ATLANTA—ZD6474 (Zactima), a once-daily oral drug that simultaneously blocks three tumor cell signaling pathways, looked promising in phase II studies vs gefitinib(Drug information on gefitinib) (Iressa) in advanced non-small-cell lung cancer (NSCLC) and can be combined with docetaxel(Drug information on docetaxel) (Taxotere), but the decision to move the drug into a phase III clinical trial triggered comments from the discussant (see Vantage Point) at the American Society of Clinical Oncology (ASCO) 42nd Annual Meeting.
Ronald B. Natale, MD, of Cedars Sinai Outpatient Cancer Center, Los Angeles, reported final results from a two-part, double-blind, randomized phase II trial that compared ZD6474 to gefitinib in patients with advanced NSCLC (abstract 7000). ZD6474 targets the vascular endothelial growth factor receptor (VEGFR), epithelial growth factor receptor (EGFR), and RET receptor tyrosine kinases. Gefitinib inhibits the EGFR tyrosine kinase. (RET receptor tyrosine kinase activity is involved in the growth of certain thyroid tumors.)
“We are moving from the era of singletargeted agents to those that are multitargeted, testing them first as monotherapy,” Dr. Natale said. He outlined three questions to be addressed in phase II studies: whether ZD6474 has singleagent activity; whether activity is due to inhibiting EGFR tyrosine kinase, VEGFR tyrosine kinase, or both; and whether it can be combined with chemotherapy.
This study enrolled 168 patients with locally advanced or metastatic (stage IIIB/IV) NSCLC, after failure of at least one platinum- based chemotherapy because of toxicity or tumor progression. Brain metastases were permitted, and squamous cell histology was not excluded. Patients were randomized to daily oral doses of ZD6474 (300 mg, n = 83) or gefitinib (250 mg, n = 85) until disease progression or evidence of toxicity (Part A). After a 4-week washout period, eligible patients then had the option of crossing over to the alternative treatment, which continued until disease progression or toxicity. The primary endpoints in Part A were progression-free survival (PFS) and safety/tolerability.
Median PFS in Part A (before crossover) was 11.9 weeks for ZD6474 and 8.1 weeks for gefitinib (HR 0.69, P = .025). The objective response rate was 8% with ZD6474 vs 1% with gefitinib. Disease control lasted more than 8 weeks in 45% of patients receiving ZD6474 and in 34% of patients receiving gefitinib. Adverse events with ZD6474 included diarrhea (grade 3-4, 8.4%), rash (grade 3-4, 4.8%) and asymptomatic QTc prolongation (all grade 1, 20.5%). In Part B of the study, 29 patients crossed over from ZD6474 to gefinitib and 32 crossed over from gefitinib to ZD6474. Dr. Natale said that disease control lasting for more than 8 weeks was achieved in 24% of patients who switched from ZD6474 to gefitinib and in 43% of those who switched from gefitinib to ZD6474.
Overall survival was 6.1 months in patients initially randomized to ZD6474 and 7.4 months in patients initially randomized to gefitinib (P = NS). Dr. Natale said that the investigators have no clear explanation for why improvement in PFS did not translate into an overall survival advantage, but they suspect that the crossover design confounded the survival analysis.
He concluded that since this study achieved its primary efficacy objective of prolonging PFS, compared with gefitinib, the data demonstrate that ZD6474 and gefitinib are both active in NSCLC and support further confirmatory trials of ZD6474 monotherapy.