Targeted Therapies May Have a Role in Urothelial Cancer

Andrea Necchi, MD

Department of Medicine, Fondazione IRCCS Istituto, Nazionale dei Tumori, Milan, Italy

The multikinase inhibitor pazopanib (Votrient) has demonstrated activity in a majority of patients with refractory urothelial cancer, providing the first evidence that targeted therapies might have a role in the disease, investigators have reported.

Results of an open-label trial involving 41 patients showed that three-fourths had at least stable disease during treatment with pazopanib. The trial results also pointed to interleukin-8 (IL-8) as a potential marker of response, as high baseline levels of the cytokine or rising levels during treatment were associated with progressive disease.

Morphologic assessment by computed tomography (CT) and metabolic/functional assessment by positron emission tomography (PET), added to conventional Response Evaluation Criteria In Solid Tumors (RECIST), suggested that as many as twothirds of the patients had meaningful reductions in tumor size.

“A remarkable rate of disease stabilization was achieved, as well as a remarkable rate of responses other than by RECIST criteria,” said Andrea Necchi, MD, in presenting his research during the American Association for Cancer Research Annual Meeting in Chicago, Illinois, earlier this year. “Their impact on efficacy outcomes is still to be elucidated.”

Necchi also presented the results of the phase II study at the American Society of Clinical Oncology (ASCO) annual meeting in June, where he received a Merit Award for his abstract.

During his ASCO presentation, Necchi noted that no new treatments for urothelial cancer have been approved in the United States in several decades, and that second and further lines of therapy have been ineffective. Urothelial cancer, also called transitional cell carcinoma, makes up about 95% percent of bladder cancers, according to the American Cancer Society. Five-year survival rates for patients with stages III or IV bladder cancers are 46% and 15%, respectively.

The study involved patients who had progressed on at least one prior regimen, and half of the patients had progressed beyond second-line therapy. Such patients typically have a poor prognosis, Necchi noted.

All of the patients received pazopanib 800 mg once daily until disease progression. Investigators assessed response RECIST, but also by whole-body contrast-enhanced CT imaging and PET imaging. Imaging studies were performed at baseline, and then every four weeks.

Additionally, blood samples were drawn at fourweek intervals to measure changes in vascular endothelial growth factor (VEGF), VEGF receptor (subtypes 1, 2, and 3), c-Kit, IL-6, IL-8, and IL-12.

Investigators set a threshold of five objective responses by RECIST as the definition of active therapy. Subsequently, seven patients had confirmed partial responses, and 24 patients had stable disease.

CT imaging suggested meaningful responses in 13 patients, and PET results suggested that 19 patients responded.

The patients had a median progression-free survival (PFS) of 2.6 months and a median overall survival of 4.7 months. More than 60% of patients were alive and progression-free at two months. Seven patients had PFS exceeding 10 months, and four patients had PFS exceeding 19 months.

Adverse events included grade 3 hypertension in two patients, grade 1-2 asthenia in 11 patients, diarrhea in five patients, and anemia and handfoot syndrome in three patients each. No patient discontinued therapy because of adverse events, and no dose reductions were required.

From baseline to four weeks, laboratory results showed significant increases in IL-8 (P < .0013). Elevations at either time point were associated with shorter overall survival (P = .0170, P = .0107, respectively).

“This trial gave a clear proof of concept that will require confirmation on a larger number of patients,” Necchi said in a press release. “However, the preliminary findings, mainly regarding the role of interleukin-8 levels, have the potential to change at least the concept of new trial design with antiangiogenic agents in this disease.”

The FDA approved pazopanib in 2009 for the treatment of advanced renal cell carcinoma and expanded the label in April to include patients with advanced soft tissue sarcoma who have received prior chemotherapy. GlaxoSmithKline, which developed Votrient, also is evaluating the drug in a phase III trial in ovarian cancer.

Necchi A, Zaffaroni N, Mariani L, et al. Biomarker analysis and final results of INT70/09 phase II proof-of-concept study of pazopanib (PZP) in refractory urothelial cancer (UC). Presented at the American Association for Cancer Research Annual Meeting; March 31-April 4, 2012; Chicago, IL. Abstract LB-433.