Promising outcomes in a phase I/II
trial of the bevacizumab (Avastin)
and erlotinib (Tarceva) combination
against recurrent non-small-cell lung
cancer (NSCLC) have prompted a
phase II study testing bevacizumab/
erlotinib against bevacizumab/docetaxel
(Taxotere) and docetaxel/placebo.
Alan B. Sandler, MD, of Vanderbilt
University Medical Center,
Nashville, Tennessee, described the
results of the phase I/II bevacizumab/
erlotinib study (abstract 2000).
The rationale for combining bevacizumab,
a vascular endothelial growth
factor blocker, and erlotinib, an
HER1/epithelial growth factor receptor
tyrosine kinase blocker, is grounded
in preclinical work showing synergy
for these two targeted agents used
together in mice with human tumor
xenografts, Dr. Sandler explained.
Dosing and Toxicities
The primary objective of the phase
I/II study was to establish the maximum
tolerated doses of the combination
and to examine dose-limiting toxicities.
The secondary objective was to
evaluate the pharmacokinetics for potential
The phase I/II trial enrolled 40 patients
(21 female, 19 male) with recurrent,
nonsquamous, stage IIIB (with
pleural effusion), stage IV, or recur-
rent NSCLC. All had received at least
one prior chemotherapy regimen.
Thirty (75%) had adenocarcinomas,
one (5%) had bronchoalveolar carcinoma
(BAC), and nine (22.5%) had
NSCLC not otherwise specified. Median
age was 59 (range 36-72).
The phase I part of the study was
toxicity analysis in the first 12 patients.
The main toxicities reported
were mild rash, diarrhea, and proteinuria.
There were no hemorrhages
in any of these patients. The highest
dose tested in this phase I part of the
study, erlotinib 150 mg/d po plus be
vacizumab 15 mg/kg IV every 21 days,
was selected as the phase II dose, although
no true dose-limiting toxicities
were seen. There were also no pharmacokinetic
indications of drug
interactions. Among the 12 patients
treated in the phase I segment were 4
with partial responses (PR) and 6 with
stable disease (SD).
These promising outcomes encouraged
the investigators to press on with
phase II part of the study. Among
the 34 patients in this phase were 1
patient with grade 4 pulmonary
toxicity that is still under investigation,
2 patients (6%) with grade 3
hypertension, and 1 with grade 3
The phase II treatment produced
20% PR and 65% SD, for a clinical
control rate of 85%. Median time to
progression was 7.0 months (see Table
1). Dr. Sandler said that response was
quite durable in many patients, including
one patient who has continued
on treatment without progression
for almost 2 years.
"The response rate was 20% and
median survival was 12.6 months, but
it is important to remember that a
high number of patients had adenocarcinomas,
and patients with brain
metastases were excluded," he said.
Dr. Sandler reported that a randomized
phase II trial was expected
to begin in summer 2004 and would
seek to enroll about 200 patients.