Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer

Makker, Vicky M.D.
Colombo, Nicoletta M.D.
Herráez, Antonio Casado M.D.
Santin, Alessandro D. M.D.
Colomba, Emeline M.D.
Miller, David S. M.D.
Fujiwara, Keiichi M.D.
Pignata, Sandro M.D.
Baron-Hay, Sally M.B., B.S.
Ray-Coquard, Isabelle M.D.
Shapira-Frommer, Ronnie M.D.
Ushijima, Kimio M.D.
Sakata, Jun M.D.
Yonemori, Kan M.D.
Kim, Yong Man M.D.
Guerra, Eva M. M.D.
Sanli, Ulus A. M.D.
McCormack, Mary M. F.R.C.R.
Smith, Alan D. M.D.
Keefe, Stephen M.D.
Bird, Steven M.S.
Dutta, Lea Pharm.D.
Orlowski, Robert J. M.D.
Lorusso, Domenica M.D.

From the Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York (V.M.); the European Institute of Oncology IRCCS, University of Milan-Bicocca, Milan (N.C.), Istituto Nazionale Tumori IRCCS-Fondazione G. Pascale, Naples (S.P.), and Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Catholic University of the Sacred Heart, Rome (D.L.) — all in Italy; San Carlos University Teaching Hospital (A.C.H.) and Hospital Universitario Ramón y Cajal (E.M.G.) — both in Madrid; Yale University School of Medicine, New Haven, CT (A.D. Santin); Gustave Roussy Cancerology Institute, Groupe d'Investigateurs Nationaux pour l’Étude des Cancers Ovariens (GINECO), Villejuif (E.C.), and Centre Léon-Bérard, University Claude Bernard, GINECO, Lyon (I.R.-C.) — both in France; the University of Texas Southwestern Medical Center, Dallas (D.S.M.); Saitama Medical University International Medical Center, Hidaka (K.F.), Kurume University School of Medicine, Kurume (K.U.), Aichi Cancer Center Hospital, Nagoya (J.S.), and National Cancer Center Hospital-Kokuritsu Gan Kenkyu Center Chuo Byoin, Tokyo (K.Y.) — all in Japan; Royal North Shore Hospital, St. Leonards, NSW, Australia (S.B.-H.); Sheba Medical Center, Ramat Gan, Israel (R.S.-F.); Asan Medical Center, University of Ulsan, Seoul, South Korea (Y.-M.K.); Ege University, Izmir, Turkey (U.A.S.); University College London Hospitals NHS Foundation Trust, London (M.M.M.), and Eisai, Hatfield (A.D. Smith) — both in the United Kingdom; and Merck, Kenilworth (S.K., S.B., R.J.O.), and Eisai, Woodcliff Lake (L.D.) — both in New Jersey.

Dr. Makker can be contacted at [email protected] or at the Memorial Sloan Kettering Cancer Center, 300 E. 66th St., New York, NY 10065.

^*A list of the Study 309-KEYNOTE-775 investigators is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on January 19, 2022, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Presented in part at the Annual Meeting on Women's Cancer held by the Society of Gynecologic Oncology, March 19-25, 2021; the Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2021; the Annual Meeting of the Japan Society of Gynecologic Oncology, July 16-18, 2021; the European Society for Medical Oncology Congress, September 16-21, 2021; the Annual Global Meeting of the International Gynecologic Cancer Society, August 30-September 2, 2021; and the European Society of Gynaecological Oncology Congress, October 23-25, 2021.

Supported by Eisai and Merck Sharp and Dohme, a subsidiary of Merck.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

New England Journal of Medicine 386(5):p 437-448, February 3, 2022. | DOI: 10.1056/NEJMoa2108330

Abstract

Background

Standard therapy for advanced endometrial cancer after failure of platinum-based chemotherapy remains unclear.

Methods

In this phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with advanced endometrial cancer who had previously received at least one platinum-based chemotherapy regimen to receive either lenvatinib (20 mg, administered orally once daily) plus pembrolizumab (200 mg, administered intravenously every 3 weeks) or chemotherapy of the treating physician's choice (doxorubicin at 60 mg per square meter of body-surface area, administered intravenously every 3 weeks, or paclitaxel at 80 mg per square meter, administered intravenously weekly [with a cycle of 3 weeks on and 1 week off]). The two primary end points were progression-free survival as assessed on blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival. The end points were evaluated in patients with mismatch repair-proficient (pMMR) disease and in all patients. Safety was also assessed.

Results

A total of 827 patients (697 with pMMR disease and 130 with mismatch repair-deficient disease) were randomly assigned to receive lenvatinib plus pembrolizumab (411 patients) or chemotherapy (416 patients). The median progression-free survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 6.6 vs. 3.8 months; hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.50 to 0.72; P<0.001; overall: 7.2 vs. 3.8 months; hazard ratio, 0.56; 95% CI, 0.47 to 0.66; P<0.001). The median overall survival was longer with lenvatinib plus pembrolizumab than with chemotherapy (pMMR population: 17.4 vs. 12.0 months; hazard ratio for death, 0.68; 95% CI, 0.56 to 0.84; P<0.001; overall: 18.3 vs. 11.4 months; hazard ratio, 0.62; 95% CI, 0.51 to 0.75; P<0.001). Adverse events of grade 3 or higher occurred in 88.9% of the patients who received lenvatinib plus pembrolizumab and in 72.7% of those who received chemotherapy.

Conclusions

Lenvatinib plus pembrolizumab led to significantly longer progression-free survival and overall survival than chemotherapy among patients with advanced endometrial cancer. (Funded by Eisai and Merck Sharp and Dohme [a subsidiary of Merck]; Study 309-KEYNOTE-775 ClinicalTrials.gov number, NCT03517449.)

Lenvatinib-Pembrolizumab in Advanced Endometrial Cancer

Women with advanced endometrial cancer that progressed during platinum-containing therapy were randomly assigned to lenvatinib plus pembrolizumab or physician's choice of chemotherapy (doxorubicin or paclitaxel). The median progression-free survival was 7.2 months with lenvatinib plus pembrolizumab and 3.8 months with chemotherapy; the median overall survival was 18.3 months and 11.4 months, respectively.