SAN FRANCISCORhuMAb VEGF (recombinant humanized monoclonal
antibody to vascular endothelial cell growth factor) in combination
with 5-fluorouracil/leucovorin chemotherapy (5-FU/LV) is well
tolerated and may increase response rates and prolong time to disease
progression in previously untreated metastatic colorectal cancer, as
compared with 5-FU/LV alone.
The finding comes from a study among 104 patients who were either
chemotherapy-naive or who had received adjuvant therapy at least 12
months before enrollment. Study results were presented at the ASCO
meeting by Emily Bergsland, MD, University of California, San
VEGF, a potent regulator of angiogenesis, is overexpressed in many
human cancers, Dr. Bergsland noted. In the case of colon
cancer, she said, high levels of VEGF expression
frequently portend a poor prognosis.
Response Rates Increased
Patients with prior therapy for metastatic disease were excluded from
the study, although adjuvant therapy at least 1 year prior was
allowed. Patients at 35 separate sites were randomized to one of
three arms: 5-FU/LV alone or in combination with low-dose (5 mg/kg)
or high-dose (10 mg/kg) rhuMAb VEFG. Patients were treated until
disease progression or the end of the 1-year treatment period.
5-FU/LV was administered via the Roswell Park regimen consisting of
weekly infusions for 6 weeks followed by a 2-week rest. Those
receiving rhuMAb VEGF were given an intravenous injection every 2
weeks continuously. Tumor assessments were conducted at the end of
every 8-week cycle.
Response rates in the rhuMAb VEGF arms were increased to a
statistically significant level (P = .03) in the lower-dose
arm. The response rates were 40% for the low-dose arm and 24% for the
high-dose arm, compared with 17% for the control group.
Time to progression was increased significantly again in the 5-mg arm
to 9 months (P = .005). For the high-dose group, time to
progression was 7.2 months, compared with 5.2 months for the control
Preliminary survival analysis also favored the 5-mg dose. Survival
was 13.8 months for the control group, 17.3 (median not yet reached)
for the 5-mg group, and 16.1 months for the 10-mg group.
This analysis, Dr. Bergsland underscored, may be confounded by the
crossover of 22 of 36 control patients to rhuMAb VEGF after disease
progression. Ten of 22 rhuMAb VEGF patients received treatment for
more than 4 months, and 2 had partial responses lasting 3 and 5 months.
At Least One Adverse Event
Dr. Bergsland reported that while therapy was generally well
tolerated, all participants experienced at least one adverse event,
and those in the rhu-MAb VEGF arms experienced more grade 3-4 events
(74% at 5 mg; 72% at 10 mg). She commented, however, that those
patients were in treatment longer, which may have accounted for the
higher event incidence.
Diarrhea was the most common side effect. Typical chemotherapy
toxicity rates (leukopenia, stomatitis, diarrhea) were not increased.
The rhuMAb VEGF arms also experienced increases in GI bleeding,
epistaxis, and hypertension.
A trend toward increased thrombotic events (9% with 5-FU/LV alone,
26% with 5 mg rhuMAb, 13% with 10 mg rhuMAb) included phlebitis at
the site of chemotherapy infusion, deep-vein thrombosis, and femoral
artery embolism. While in all but four cases treatment was continued,
there was one fatality attributed to pulmonary embolism in the
Dr. Bergsland concluded that rhuMAb VEGF at 5 mg/kg plus 5-FU/LV
resulted in statistically significant increases in response rates and
time to progression compared with chemo alone. The relationship
between dose and efficacy, she noted, remains unclear.
Taken together, these data suggest that rhuMAb VEGF may have
activity in colon cancer and warrants additional study, Dr.