Pazopanib Combined With TRC105 Shows Responses in Soft Tissue Sarcoma

Steven Attia, DO

Steven Attia, DO

TRC105, an anti-endoglin antibody, demonstrated complementary antitumor effects with pazopanib, a vascular endothelial growth factor (VEGF) inhibitor in the treatment of patients with soft tissue sarcomas (STS), according to data from a phase Ib dose-escalation study, presented at the 2015 Connective Tissue Oncology Society (CTOS) Annual Meeting.

“[In preclinical studies], genetic knockdown and knockout of endoglin sensitized tumors to VEGF inhibition,” said Steven Attia, DO, of the Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, who presented the results. “Targeting VEGF and endoglin concurrently improves angiogenesis inhibition over targeting either pathway alone. Endoglin appears particularly relevant in sarcoma.”

Patients with soft tissue sarcoma who progressed following chemotherapy enrolled in the study. Subtypes included leiomyosarcoma (n = 9), angiosarcoma (n = 2), synovial sarcoma (n = 2), myxofibrosarcoma (n =2), epithelioid sarcoma (n = 1), epithelioid hemangioendothelioma (n = 1), and myxoid spindle cell sarcoma (n = 1). The primary endpoints were recommended phase II dose and safety. Patients were required to have an ECOG performance status of 0 or 1. The median number of prior lines of systemic therapies was two. Prior treatment with pazopanib was permitted.

TRC105 was administered after a two- to four-week lead-in period of pazopanib alone, starting at 800 mg orally once per day, after which TRC105 was randomized to weekly doses of 8 mg/kg and 10 mg/kg in cycle 2 of the study. A total of 18 of 20 patients (median age of 55) tolerated pazopanib alone in cycle 1 and received TRC105 in the second cycle of the study.

“Half of the patients had some degree of tumor reduction including four patients who had progression on prior pazopanib,” said Attia. Median progression-free survival (PFS) was 5.5 months. Four patients received treatment for over a year.

A total of 6 of 18 (33%) patients experienced ≥10% tumor reduction according to RECIST 1.1 criteria, including one ongoing completed response (CR), which lasted over 30 weeks (as of June 2015). This patient had cutaneous angiosarcoma that had previously progressed on pazopanib/docetaxel therapy. Duration of therapy ranged from 8 to over 60 weeks.

Adverse events (AEs) of grade ≤2 that are characteristic of each drug did not increase in frequency or severity during concurrent dosing, according to Attia. The most common TRC105 AE included grade ≤2 telangiectasia (including associated epistaxis and gingival bleeding). The most common AE experienced with pazopanib included grade ≤2 fatigue and diarrhea.

“Of note, there were no grade 4 drug-related toxicities, and infrequent grade 3 drug-related toxicities,” Attia said. “Dose escalation increased from 8 mg/kg to 10 mg/kg without dose-limiting toxicity. Importantly, the addition of TRC105 did not potentiate the toxicities of pazopanib.”

The endoglin pathway is upregulated following VEGF inhibition and is expressed on sarcoma tissue, according to Attia. Immunohistochemistry (IHC) has shown that endoglin is densely expressed on tumor vessels and on certain STS tumor tissue, particularly angiosarcoma. In fact, Attia mentioned that tumor endoglin expression by IHC may serve as a biomarker to predict highly responsive STS subtypes. Efficacy endpoints of the phase Ib study will be correlated with endoglin IHC expression.

After the phase I study, a multicenter phase II open-label, nonrandomized study in metastatic STS was initiated and is ongoing. Patients are permitted up to four lines of prior therapy including two combination regimens. In this study, TRC105 is given at the recommended 10-mg/kg/week dose with pazopanib at 800 mg/day. Prior pazopanib is not permitted. The endpoint is PFS and the study is stratified by tumor-mitigated endoglin expression using IHC. According to Attia, a randomized phase III study of TRC105 with pazopanib is planned.

Attia S, Riedel RF, Robinson SI, et al. A phase IB dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS). Presented at: 2015 CTOS Annual Meeting: November 4-7; Salt Lake City Utah. Paper 002.