setting, an FDA decision has indicated that the combination of pembrolizumab and lenvatinib may soon be available for certain patients with endometrial tumors and renal cell carcinoma.

A set of applications for pembrolizumab (Keytruda) and lenvatinib (Lenvima) have been accepted by the FDA and granted priority review for 2 separate disease indications in renal cell carcinoma (RCC) and endometrial cancer, according to the companies responsible for the agents Merck and Eisai, Inc.1

The PD-1 plus tyrosine kinase inhibitor combination is being examined as frontline therapy for patients with advanced RCC based on data from the phase 3 CLEAR trial (NCT02811861). The application for endometrial cancer is for patients with advanced disease who are not candidates for curative surgery or radiation and who have received prior systemic therapy, based on results of the phase 3 KEYNOTE-775/Study 309 trial (NCT03517449).

“Advanced renal cell carcinoma and advanced endometrial carcinoma are aggressive cancers, and patients urgently need new treatment options that may help improve outcomes,” Gregory Lubiniecki, MD, Vice President of Oncology Clinical Research at Merck Research Laboratories, said in a 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.”

CLEAR Study Data

Data from CLEAR were recently presented at the 2021 Genitourinary Cancers Symposium and published in The New England Journal of Medicine.2 Findings demonstrated that combining lenvatinib with pembrolizumab (n = 355) improved progression-free survival (PFS) and objective response rate (ORR) over standard-of-care sunitinib (Sutent; n = 357) for the treatment of patients with advanced RCC receiving therapy in the frontline setting.

The median PFS with lenvatinib and pembrolizumab was 23.9 months (95% CI, 20.8-27.7) versus 9.2 months (95% CI, 6.0-11.0) with single-agent sunitinib (HR, 0.39; 95% CI, 0.32-0.49; P <.001). ORR was higher with the combination (71%; 95% CI, 66.3-75.7) versus the control (36.1%; 95% CI, 31.2-41.1), and there was a notable proportion of patients with complete responses in the former group (16.1% vs 4.2%, respectively).

Although median overall survival was not reached in either arm, there was a trend toward benefit with the experimental therapy (HR, 0.66; 95% CI, 0.49-0.88; P = .005). As such, the application with the FDA is based on PFS, ORR, and OS data reported from the trial thus far.

Nearly all patients in both arms experienced treatment-related adverse effects (TRAEs) of therapy, at 96.9% for pembrolizumab plus lenvatinib and 92.1% for sunitinib. Dose reductions due to TRAEs occurred in 67.3% and 49.7%, respectively.

The trial comprised 1069 patients who were then randomized in a 1:1:1 fashion to receive oral lenvatinib at 20 mg daily plus intravenous pembrolizumab at 200 mg every 3 weeks or oral sunitinib at 50 mg daily for 4 weeks on and 2 weeks off (n = 357). A third treatment arm of lenvatinib plus everolimus (Afinitor; n = 357) was also examined.

Results in Endometrial Tumors

Data presented during a plenary session at the virtual Society of Gynecologic Oncology (SGO) 2021 Annual Meeting on Women’s Cancer demonstrated that women with advanced, metastatic, or recurrent endometrial tumors who previously received 1 prior platinum-based regimen in any setting had better outcomes with the combination therapy versus those receiving physician’s choice of therapy.

The dual primary end points of the trial, PFS and OS, were statistically significantly greater in the experimental arm (n = 411) compared with the control arm (n = 416). In the all-comer population, the median PFS was 7.2 months with pembrolizumab/lenvatinib versus 3.8 month (HR, 0.56; 95% CI, 0.47-0.66; P <.0001). The corresponding median OS in either group was 18.3 months versus 11.4 months (HR, 0.62; 95% CI, 0.51-0.75; P <.0001).

The key secondary end point of ORR was also improved with pembrolizumab/lenvatinib at 31.9% (95% CI, 27.4-36.6) versus 14.7% (95% CI, 11.4-18.4) with physicians’ choice therapy. Rates of complete or partial response were 6.6% and 25.3%, respectively, for the experimental combination compared with 2.6% and 12.0% with the control arm. The median duration of response was 14.4 months (range, 1.6-23.7) versus 5.7 months (range, 0.0-24.2), respectively.

Discontinuations due to treatment-emergent AEs (TEAEs) in the all-comer population occurred at a rate of 18.7% for pembrolizumab, 30.8% for lenvatinib, and 14.0% for both agents. In the physician’s choice arm, discontinuation due to TEAEs occurred in 8.0%.

The experimental therapy arm consisted of intravenous pembrolizumab at 200 mg every 3 weeks plus oral lenvatinib at 20 mg once daily or investigator’s choice of either intravenous doxorubicin at 60 mg/m2 every 3 weeks or intravenous paclitaxel at 80 mg/m2 for a 3-weeks-on/1-week-off schedule.

“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,” Takashi Owa, PhD, Chief Medicine Creation Officer and Chief Discovery Officer of Oncology Business Group at Eisai, said in a press release. “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.”

The FDA has set Prescription Drug User Fee Act (PDUFA) dates of August 25, 2021 for the supplemental new drug application for lenvatinib in RCC; August 26, 2021, for the supplemental biologics application for pembrolizumab in RCC; and September 3, 2021, for the advanced endometrial carcinoma 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. Merck and Eisai, Inc. May 6, 2021. Accessed May 6, 2021.

2. Motzer R, Alekseev B, Rha SY; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi: 10.1056/NEJMoa2035716

Related Videos
Brian Slomovitz, MD, MS, FACOG discusses the use of new antibody drug conjugates for treating patients with various gynecologic cancers.
Rohit Gosain, MD; Sumanta Kumar Pal, MD, FASCO; and Rahul Gosain, MD, presenting slides
Rohit Gosain, MD; Sumanta Kumar Pal, MD, FASCO; and Rahul Gosain, MD, presenting slides
Rohit Gosain, MD; Sumanta Kumar Pal, MD, FASCO; and Rahul Gosain, MD, presenting slides
Rohit Gosain, MD; Sumanta Kumar Pal, MD, FASCO; and Rahul Gosain, MD, presenting slides
Developing novel regimens may continue to improve survival outcomes of patients with advanced cervical cancer following the FDA approval of pembrolizumab and chemoradiation, says Jyoti S. Mayadev, MD.
Treatment with pembrolizumab plus chemoradiation appears to be well tolerated with no detriment to quality of life among those with advanced cervical cancer.
Related Content