Lenvatinib Combo Yields Favorable Responses in Ovarian, Endometrial Cancers

Floor J. Backes, MD

Lenvatinib (Lenvima) in combination with weekly paclitaxel induced activity among those with recurrent endometrial and platinum-resistant epithelial ovarian cancer, resulting in a 65% overall response rate (ORR), according to results from a phase I study presented at the 50th SGO Annual Meeting, held March 16-19 in Honolulu, Hawaii.

Moreover, the activity seen was favorable compared with responses seen in other studies with weekly paclitaxel.

Lenvatinib is a multitargeted tyrosine kinase inhibitor that is currently FDA approved for the treatment of recurrent or metastatic thyroid cancer, advanced renal cell carcinoma, and hepatocellular carcinoma. Previously, lenvatinib has been studied in recurrent endometrial cancer (ORR, 14%-22%), while weekly paclitaxel has been evaluated in combination with a VEGF inhibitor for the treatment of recurrent ovarian cancer (ORR, 27%-53%) and recurrent endometrial cancer (ORR, 20%-28%).

“It is interesting to see, if we look at other studies of platinum-resistant ovarian cancer, when weekly paclitaxel is combined with other antiangiogenic agents, the median response rates were around 30% and median progression-free survival between 6% to 10%. Also, in endometrial cancer, with single-agent antiangiogenics, the response rates have been high, but with relatively low progression-free survival,” said Floor J. Backes, MD, associate professor, Department of Obstetrics & Gynecology, College of Medicine, The Ohio State University Comprehensive Cancer Center.

In the single-institution study, the researchers hypothesized that weekly paclitaxel and lenvatinib would be safe and effective in patients with recurrent endometrial cancer and platinum-resistant ovarian cancer. Their primary objective in the study was to determine the recommended phase II dose of the combination. Secondary objectives included safety and tolerability, objective antitumor activity, PFS, and pharmacokinetics of the regimen.

Eligibility criteria included recurrent, platinum-resistant ovarian cancer or recurrent endometrial cancer (all histologies); unlimited prior treatments, with at least 1 prior platinum-based therapy; measurable disease; and adequate organ function. Prior weekly taxanes and bevacizumab (Avastin) were allowed. Patients were a median age of 63 years (range, 45-74), the majority were white (n = 23), and they had received a median of 3 prior lines of therapy (range, 1-5).

Using a 3+3 design, 26 patients, including 19 with ovarian cancer (13 high-grade serous, 2 low-grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma) and 7 with endometrial cancer (4 endometrioid and 3 serous), were enrolled to receive 80 mg/m² of weekly paclitaxel on days 1, 8, and 15; and oral lenvatinib daily on a 28-day cycle.

Lenvatinib dose levels were 8 mg (DL1; n = 4), 12 mg (DL2; n = 3), 16 mg (DL3; n = 7), and 20 mg (DL4; n = 6). After determining the maximum tolerated dose (MTD), 6 additional patients were enrolled to the expansion cohort.

Patients in the DL1 and DL2 cohorts did not experience dose-limiting toxicities, while 1 patient had mucositis in the DL3 group. The researchers noted that the frequent need for dose reductions for grade 3 toxicity (hypertension and fatigue) at DL4 led them to establish the phase II dose of 16 mg of lenvatinib with weekly paclitaxel.

Of the 23 patients evaluable for response, the ORR was 65%, including 1 patient who experienced a complete response (CR; 4%), 14 who had a partial response (PR; 61%), 7 (30%) with stable disease, and 1 (4%) with progressive disease. The overall clinical benefit rate was 96%.

The ORR was 71% in ovarian cancer and 50% in endometrial cancer. In patients with ovarian cancer the median PFS was 14.0 months and 12.8 months for patients with endometrial cancer.

Median duration of response among patients who experienced a CR or PR was 10.9 months. Seven patients are continuing on the study treatment. The overall median PFS was 14.0 months (95% CI, 5.1—not reached), and 54% of patients experienced PFS of more than 6 months.

The most common adverse events (AEs) of any grade included leukopenia (58%), anemia (50%), mucositis (46%), diarrhea (46%), lymphopenia (42%), anorexia (42%), hypertension (42%), fatigue (42%), nausea (35%), proteinuria (27%), epistaxis (27%), and hoarseness (27%). Grade ≥3 AEs were hypertension (19%), neutropenia (15%), leukopenia (12%), anemia (12%), lymphopenia (8%), fatigue (8%), diarrhea (8%), mucositis (4%), vomiting (4%), hematuria (4%), rash (4%), thrombocytopenia (4%), and bowel perforation (4%).

“This is a small phase I study, so we certainly have to confirm these findings in a larger study,” said Backes. “We’ve also started thinking about evaluating additional combinations,” such as weekly paclitaxel and lenvatinib in combination with pembrolizumab (Keytruda).

Backes FJ, Wei L, Cohn DE, et al. Phase I evaluation of lenvatinib and weekly paclitaxel in patients with recurrent endometrial, ovarian, fallopian tube, or primary peritoneal cancer. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract LBA5.

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