Phase 3 Trial to Determine the Potential Superiority of Pembrolizumab/Lenvatinib vs Chemotherapy in Advanced Endometrial Cancer

Pending results from the ENGOT-en9/LEAP-001 will determine whether the combination of pembrolizumab and lenvatinib prolongs survival more than chemotherapy in patients with endometrial cancer.

The phase 3 trial ENGOT-en9/LEAP-001 [NCT03884101] is set to present results this year, after 24 months of enrollment, on the study of pembrolizumab (Keytruda) plus lenvatinib (Lenvima) versus chemotherapy in the first-line treatment of patients with advanced or recurrent endometrial cancer, according to an abstract published in Gynecological Cancer.1

ENGOT-en9/LEAP-001 is a phase 3, 1:1 randomized, open-label, active-controlled trial that has a sample size of approximately 875 patients. The primary objective of the study is to compare efficacy and safety of first-line pembrolizumab in combination with lenvatinib versus paclitaxel plus carboplatin in patients with newly diagnosed stage III/IV disease or recurrent endometrial cancer who have a measurable or radiographically apparent disease.

“Pembrolizumab plus lenvatinib is superior to chemotherapy with respect to progression free survival (PFS) and overall survival (OS) in patients with mismatch repair proficient tumors and all patients,” researchers wrote as their study hypothesis. “In patients with mismatch repair- proficient endometrial cancer, superiority will be tested after non-inferiority to chemotherapy with respect to overall survival has been evaluated,” they further explained.

According to the researchers, the novel combination of pembrolizumab plus lenvatinib has demonstrated promising efficacy results in phase 1b/2 trials that looked at this combination after 2 or more prior lines of therapy.2 Further phase 3 trials, the KEYNOTE-775 and study 309, in patients with 1 to 2 previous lines of therapy showed improved objective response rates (ORR), PFS, and OS compared to standard chemotherapy.3

“The standard of care for patients with advanced or recurrent disease is multiagent systemic chemotherapy, including paclitaxel plus carboplatin in the first-line setting,” the researchers wrote. “There is an urgent need to provide treatment options that yield better outcomes because the prognosis for these patients remains poor, with a 5- year survival rate of 17% in the recurrent metastatic setting.”

Patients on the trial are receiving either 200 mg of pembrolizumab intravenously every 3 weeks combined with 200 mg of lenvatinib given orally daily, or 175 mg/m2 of paclitaxel combined with carboplatin area under the curve 6 mg/mL/min intravenously every 3 weeks. Treatment is set to be discontinued if patients experienced disease progression or an unacceptable toxicity, but pembrolizumab is set to be discontinued after 35 cycles. However, lenvatinib could be continued after pembrolizumab was discontinued but Lenvatinib dosing was reduced, interrupted, or discontinued if patients had intolerable grade 2 to 3 adverse events (AEs) or any grade 4 AE.

Patients eligible for the trial had to have an ECOG performance score of 1 or less and patients had to have received prior chemotherapy as neoadjuvant or adjuvant therapy and/or concurrently with the radiation if the recurrence of disease occurred 6 months or more after the last dose of chemotherapy. Patients excluded from the trial had carcinosarcoma, endometrial leiomyosarcoma, or other high-grade sarcomas, or endometrial stromal sarcomas, were excluded. Breakdown of the 875 patients included 612 patients with mismatch repair-proficient participants and approximately 263 mismatch repair-deficient patients.

“This trial has the potential to define the new standard of first-line treatment in recurrent endometrial cancer,” the researchers concluded. “Data from the ENGOT-en9/LEAP-001 study will be presented at upcoming scientific meetings, submitted to a peer-reviewed journal for publication, and posted on trial registries.”


1. Marth C, Tarnawski R, Tyulyandina A, et al. Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Int J Gynecol Cancer. 2022 Jan;32(1):93-100. doi: 10.1136/ijgc-2021-003017

2. Taylor MH, Lee CH, Makker V, et al. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. J Clin Oncol. 2020 Apr 10;38(11):1154-1163. doi: 10.1200/JCO.19.01598

3. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. J Clin Oncol. 2020 Sep 10;38(26):2981-2992. doi: 10.1200/JCO.19.02627