Bevacizumab Plus TRC105 Failed to Improve PFS in Refractory, Metastatic RCC

TRC105, a monoclonal antibody against endoglin, failed to improve progression-free survival (PFS) when added to bevacizumab compared with bevacizumab alone in patients with refractory metastatic renal cell carcinoma (RCC), according to the results of a study published in Cancer.

Endoglin is an angiogenic pathway that is upregulated after VEGF inhibition and is thought to contribute to resistance.

In this study, Tanya B. Dorff, MD, of the University of Southern California Keck School of Medicine and Norris Comprehensive Cancer Center in Los Angeles, and colleagues enrolled 59 patients with previously treated metastatic RCC. Patients could have 1 to 4 prior lines of therapy, including VEGF-targeted agents. Patients were randomized 1:1 to bevacizumab 10 mg/kg every 2 weeks with or without TRC105 10 mg/kg every 2 weeks.

Only one patient in each study arm had a confirmed partial response.

The median PFS for bevacizumab monotherapy was 4.6 months compared with 2.8 months for bevacizumab in combination with TRC105. Rates of grade 3 or higher adverse events were similar between the two study arms.

The researchers also tested whether tissue levels of transforming growth factor β (TGFβ) receptor expression were related to treatment response.

“Because CD105 is required for heterodimerization and signaling activation by TGFβ, it was postulated that tumors using more TGFβ would be more sensitive to CD105 inhibition,” the researchers wrote.

They found that baseline serum TGFβ levels below a median of 10.6 ng/mL were associated with a more than twice as long PFS (5.6 vs 2.1 months; P = .014) compared with levels at or above the median.

“These data support further study of TGFβ pathway expression to yield potential predictive markers in future studies of patients with advanced RCC, particularly in the setting of treatment with TRC105,” the researchers wrote.

Despite the negative results, Dorff and colleagues noted several novel insights from the study. First, the continued use of bevacizumab in the second-line setting will assist practicing physicians in conversations about use of bevacizumab monotherapy in patients previously treated with VEGF inhibitors. Second, 22% of patients in the trial had non–clear cell histology and these data provide insight into the response to bevacizumab in this patient group.

“In the current study, disease stabilization did occur in patients with non–clear cell RCC who received bevacizumab alone or in combination, with similar PFS,” the researchers wrote.

Finally, the data provide more insight into weighing the risks and benefits of continued VEGF therapy, since “the toxicity profile in this study is notable for relatively few constitutional and gastrointestinal side effects, which contrasts with VEGF tyrosine kinase inhibitor therapy.”