Cabozantinib Maintenance Fails to Improve PFS in High-Grade Uterine Sarcoma

Maintenance therapy with cabozantinib (Cabometyx) after chemotherapy did not improve progression-free survival (PFS) compared with placebo in patients with high-grade uterine sarcomas (HGUtS) who achieved disease control after first-line chemotherapy, according to results presented at the European Society of Medical Oncology Sarcoma and Rare Cancers Congress.¹

In the randomized double-blind phase 2 EORTC 62113-55115 study (NCT01979393), cabozantinib failed to meet its primary end point of improving 4-month PFS, with nearly identical outcomes observed between the experimental and placebo arms. Investigators also reported higher rates of grade 3 or greater adverse events with cabozantinib, raising questions about the risk-benefit profile of maintenance tyrosine kinase inhibition in this setting. The findings highlight the ongoing challenges in optimizing postchemotherapy management in this rare and aggressive group of malignancies.

Trial Overview

The EORTC 62113-55115 study enrolled patients with HGUtS subtypes, including leiomyosarcoma, high-grade endometrial stromal sarcoma, undifferentiated uterine sarcoma, and high-grade adenosarcoma.² Eligible patients had achieved stable disease or an objective response following doxorubicin-based chemotherapy, with or without ifosfamide, administered in the adjuvant or metastatic first-line setting.

Participants were randomly assigned 1:1 to receive cabozantinib 60 mg daily or placebo for up to 2 years. The primary end point was PFS at 4 months, with secondary end points including median PFS, overall survival (OS), response rate, and safety.

A total of 59 patients were randomly assigned between 2015 and 2021, with 64% having metastatic disease at baseline. Histologic distribution included undifferentiated uterine sarcoma (46%), leiomyosarcoma (39%), and smaller proportions of other high-grade subtypes.¹

At the primary analysis, the 4-month PFS rate was 43.3% in the cabozantinib arm vs 41.4% in the placebo arm, a nonsignificant difference (P =.544). Median PFS was identical at 3.7 months in both groups. Median OS was also similar, at 27.7 months with cabozantinib and 28.4 months with placebo.¹

An exploratory observation suggested a potential signal for benefit when cabozantinib was administered after progression. Among patients who crossed over from placebo to cabozantinib at disease progression, median OS from progression was 19.0 months, compared with 6.9 months in patients who had received cabozantinib upfront and discontinued after progression. However, this comparison is limited by small sample size and potential selection bias.

Safety Findings

Treatment-related toxicity was notably higher in the cabozantinib arm. Grade 3 or higher adverse events occurred in 65.5% of patients receiving cabozantinib vs 14.8% in the placebo group.¹ The most common toxicities included gastrointestinal and vascular events, particularly hypertension. One treatment-related death due to pulmonary embolism was reported in the cabozantinib arm.

Clinical Context and Implications

HGUtS are rare, heterogeneous malignancies associated with poor prognosis and high recurrence rates. Standard first-line systemic therapy typically includes anthracycline-based regimens such as doxorubicin with or without ifosfamide, with clinical trials strongly recommended.³ Despite initial responses, most patients experience disease progression, and there is no established maintenance strategy to prolong remission.

The negative findings from EORTC 62113-55115 suggest that maintenance cabozantinib does not provide clinically meaningful benefit in patients with HGUtS following initial chemotherapy. The absence of PFS or OS improvement, coupled with increased toxicity, discourages this maintenance approach, although the exploratory signal observed with delayed cabozantinib initiation after progression is hypothesis-generating.

These results underscore the need for alternative strategies, including biomarker-driven approaches, novel targeted agents, and immunotherapy combinations, to improve outcomes in this patient population.

Further research is needed to identify subsets of patients who may benefit from targeted therapies and to clarify the optimal sequencing of available agents. Ongoing trials in soft tissue sarcomas may help inform future approaches in uterine sarcoma.

REFERENCES

1. Ray-Coquard I, Hatcher H, Herraez AC, et al. 85MO Cabozantinib as maintenance therapy in high grade uterine sarcoma after stabilization or response to doxorubicin +/- ifosfamide regimen: Results from EORTC 62113-55115-STBSG-GCG (NCT01979393), randomized double-blind phase II study. ESMO Rare Cancers. 2026;5(suppl):100291. doi:10.1016/j.esmorc.2026.100291

2. Ray-Coquard I, Hatcher H, Bompas E, et al. A randomized double-blind phase II study evaluating the role of maintenance therapy with cabozantinib in high-grade uterine sarcoma after stabilization or response to doxorubicin ± ifosfamide following surgery or in metastatic first line treatment (EORTC62113). Int J Gynecol Cancer. 2020;30(10):1633-1637. doi:10.1136/ijgc-2020-001519

3. NCCN. Clinical Practice Guidelines in Oncology. Uterine Neoplasms, version 2.2026. Accessed March 18, 2026. https://tinyurl.com/44zhw6tv