A Single-Arm Phase Ib/II Study of Lenvatinib plus Eribulin in Advanced Liposarcoma and Leiomyosarcoma

Abstract

Purpose: Satisfactory treatment options for advanced leiomyosarcoma (LMS) and liposarcoma (LPS) are limited. The LEADER study (NCT03526679) investigated the safety and efficacy of lenvatinib plus eribulin. Patients and Methods: LEADER is a multicenter phase Ib/II study for advanced LMS or LPS. The phase Ib part enrolled six patients to determine the dose-limiting toxicity (DLT) and recommended phase II dose (RP2D) with the starting dose of lenvatinib 18mg/day and eribulin 1.1mg/m2 D1, D8 every 21 days. The primary endpoint of the phase II part was objective response rate (ORR) based on RECIST 1.1, with phase Ib patients preplanned to be included in the efficacy analysis. Translational analyses were based on the transcriptomic data obtained from the Nanostring nCounter platform. Results: Thirty patients were enrolled (LMS 21, LPS 9); the median age was 59. One patient had to temporarily stop lenvatinib due to grade 2 arthritis in the first cycle, meeting DLT criteria. Four out of six patients had to decrease the dose of lenvatinib to 14mg between cycles two and three. RP2D was determined at lenvatinib 14 mg/day and eribulin 1.1 mg/m2. The confirmed ORR was 20%, and the ORR was not significantly different between phase Ib/II cohorts (p = 0.23). The median progression-free survival was 8.56 months (95% CI 4.40–not reached). Translational studies suggested increased dendritic cells in the tumor microenvironment after treatment. Conclusions: Lenvatinib plus eribulin has a manageable safety profile and exhibits promising efficacy for treating advanced LMS and LPS.

Therapeutic advances in leiomyosarcoma

“…A total of 30 patients were enrolled, including 21 patients with LMS. For the LMS population, the median PFS was 8.6 months with ORR of 19% (4/21, 3 uterine and 1 nonuterine LMS) ( 72 ). These data may suggest that the addition of lenvatinib potentiates the effects of eribulin, as historical controls of eribulin monotherapy in LMS exhibit worse outcomes, with a median PFS of 2.2 months, OS of 12.7 months, and ORR of 5%, summarized in Table 2 ( 11 ).…”

Targeted therapies for the treatment of soft tissue sarcoma

“…A phase Ib/II study of lenvatinib plus eribulin has been conducted for patients with leiomyosarcoma and LPS ( 75 ). Thirty patients enrolled in the study (21 with leiomyosarcoma, 9 with LPS).…”

Emerging innovations and advancements in the treatment of extremity and truncal soft tissue sarcomas

“…Combination therapies with TKIs are evolving, with current guidelines recommending axitinib and pembrolizumab dual therapy for STS, 119 and gemcitabine and pazopanib being popularized after showing efficacy in patients who are refractory to anthracycline‐based regimens in a recent study in JAMA oncology 120 . In addition, other combinations such as nintedanib and ifosfamide, 121 levantinib and erbulin, 122 and suntinib and nivolumab 123 are being explored in trials with early promising results. Beyond TKIs, tazemetostat, an EZH2 inhibitor, was granted accelerated approval for tumors with loss of INI1/SMARCB1 based on a phase 2 trial showing clinical efficacy in advanced epithelioid sarcoma 124,125 .…”