ZD6474 (Zactima) Advances to Phase III Trial in NSCLC

ZD6474 (Zactima) Advances to Phase III Trial in NSCLC

ATLANTA--ZD6474 (Zactima), a
once-daily oral drug that simultaneously
blocks three tumor cell signaling pathways,
looked promising in phase II studies
vs gefitinib (Iressa) in advanced non-small-cell lung cancer (NSCLC) and can
be combined with 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.

Monotherapy Trial
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

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

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.


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