New Multi-Targeted Drugs Are Moving Through the Pipeline

ORLANDO-In the wake of the three new targeted drugs for nonsmall- cell lung cancer (NSCLC)-erlotinib (Tarceva), gefitinib(Drug information on gefitinib) (Iressa), and bevacizumab(Drug information on bevacizumab) (Avastin)-dozens of candidate drugs have emerged with the same or similar targets, according to reports at this year's ASCO. Many are aiming at the vascular endothelial growth factor receptor (VEGFR), like bevacizumab, and others are targeting the epidermal growth factor receptor (EGFR), as erlotinib and gefitinib do. What is different about many of these agents is that they are targeting multiple proteins. One of the compounds that is farthest along in development aims at both EGFR and VEGFR and shows promise in NSCLC. ZD6474 has emerged from a phase II trial in NSCLC with high marks, according to investigators (abstract 3023). 'Dramatic Responses' With ZD6474 ZD6474 produced "very dramatic responses" said Roy S. Herbst, MD, a coinvestigator of the study and a lead presenter at ASCO's scientific symposium on angiogenesis. The drug "should go forward to phase III," noted Dr. Herbst, a professor in the departments of thoracic/head & neck medical oncology at The University of Texas M.D. Anderson Cancer Center, Houston. The double-blind, multicenter study included 127 patients with locally advanced or metastatic NSCLC (stage IIIb or IV) who had received first-line therapy with platinum-based drugs. Patients were randomized to receive either docetaxel(Drug information on docetaxel) (Taxotere) with a placebo, docetaxel with ZD6474 at 100 mg, or docetaxel with ZD6474at a dose of 300 mg. At the 100-mg dose, ZD6474 with docetaxel improved progression-free survival by 57% compared with docetaxel and placebo. Median progression- free survival time was 18.7 weeks for the patients taking both drugs and 12 weeks for those on the control arm. The objective response rate was also improved for patients taking the targeted drug-26% vs 12%. On the experimental arm, 83% of patients had their disease controlled for more than 6 weeks, compared with 56% on the control arm. ZD6474 at 100 mg did not add a significant amount of toxicity to docetaxel, said John Heymach, MD, PhD, of Dana-Farber Cancer Institute, who presented the results. He said that the higher dose is being tested in a trial of the drug as a single agent but that in combination with docetaxel, the 100-mg dose produced a response and toxicity profile. ZD6474 is not the only drug that aims at both VEGFR and EGFR. Another,called AEE788, targets both. AEE788 Targets VEGFR, EGFR In a phase I trial presented at ASCO, AEE788 showed some activity in advanced solid tumors (abstract 3028). ZD6474 and AEE788 are among more than a dozen drugs in the pipeline that are aiming at growth factors. In his discussion of several of these agents, Jose Baselga, MD, chief of the Medical Oncology Service, Vall d'Hebron University Hospital, Barcelona, listed 17 VEGFR-targeted drugs in early trials, most of which also target other proteins, such as platelet derived growth factor receptor and different versions of VEGFR. Noting that the field of candidates is crowded, he suggested that integration of these drugs with other biologics and conventional agents will be key to their further development. Other important issues, he said, will be dose and schedule and the identification of surrogate markers for therapeutic efficacy.