ORLANDO-Preliminary datafrom a randomized, double-blind, placebo-controlled phase III trial showedthat the angiogenesis inhibitor PTK/
ORLANDO-Preliminary datafrom a randomized, double-blind, placebo-controlled phase III trial showedthat the angiogenesis inhibitor PTK/ZK added little to the efficacy of FOLFOX4in first-line treatment of advancedcolorectal cancer. J. RandolphHecht, MD, of the University of California,Los Angeles, presented thestudy, which is known as the CONFIRM-1 trial (abstract LBA3).Dr. Hecht said that PTK/ZK is anattractive candidate in this setting becauseit is an oral, small-molecule vascularendothelial growth factor(VEGF) receptor inhibitor. Preliminarystudies showed that PTK/ZK produceda rapid reduction in the amountof contrast in colorectal tumors andseemed to correlate with clinical benefit.The multinational CONFIRM-1study randomized 1,168 patients toreceive FOLFOX4 (oxaliplatin [Eloxatin]/fluorouracil/leucovorin) witheither oral PTK/ZK (1,250 mg oncedaily) or placebo. The study was sponsoredby Novartis and Schering.Study EndpointsThe main study endpoints were diseaseprogression-free survival (PFS)and overall survival. Dr. Hecht presenteddata for PFS but not for OS.The PFS hypothesis was that treatmentwould produce a 25% reductionin risk of disease progression (hazardratio [HR], 0.75). The OS hypothesiswas that 1-year survival would increaseby 71% to 76% (HR, 0.8). Dr. Hechtreported data on 585 patients treatedwith FOLFOX4 plus PTK/ZK and 583patients treated with FOLFOX4 plusplacebo.
PTK/ZK produced a 12% reductionin risk of progression in patientswith metastatic colorectal cancer whengiven with initial FOLFOX4 chemotherapy,but this difference did notachieve statistical significance. Aplanned secondary analysis showed areduction in risk of progression of17%, which was statistically significant.Grade 3/4 toxicities occurred inmore than 5% of patients and wereconsistent with those associated withFOLFOX4 alone. Most side effectswere mild to moderate, reversible, andsimilar to those of other VEGF path-way inhibitors (see Table 1).Dr. Hecht stressed the importanceof testing other PTK/ZK dosing schedulesbefore drawing conclusions aboutthe drug's potential. Discussant LeeEllis, MD, agreed. Dr. Ellis (Universityof Texas M.D. Anderson Cancer Center,Houston), said, "Just because atrial does not meet its primary endpointdoes not mean that the drug isnot active. He pointed out that recentlypublished work by Thomas et alsuggests that twice-daily dosing ofPTK/ZK is required to obtain optimalefficacy due to the drug's pharmacokineticprofile (Thomas AL, Morgan B,Horsfield MA, et al: Phase I study ofthe safety, tolerability, pharmacokinetics,and pharmacodynamics ofPTK787/ZK 222584 administeredtwice daily in patients with advancedcancer. [Early Release, published onlineahead of print May 2, 2005, J ClinOncol.])