Novel TKIs Produce Major Responses in Renal Cell Ca

SAN FRANCISCO-Severaltargeted therapies for advanced renalcell carcinoma (RCC) "merit furtherinvestigation if not Food and DrugAdministration approval," assertedMichael Atkins, MD, of Beth IsraelDeaconess Medical Center, Boston, indiscussing trials of some of the RCCtargeted drugs reported at ASCO.A novel tyrosine kinase inhibitor(TKI), AG-013736, has produced highresponse rates in patients with metastaticRCC, according to results of aphase II trial (abstract 4509).High ORRs With AG-013736"The objective response rate of thisdrug for patients with advanced renalcancer is better than that of any otherdrug approved for this indication,"said lead investigator Brian Rini, MD,assistant professor of medicine at theUniversity of California, San Francisco.One of the molecular features of RCCis overexpression of genes that promotetumor cell growth, includingvascular endothelial growth factor(VEGF), epidermal growth factor(EGF), and platelet-derived growthfactor (PDGF). AG-013736 is a tyrosinekinase inhibitor that targets theVEGF receptors and the PDGF betareceptor.Favorable Outcomes vsStandard TxDr. Rini reported that 46% of the52 patients on the trial had a partialresponse and 40% had stable disease.Only about 15% of patients usuallyrespond to interleukin-2 and interferon-alpha, the current standard treatmentsfor metastatic RCC.At a median follow-up of 1 year, 1patient with a partial response hadrelapsed, and 16 patients (32%) hadprogressive disease. Dr. Rini later notedthat 3 of the 21 patients whoachieved a partial response subsequentlyprogressed. Seven, or 13%,withdrew from the trial because ofadverse events. Median time to progressionhad not yet been reached, Dr.Rini reported.Toxicities were manageable and includedrash, diarrhea, and hypertension.The most common grade 3/4toxicity was hypertension, which wascontrolled with medication.Other targeted therapies are alsoshowing promise in RCC.BAY 43-9006The novel multikinase inhibitorBAY 43-9006 (Sorafenib) is beingtested in a phase III trial, and preliminaryresults reported at ASCO show asignificant effect on disease progres-sion (abstract LBA4510). After 12weeks, progression-free survival for theBAY 43-9006 arm of this trial was 79%,compared with 50% for the placeboarm. Partial response rates were low,occurring in only 2% of patients basedon RECIST (Response EvaluationCriteria in Solid Tumors), but therewas tumor shrinkage in a large numberof patients, according to Bernard J.Escudier, MD, of Institut GustaveRoussy, who led the study.Erlotinib Plus BevacizumabErlotinib (Tarceva) combined withthe anti-VEGF monoclonal antibodybevacizumab (Avastin) also had verypromising results in a phase II study(abstract 4540) (see report on page 12of this supplement).Questions RemainNoting that "we've come a longway in renal cancer," Dr. Atkins cautionedthat many questions remain,including whether optimal schedulesof the drugs are intermittent or continuous,whether there is cross-resistanceamong them, and how they combinewith interferon and other drugsfor RCC.Another unknown is whetherAG-013736 and other novel therapieswill do better as single agents or incombination with other drugs."Despite our zeal for combinationtherapies, it remains to be seen whethercombinations of targeted therapiescan produce better results than optimalmulti-targeted single agents," hesaid.