Disappointing Early Results With PTK/ZK in Patients With Advanced Colorectal Cancer

ORLANDO-Preliminary data from a randomized, double-blind, placebo- controlled phase III trial showed that the angiogenesis inhibitor PTK/ ZK added little to the efficacy of FOLFOX4 in first-line treatment of advanced colorectal cancer. J. Randolph Hecht, MD, of the University of California, Los Angeles, presented the study, which is known as the CONFIRM- 1 trial (abstract LBA3). Dr. Hecht said that PTK/ZK is an attractive candidate in this setting because it is an oral, small-molecule vascular endothelial growth factor (VEGF) receptor inhibitor. Preliminary studies showed that PTK/ZK produced a rapid reduction in the amount of contrast in colorectal tumors and seemed to correlate with clinical benefit. The multinational CONFIRM-1 study randomized 1,168 patients to receive FOLFOX4 (oxaliplatin [Eloxatin]/ fluorouracil(Drug information on fluorouracil)/leucovorin) with either oral PTK/ZK (1,250 mg once daily) or placebo. The study was sponsored by Novartis and Schering. Study Endpoints The main study endpoints were disease progression-free survival (PFS) and overall survival. Dr. Hecht presented data for PFS but not for OS. The PFS hypothesis was that treatment would produce a 25% reduction in risk of disease progression (hazard ratio [HR], 0.75). The OS hypothesis was that 1-year survival would increase by 71% to 76% (HR, 0.8). Dr. Hecht reported data on 585 patients treated with FOLFOX4 plus PTK/ZK and 583 patients treated with FOLFOX4 plus placebo. PTK/ZK produced a 12% reduction in risk of progression in patients with metastatic colorectal cancer when given with initial FOLFOX4 chemotherapy, but this difference did not achieve statistical significance. A planned secondary analysis showed a reduction in risk of progression of 17%, which was statistically significant. Grade 3/4 toxicities occurred in more than 5% of patients and were consistent with those associated with FOLFOX4 alone. Most side effects were mild to moderate, reversible, and similar to those of other VEGF path- way inhibitors (see Table 1). Dr. Hecht stressed the importance of testing other PTK/ZK dosing schedules before drawing conclusions about the drug's potential. Discussant Lee Ellis, MD, agreed. Dr. Ellis (University of Texas M.D. Anderson Cancer Center, Houston), said, "Just because a trial does not meet its primary endpoint does not mean that the drug is not active. He pointed out that recently published work by Thomas et al suggests that twice-daily dosing of PTK/ZK is required to obtain optimal efficacy due to the drug's pharmacokinetic profile (Thomas AL, Morgan B, Horsfield MA, et al: Phase I study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of PTK787/ZK 222584 administered twice daily in patients with advanced cancer. [Early Release, published online ahead of print May 2, 2005, J Clin Oncol.])