CHICAGO -- Refractory urothelial cancer had meaningful responses in the majority of patients treated with the angiogenesis inhibitor pazopanib, results of a small clinical trial showed.
Overall, 31 of 41 patients had stable disease or partial responses, resulting in a net clinical benefit rate of 76%.
Ten patients had prolonged responses or stable disease, associated with a median duration of 19 months.
The results have made pazopanib (Votrient) the first targeted therapy to demonstrate meaningful activity in patients with refractory urothelial cancer, Andrea Necchi, MD, said here at the American Association for Cancer Research (AACR) meeting.
"A remarkable rate of disease stabilization was achieved," Necchi, of Instituto Nazionale dei Tumori in Milan, Italy, said during an AACR press briefing. "A remarkable rate of responses other than RECIST was observed, but their impact on efficacy outcomes is still to be elucidated."
Biomarker analysis showed that elevated levels of interleukin-8 (IL-8), as well as rising levels during treatment, appeared to identify patients who were unlikely to benefit from treatment with pazopanib. If confirmed in additional studies, the observation could have a practice-changing impact on management of the disease, he added.
Patients with advanced urothelial cancer have a poor prognosis, with a median overall survival of 4 to 5 months. Conventional chemotherapy achieves objective responses in 60% to 70% of patients, but second-line therapies have proven ineffective.
Metastatic disease remains incurable and is associated with a 5-year overall survival of 10% to 15%, Necchi said.
In general, bladder cancer is a target-rich disease across the spectrum from superficial to invasive disease, he continued. However, targeted therapies have demonstrated limited activity in clinical trials and have failed to provide insights into strategies to define disease types and patient subgroups that would help optimize use of the therapies.
Pazopanib inhibits tumor angiogenesis by targeting vascular endothelial growth factor (VEGF) receptor. Preclinical studies have shown that urothelial cancer cells express VEGF receptor 1 and 2, and pazopanib has demonstrated antiangiogenic and antitumor activity in several preclinical models.
Necchi reported findings from a phase II, open-label, proof-of-concept study involving patients with advanced or metastatic urothelial cancer. Half the patients had progressed beyond second-line therapy, 19 had cisplatin-refractory tumors, and 22 had liver metastases.
All patients received daily pazopanib until disease progression, development of unacceptable toxicity, or withdrawal.
Response was assessed by conventional criteria, by morphologic criteria based on CT imaging, and by functional/metabolic imaging with PET.
By dimensional (RECIST) criteria, seven patients had objective responses and 24 had stable disease. Median progression-free survival (PFS) was 2.6 months and median overall survival was 4.7 months. Additionally, 61% of the patients remained alive without progression at 2 months, and 10% of the patients had durable PFS that persisted after a median follow up of 19 months.
CT assessment of tumor morphology showed that 13 patients had objective responses. PET imaging demonstrated that 19 patients responded to therapy.
Analysis of angiogenesis-associated biomarkers revealed IL-8 as a potential predictor of worse outcomes. Elevated IL-8 at baseline, or after 4 weeks of pazopanib therapy, was associated with worse survival. Rising IL-8 levels during the first 4 weeks also correlated with worse outcomes.
"Patients with rising IL-8 levels have tumors that rapidly adapt to pazopanib and develop resistance, resulting in tumor progression and reduced survival," Necchi said.
"IL-8 levels after 4 weeks of pazopanib may be useful to discriminate patients who are more likely to achieve a durable response to antiangiogenic agents from those who may benefit from an early shift toward alternative treatments," he noted.
Press briefing moderator Jose Baselga, MD, said the results provide some encouragement for an otherwise difficult disease.
"Urothelial cancer is one of the most difficult diseases to treat when refractory and there is a desperate need to have new therapies in this area," said Baselga, of Massachusetts General Hospital in Boston. "This work is extremely exciting and could move the field forward."
A study reported at the 2011 American Society of Clinical Oncology meeting showed that patients with metastatic urothelial cancer did not benefit from treatment with pazopanib (J Clin Oncol 2011; 29: Abstract 259).
Asked to comment on the different results from that trial and his own, Necchi suggested multiple factors that might have accounted for the disparate outcomes, including patient characteristics and response criteria and assessment. The most likely explanation is that the other trial had too few patients (18) to evaluate pazopanib's activity, he added.
Necchi and Baselga had no relevant disclosures.
Primary source: American Association for Cancer Research
Source reference:
Necchi A, et al "Biomarker analysis and final results of INT70/09 phase II proof-of-concept study of pazopanib in refractory urothelial cancer" AACR 2012; Abstract LB-433.
Source reference:
Necchi A, et al "Biomarker analysis and final results of INT70/09 phase II proof-of-concept study of pazopanib in refractory urothelial cancer" AACR 2012; Abstract LB-433.
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