Presurgical Pazopanib Safe for Metastatic Clear Cell Renal Cancer

The majority of patients with clear cell renal cancer saw benefit from pazopanib therapy prior to undergoing cytoreductive nephrectomy, according to the results of a single-arm study published in JAMA Oncology.

However, with a median reduction of 14% in the size of the primary tumor, researcher Thomas Powles, MD, of Queen Mary University of London, and colleagues wrote, “Upfront targeted therapy does not adequately reduce the size of the primary tumor to recommend pazopanib therapy prior to cytoreductive nephrectomy to facilitate surgery. However, the approach achieved rapid control of disease in the majority of patients and was associated with acceptable outcomes.”

The study included 104 patients with previously untreated metastatic clear cell renal cancer. Patients were recruited from 2008 to 2012 and received 12 to 14 weeks of preoperative pazopanib prior to surgery. Patients continued pazopanib therapy after surgery and were followed for a minimum of 30 months. The primary endpoint was clinical benefit prior to surgery at 12 to 14 weeks.

The researchers assessed clinical benefit in 100 patients. Of these patients, 84% achieved clinical benefit from pazopanib. Overall, 71% of patients had stable disease, 13% had partial response to therapy, and 16% had progression of disease.

Only 61% of patients underwent the planned nephrectomy; 13 patients did not undergo the procedure because of disease progression, and 9 because of patient choice. About one-fourth of patients had surgical complications after the procedure.

The median progression-free survival for the 104 patients evaluated was 7.1 months and the mean overall survival was 22.7 months. According to the study, those patients who did not achieve clinical benefit from pazopanib had a median overall survival of 3.9 months compared with 24 months for those who did achieve benefit.

A biomarker analysis showed a significant decrease in expression of VEGFR2 (P < .001), C-MET (P < .001), and von Hippel-Lindau tumor suppressor (P < .001) after pazopanib therapy; however, the researchers wrote, “Suppression of VEGF-related biomarkers did not correlate with outcome.” Additionally, expression of programmed death ligand 1 in the immune component increased after therapy (P < .001) and CD8 expression significantly decreased (P = .05).

The researchers pointed out that although this approach seemed safe, there were areas of concern.

“Delays in wound healing, thought to be related to VEGF-targeted therapy, were reported in this and other smaller series,” they wrote. “Also, 39% of patients did not undergo nephrectomy. This is higher than figures for nephrectomy prior to systemic therapy and is probably a result of patients with primary progressive disease not undergoing nephrectomy.”

In an editorial that accompanied the study, Neeraj Agarwal, MD, of University of Utah, Brian Shuch, MD, of Yale University School of Medicine, and Sumanta K. Pal, MD, of City of Hope Comprehensive Cancer Center, wrote, “The results of this phase II study by Powles and colleagues suggest that upfront targeted therapy with pazopanib may be feasible. However, in appropriate patients who are willing and able to undergo cytoreductive nephrectomy at the time of diagnosis, especially those who are symptomatic from a large primary tumor, the procedure should likely still be conducted upfront rather than in a delayed fashion.”