Novel Drug Combination Shows Activity in Angiosarcoma

A combination of the endoglin antibody TRC105 and the multi-kinase inhibitor pazopanib shows promising activity in patients with advanced soft-tissue sarcoma (STS), in particular those with angiosarcoma, according to a new study presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 3–7 in Chicago (abstract 11016).

Endoglin is a membrane receptor required for angiogenesis that is highly expressed by proliferating endothelial cells in solid tumors, and is upregulated following vascular endothelial growth factor (VEGF) inhibition. Endoglin expression allows continued angiogenesis despite VEGF inhibition, said lead author Steven Attia, DO, assistant professor of oncology at the Mayo Clinic in Jacksonville, Florida.

TRC105 is an endoglin monoclonal antibody that inhibits angiogenesis. It has been combined safely and demonstrated antitumor activity with bevacizumab, sorafenib, and axitinib, and received Orphan Drug Designation for STS in 2016.

Pazopanib is approved for the treatment of STS and has demonstrated a partial response rate of 4% and progression-free survival (PFS) of 4.6 months following treatment with chemotherapy.

“By targeting a non-VEGF pathway that is upregulated following VEGF inhibition and, because it is expressed directly on malignant cells, TRC105 may complement pazopanib, particularly in angiosarcoma,” said Attia.

The open-label study included 81 patients, median age 57, primarily with leiomyosarcoma and undifferentiated pleomorphic sarcoma, who received a combination of the two drugs.

The recommended phase II dose of 10 mg/kg weekly of TRC105 plus 800 mg of pazopanib led to a median PFS of 4 months in all STS patients. Three patients achieved a complete response and 1 patient had a partial response.

In 5 patients with angiosarcoma, the median PFS was 13 months. In an additional advanced angiosarcoma cohort, tumor reductions or clinical improvement were observed in 8 of 9 patients with the dual combination.

In conclusion, Attia said, “TRC105 combined with pazopanib demonstrated encouraging activity in angiosarcoma patients, including durable complete responses. The clinical safety profile of the combination was tolerable and allowed for prolonged dosing.”

PFS in non-angiosarcoma STS patients was not significantly different from PFS expected with pazopanib. Also, PFS was not increased in non-angiosarcoma STS patients with tumor endoglin expression on archival tumor specimens, possibly reflecting the effect of subsequent therapies and tumor heterogeneity on tumor endoglin expression.

Endoglin tumor expression on circulating tumor cells may be explored as a biomarker in future STS studies, said Attia. A randomized phase III study with TRC105 in combination with pazopanib compared with single-agent pazopanib in patients with angiosarcoma is planned for this year.

ASCO discussant Mrinal Gounder, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, said in an interview, “VEGF and endoglin are critical for angiosarcoma. Single-agent pazopanib leads to a PFS of 3 months and a response rate of 15%. Dual inhibition is compelling in angiosarcoma.”

“From a mechanistic standpoint, this clinical trial proved where we should be heading. It’s where the biology tells us to go,” concluded Gounder. “This combination looks great. For now, patients with angiosarcoma should be referred to the phase III trial. If that trial is positive, angiosarcoma will likely be treated with a combination of these two drugs.”