K. Kumar Sankhala MD
The combination of TRC105, an endoglin antibody, and pazopanib (Votrient) demonstrated promising antitumor activity in patients with advanced angiosarcoma, according to findings presented at the Connective Tissue Oncology Society (CTOS) conference in Lisbon, Portugal.
Tumor reduction was reported in 8 patients (89%), and 2 patients with cutaneous angiosarcoma achieved a complete response (CR). Improvements in progression-free survival (PFS) were also noted with the combination treatment.
“TRC105 combined with pazopanib demonstrated encouraging activity in angiosarcoma patients, including durable complete response and improved median PFS compared with studies of single agent VEGF inhibitors in advanced angiosarcoma,” said lead author K. Kumar Sankhala MD, of the Sarcoma Oncology Center in Santa Monica, USA.
TRC105 targets endoglin, which is a membrane receptor required for the angiogenesis that supports the cell proliferation observed in solid tumors. Endoglin is highly expressed by proliferating endothelial cells, and it is upregulated following vascular endothelial growth factor (VEGF) inhibition and enables continued angiogenesis despite this inhibition. TRC105 has been safely combined with bevacizumab (Avastin), sorafenib (Nexavar), and axitinib (Inlyta), where antitumor activity was demonstrated, says Sankhala.
“Angiosarcoma is an aggressive form of soft tissue sarcoma of endothelial cell origin that is associated with poor progression-free and overall survival,” noted Sankhala. “By targeting endoglin in a non-VEGF pathway that is upregulated following VEGF inhibition and, because endoglin is highly expressed directly on malignant cells, TRC105 may complement pazopanib, particularly in angiosarcoma.”
In this study, endoglin was paired with the multikinase inhibitor pazopanib, which has activity particularly against VEGF. This agent has been approved for the treatment of soft tissue sarcoma after demonstrating a partial response (PR) rate of 4%.
The study originally was a phase Ib/II trial that enrolled 5 patients with angiosarcoma who progressed on anthracycline therapy. The patients had received up to 4 prior treatment lines, including pazopanib. An expansion cohort enrolled 4 additional patients with angiosarcoma with similar entrance criteria to receive TRC105 plus pazopanib. An additional 9 angiosarcoma patients were treated with single agent TRC105 and pazopanib was added upon disease progression. All patients had measurable disease by RECIST 1.1 and ECOG performance status < 1 at enrollment.
The patients received 10 mg/kg weekly of TRC105 plus 800 mg of pazopanib. The patients’ median age was 59 years (range, 29-90); 12 patients were male and 6 were female.
In the 9 patients receiving the combination, median PFS was 5.59 months. Three of these patients had progressed on prior pazopanib. The 5 patients originally enrolled showed PFS ≥16.6 months.
“The median PFS compares favorably with PFS reported with single agent pazopanib of 3 months,” noted Sankhala.
In the patients treated with single agent TRC105 that received pazopanib upon progression, 1 patient achieved partial response. The median PFS in this cohort was <2 months. “PFS in this cohort is similar to median PFS reported in trials of single agent VEGF inhibitors and 4 patients remain on study,” he noted.
The authors concluded that combined TRC105 and pazopanib showed a tolerable clinical safety profile that allowed prolonged dosing.
Based upon these encouraging results, a confirmatory phase III trial is planned comparing the combination with pazopanib alone. The trial plans to enroll 200 patients with angiosarcoma who will be stratified according to cutaneous versus non-cutaneous angiosarcoma, and the number of prior therapies (0 versus 1 or 2), and randomized 1:1 to each treatment.
Following results from the interim analysis, patients will be categorized into 1 of 4 ‘zones.’ The favorable zone has a planned number of 104 patients to continue the study as planned, and the promising zone will increase sample size to 200 patients with cutaneous and non-cutaneous disease. An enrichment zone is planned to enroll a minimum of 170 patients with cutaneous disease only. Patients in the unfavorable zone will continue on study as planned.
“The trial is planned as an adaptive design that allows for sample size re-estimation or enrichment of cutaneous disease based on an interim analysis with >80% power to detect a hazard ratio of 0.55 using a 2-heated alpha of 0.05,” explained Sankhala.
The study may also include evaluation of endoglin expression on circulating tumor cells as a biomarker for response to TRC105 plus pazopanib.
Shankhala KK, et al. TRC105 (Endoglin Antibody) in Combination With Pazopanib in Patients With Advanced Soft Tissue Sarcoma. Presented at: Connective Tissue Oncology Society Annual Meeting; Lisbon, Portugal; November 9-12, 2016. Poster P110.