Clinical Activity of Single-Agent Cabozantinib (XL184), a Multi-receptor Tyrosine Kinase Inhibitor, in Patients with Refractory Soft-Tissue Sarcomas

Abstract

Purpose: Soft-tissue sarcomas (STS) are a rare, heterogeneous group of mesenchymal tumors. For decades the mainstay of treatment for advanced, unresectable STS has been palliative chemotherapy. High levels of activated MET receptor have been reported in various sarcoma cell lines, together with elevated vascular endothelial growth factor (VEGF) levels in patients with STS, suggesting that dual targeting of the VEGF and MET pathways with the multi-receptor tyrosine kinase inhibitor cabozantinib would result in clinical benefit in this population.

Patients and methods: We performed an open-label, multi-institution, single-arm phase II trial of single-agent cabozantinib in adult patients with advanced STS and progressive disease after at least 1 standard line of systemic therapy. Patients received 60 mg oral cabozantinib once daily in 28-day cycles, and dual primary endpoints of overall response rate and 6-month progression-free survival (PFS) were assessed. Changes in several circulating biomarkers were assessed as secondary endpoints.

Results: Six (11.1%; 95% CI, 4.2%-22.6%) of the 54 evaluable patients enrolled experienced objective responses (all partial responses). Six-month PFS was 49.3% (95% CI, 36.2%-67.3%), with a median time on study of 4 cycles (range, 1-99). The most common grade 3/4 adverse events were hypertension (7.4%) and neutropenia (16.7%). Patients' levels of circulating hepatocyte growth factor (HGF), soluble MET, and VEGF-A generally increased after a cycle of therapy, while soluble VEGFR2 levels decreased, regardless of clinical outcome.

Conclusions: Cabozantinib single-agent antitumor activity was observed in patients with selected STS histologic subtypes (alveolar soft-part sarcoma, undifferentiated pleomorphic sarcoma, extraskeletal myxoid chondrosarcoma, and leiomyosarcoma) highlighting the biomolecular diversity of STS.

Figure 1.

Patient outcomes and time on study. A, Completed cycles of treatment and outcomes for all evaluable patients. ‘Ongoing’ indicates the patient is still receiving treatment. B, PFS for all evaluable patients. C, Completed cycles of treatment and outcomes for patients who received 6 or more cycles of treatment; colored by STS subtype. The arrow indicates the patient still receiving treatment. D, Completed cycles of treatment and outcomes for patients with leiomyosarcoma. E, Completed cycles of treatment and outcomes for patients with ASPS. F, Completed cycles of treatment and outcomes for patients with UPS.

Figure 2.

Representative pre- and post-treatment images for three patients on study. A, CT axial images for patient 1010024, well-differentiated/dedifferentiated liposarcoma, at baseline and after 8 cycles. The patient experienced a PR, but the response was not confirmed. B, CT axial images, baseline and after 22 cycles, for patient 1010016. Circles denote the changes in the right shoulder ASPS primary, with marked reduction in the tumor mass posttreatment and improvement in associated pectoral girdle pain and function. C, CT axial images, lung windowing, for patient 1010003, EMC. Multiple bilateral lung parenchymal nodules and noncalcified pleural masses are noted at baseline, contrasting with the improvement, and durable response in the disease noted in a similar level image after 98 cycles of therapy.

Figure 3.

Changes in soluble biomarkers from baseline. Paired measurements of soluble MET ectodomain (sMET), HGF, VEGF-A, and soluble VEGFR2 (sVEGFR2) in patient blood at cycle 1 day 1 (C1D1) and cycle 2 day 1 (C2D1) compared with baseline. Differences between the posttreatment and baseline values are summarized using box and whisker plots. The boundaries of the boxes represent the lower and upper bounds of the 95% CI for the change from baseline, with the midline denoting the mean change. The upper and lower whiskers denote the most extreme (i.e., highest and lowest) observed patient-specific differences. The overlaid points represent the patient-specific differences, with the dotted line at zero representing no change from the baseline value and points above and below zero representing an increase or decrease, respectively, from the baseline value.