New Multi-Targeted Drugs Are Moving Through the Pipeline

ORLANDO-In the wake ofthe three new targeted drugs for nonsmall-cell lung cancer (NSCLC)-erlotinib(Tarceva), gefitinib (Iressa),and bevacizumab (Avastin)-dozensof candidate drugs have emerged withthe same or similar targets, accordingto reports at this year's ASCO. Manyare aiming at the vascular endothelialgrowth factor receptor (VEGFR), likebevacizumab, and others are targetingthe epidermal growth factor receptor(EGFR), as erlotinib and gefitinib do.What is different about many of theseagents is that they are targeting multipleproteins.One of the compounds that is farthestalong in development aims atboth EGFR and VEGFR and showspromise in NSCLC. ZD6474 hasemerged from a phase II trial in NSCLCwith high marks, according to investigators(abstract 3023).'Dramatic Responses'With ZD6474ZD6474 produced "very dramaticresponses" said Roy S. Herbst, MD, acoinvestigator of the study and a leadpresenter at ASCO's scientific symposiumon angiogenesis. The drug"should go forward to phase III," notedDr. Herbst, a professor in the departmentsof thoracic/head & neckmedical oncology at The University ofTexas M.D. Anderson Cancer Center,Houston.The double-blind, multicenterstudy included 127 patients with locallyadvanced or metastatic NSCLC(stage IIIb or IV) who had receivedfirst-line therapy with platinum-baseddrugs. Patients were randomizedto receive either docetaxel (Taxotere)with a placebo, docetaxel with ZD6474at 100 mg, or docetaxel with ZD6474at a dose of 300 mg.

At the 100-mg dose, ZD6474 withdocetaxel improved progression-freesurvival by 57% compared with docetaxeland placebo. Median progression-free survival time was 18.7 weeksfor the patients taking both drugs and12 weeks for those on the control arm.The objective response rate was alsoimproved for patients taking the targeteddrug-26% vs 12%. On the experimentalarm, 83% of patients hadtheir disease controlled for more than6 weeks, compared with 56% on thecontrol arm.ZD6474 at 100 mg did not add asignificant amount of toxicity todocetaxel, said John Heymach, MD,PhD, of Dana-Farber Cancer Institute,who presented the results. Hesaid that the higher dose is being testedin a trial of the drug as a single agentbut that in combination withdocetaxel, the 100-mg dose produceda response and toxicity profile.ZD6474 is not the only drug that aimsat both VEGFR and EGFR. Another,called AEE788, targets both.AEE788 Targets VEGFR, EGFRIn a phase I trial presented at ASCO,AEE788 showed some activity in advancedsolid tumors (abstract 3028).ZD6474 and AEE788 are among morethan a dozen drugs in the pipeline thatare aiming at growth factors.In his discussion of several of theseagents, Jose Baselga, MD, chief of theMedical Oncology Service, Valld'Hebron University Hospital, Barcelona,listed 17 VEGFR-targeted drugsin early trials, most of which also targetother proteins, such as plateletderived growth factor receptor anddifferent versions of VEGFR.Noting that the field of candidatesis crowded, he suggested that integrationof these drugs with other biologicsand conventional agents will be keyto their further development. Otherimportant issues, he said, will be doseand schedule and the identification ofsurrogate markers for therapeutic efficacy.