BETHESDA, MD (SUO 7th Annual Meeting - December 1-2, 2006:NIH) - In a session moderated by Dr. Michael Atkins, Beth Israel Deaconess Medical Center, Dr. Brian Rini, Cleveland Clinic spoke about the "Recent Advances with Anti-Angiogenic and Targeted Therapeutics: Bevacizumab, Sorafenib, Sunitinib, AG13736 and CCI-779".

VHL mutation occurs in 60% of RCC and promotes HIF- transcriptional activation of HIF targeted genes. Bevacizumab inhibits VEGF, and Sunitinib and Sorafenib inhibit phosphorylation and activation of VEGFR in addition to inhibiting PDGFR. Bevacizumab (10mg/kg) used in patients with metastatic RCC demonstrated a 10% risk reduction and median progression free survival (PFS) benefit (4.8 vs. 2.5 months compared to placebo). Another trial demonstrated a PFS of 8.8 months when combined with placebo vs. bevacizumab plus erlotunib (9.9 months). Sunitinib in phase II trials of patients after nephrectomy and with metastases showed a median PFS of 8.3 months. Although there was no placebo arm, the PFS is about double that of placebo. In phase III, sunitinib vs. IFN- demonstrated a PFS of 11 vs. 5 months, respectively. Overall survival is not yet mature. Sorafenib vs. placebo in phase III demonstrated PFS increase of 24 compared to 12 months.

Temsirolimus (15mg IV weekly) is an mTOR inhibitor tested in poor risk patients and was compared to IFN- alone or in combination. PFS was doubled to 3.7 months (temsirolimus alone or in combination) compared to 1.9 months. Dr. Rini also pointed out that tumor size on imaging might not be the best marker of response since necrosis can occur without overall tumor size shrinkage. Although these drugs are considered targeted therapy, side effects do occur in up to 50%, especially fatigue, diarrhea nausea, and hand-foot syndrome. Sunitinib was found to cause thyroid dysfunction in up to 85%, at least by serum evaluation.

Dr. Atkins then presented "Current Status of Immunotherapy and Patient Selection Issues". INF- is presently used as the control arm of clinical trials for testing new agents. He discussed low-dose IL-2 compared to megase in a French study, which showed no benefit, supporting the need for high-dose IL-2 if it is to be used. He feels that high-dose IL-2 remains an option for appropriated selected patients, although who these are remains unclear. Dr. Atkins discussed a new arginase mechanism of immune suppression. Tumor associated myeloid cells (TAMC) express decreased arginine and portends a worse response to immunotherapy. Evaluation of TAMC histologically can be used to make this prediction. Carbonic anhydrase IX expression is correlated with a good response to immunotherapy. A survival association could be found in patients who expressed CAIX that underwent immunotherapy. It is felt that increased CAIX expression is representative of other molecular events rather than being a direct mechanism for the enhanced immune response. He concluded that IL-2 should remain a component of clinical trials.

Dr. Keith Flaherty, University of Pennsylvania presented "Future Directions - Combination Trials, Resistance Studies, Translational Endpoints". He pointed out that over time there is upregulation of VEGFR, and this occurs at the inside of the tumors, as opposed to the periphery. He also showed data that high vascular permeability as determined by CDE-MRI helps to identify better response to VEGFR inhibitors

Report from The Society of Urologic Oncology Winter Meeting - National Institutes of Health - December 1-2, 2006

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Written by Christopher P. Evans, MD, a Contributing Editor with UroToday.

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