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Novel TKIs Produce Major Responses in Renal Cell Ca

Novel TKIs Produce Major Responses in Renal Cell Ca

SAN FRANCISCO-Several targeted therapies for advanced renal cell carcinoma (RCC) "merit further investigation if not Food and Drug Administration approval," asserted Michael Atkins, MD, of Beth Israel Deaconess Medical Center, Boston, in discussing trials of some of the RCC targeted drugs reported at ASCO. A novel tyrosine kinase inhibitor (TKI), AG-013736, has produced high response rates in patients with metastatic RCC, according to results of a phase II trial (abstract 4509). High ORRs With AG-013736 "The objective response rate of this drug for patients with advanced renal cancer is better than that of any other drug approved for this indication," said lead investigator Brian Rini, MD, assistant professor of medicine at the University of California, San Francisco. One of the molecular features of RCC is overexpression of genes that promote tumor cell growth, including vascular endothelial growth factor (VEGF), epidermal growth factor(EGF), and platelet-derived growth factor (PDGF). AG-013736 is a tyrosine kinase inhibitor that targets the VEGF receptors and the PDGF beta receptor. Favorable Outcomes vs Standard Tx Dr. Rini reported that 46% of the 52 patients on the trial had a partial response and 40% had stable disease. Only about 15% of patients usually respond to interleukin-2 and interferon- alpha, the current standard treatments for metastatic RCC. At a median follow-up of 1 year, 1 patient with a partial response hadrelapsed, and 16 patients (32%) had progressive disease. Dr. Rini later noted that 3 of the 21 patients who achieved a partial response subsequently progressed. Seven, or 13%, withdrew from the trial because of adverse events. Median time to progression had not yet been reached, Dr. Rini reported. Toxicities were manageable and included rash, diarrhea, and hypertension. The most common grade 3/4 toxicity was hypertension, which was controlled with medication. Other targeted therapies are also showing promise in RCC. BAY 43-9006 The novel multikinase inhibitor BAY 43-9006 (Sorafenib) is being tested in a phase III trial, and preliminary results reported at ASCO show a significant effect on disease progres-sion (abstract LBA4510). After 12 weeks, progression-free survival for the BAY 43-9006 arm of this trial was 79%, compared with 50% for the placebo arm. Partial response rates were low, occurring in only 2% of patients based on RECIST (Response Evaluation Criteria in Solid Tumors), but there was tumor shrinkage in a large number of patients, according to Bernard J. Escudier, MD, of Institut Gustave Roussy, who led the study. Erlotinib Plus Bevacizumab Erlotinib (Tarceva) combined with the anti-VEGF monoclonal antibody bevacizumab (Avastin) also had very promising results in a phase II study (abstract 4540) (see report on page 12 of this supplement). Questions Remain Noting that "we've come a long way in renal cancer," Dr. Atkins cautioned that many questions remain, including whether optimal schedules of the drugs are intermittent or continuous, whether there is cross-resistance among them, and how they combine with interferon and other drugs for RCC. Another unknown is whether AG-013736 and other novel therapies will do better as single agents or in combination with other drugs. "Despite our zeal for combination therapies, it remains to be seen whether combinations of targeted therapies can produce better results than optimal multi-targeted single agents," he said.

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