Promising Safety/Efficacy Signals Shown With Lenvatinib Plus Weekly Paclitaxel in Endometrial Cancer

Currently, no FDA-approved therapies are available to address the need of patients with advanced/recurrent endometrial cancer, underscoring a need to develop novel strategies like the combination of lenvatinib and weekly paclitaxel.

Lenvatinib (Lenvima) used in combination with weekly paclitaxel for the treatment of patients with endometrial cancer displayed promising early activity and had a manageable toxicity profile, according to results of a phase 1 study published in Gynecologic Oncology.

Although most patients with endometrial cancer are diagnosed in the early disease stages, the disease is diagnosed as advanced and/or recurrent in 15% to 20%, which is a population with a very poor prognosis. Currently, no FDA-approved therapies are available to address the need of patients with advanced/recurrent disease, underscoring a need to develop novel strategies. The single-agent activity observed with both paclitaxel and lenvatinib in recurrent endometrial cancers suggested that combining the agents would be safe and tolerable in this patient population.

The study was conducted in 26 patients at The Ohio State University Comprehensive Cancer Center under an investigational new drug application from the FDA. Patients were enrolled into 1 of 5 dose cohorts. In dose cohorts 1 through 4, the study followed an accelerated titration design until the first instance of dose-limiting toxicity (DLT) or any toxicity above grade 1. In the remaining dose cohort, the study followed a 3 + 3 design. The overall goal was to determine the recommended phase 2 dose of lenvatinib plus paclitaxel.

Patients in the study were treated on an outpatient basis. Intravenous paclitaxel was dosed over 1 hour on days 1, 8, and 15 of a 28-day cycle. Lenvatinib was dosed orally daily on a 28-day cycle. Prior to paclitaxel, patients were given corticosteroids, diphenhydramine, and H2 antagonists. The maximum dose of paclitaxel administered was 80 mg/m2, and the low dose was 60 mg/m2. The starting dose of lenvatinib was 8 mg, which was escalated by 4 mg for subsequent dose level (DL).

To determine tolerability, a Data Monitoring Board at The Ohio State University Comprehensive Cancer Center used the Revised NCI Common Terminology Criteria for Adverse Events version 4.03 to monitor adverse events. Efficacy was evaluated using imaging performed about every 12 weeks. Further, blood and plasma samples were used to evaluated pharmacokinetics.

Evaluation of the 26 patients occurred between August 2016 and November 2018. Of those enrolled, 7 had endometrial cancer, 3 with serous histology, and 4 with endometrioid histology. The remaining patients had ovarian cancer (n = 19). The patient population had a median age of 63 years (range, 45-74), and they received a median of 3 prior lines of therapy. The majority of patients include were White (88%), with the remaining patients identifying as either Black (8%) or multiracial (4%).

Twenty-three of the 26 patients were evaluable for efficacy. Data were excluded, however, for 3 patients who did not complete cycle 1. Of those evaluated 65% had a partial response to the combination of lenvatinib and weekly paclitaxel, 30% achieved stable disease, and 4%progressive disease for an objective response rate (ORR) of 65%. Looking specifically at the endometrial cancer cohort, the ORR was 50%.

The overall median duration of response for patients who achieve a PR was 10.9 months (range, 3.0-14.0). The median duration of response in the endometrial cancer population was 12.3 months (range, 95% CI, 5.4 to not reached [NR]).

In terms of survival, the median progression-free survival (PFS) was 12.4 months (95% CI, 4-15.7) in the overall population. Notably, 54% of the patients remained progression-free for more than 6 months. Among those with endometrial cancer, the median PFS was 14.0 months (95% CI, 3.8-NR).

During the safety analysis, investigators observed 1 grade 2 toxicity of hoarseness in a patient treated at DL1, which required transition to the traditional 3 + 3 design. No DLTs were observed at DL1 or DL2, but there was 1 withdrawal from the study for a personal reason. Further, of the 7 patients who were treated at DL3, 1 developed grade 3 mucositis. Six patients were treated at DL4, 2 of which experienced grade 3 hypertension and grade 3 fatigue. These patients in DL4 were therefore unable to be done with more than 75% of study treatment during the first cycle.

Dose reductions were required during the study due to cases of grade 2/3 mucositis and grade 3 diarrhea in 3 patients treated at DL4. Based on these findings, the RP2D of lenvatinib was determined to be 16 mg daily, and RP2D of weekly paclitaxel was determined to be 80 mg/m2.

The most common any-grade AEs observed during the study were anemia (73%), leukopenia (65%), lymphopenia (65%), fatigue (62%), and diarrhea (62%). The most common grade 3 or higher AEs were hypertension (27%), anemia (19%), lymphopenia (19%), neutropenia (19%), and leukopenia (15%).

“Toxicity observed in this study was mostly expected, related and similar to studies targeting the anti-angiogenesis pathway. Hypertension was the most common side effect, but fortunately, less than a fifth of patients experienced grade 3 or greater hypertension,” wrote the study authors led by Floortje J Backes, MD, associate professor in the Division of Gynecologic Oncology at The Ohio State University and the vice chair of the Cancer Institutional Review Board at the OSUCCC – James.

Backes et al concluded from this study further study of lenvatinib plus weekly paclitaxel is warranted for patients with recurrent endometrial cancer as well as those with ovarian cancer.


Backes FJ, Wei L, Chen M, et al. Phase I evaluation of lenvatinib and weekly paclitaxel in patients with recurrent endometrial, ovarian, fallopian tube, or primary peritoneal cancer. Gynecol Oncol. 2021;162(3):619-625. doi: 10.1016/j.ygyno.2021.06.032.