After the recent success of Genentech's Avastin (bevacizumab) in metastatic colorectal, lung, breast and brain cancers, it was a little surprising to hear that the adjuvant data in colorectal cancer missed the mark, with the survival data not showing a significant benefit to the Avastin arm.  The Genentech press release announced:

"Results from a phase III study of Avastin® (bevacizumab) plus six months of
chemotherapy following surgery in patients with early-stage (adjuvant)
colon cancer (NSABP C-08). The study showed the addition of one year of
Avastin to chemotherapy did not result in a statistically significant
improvement in overall disease-free survival (DFS), the primary
endpoint, compared to chemotherapy alone after surgery. Patients who
received Avastin plus chemotherapy had a lower risk of the cancer
returning during the year of treatment, however, the improvement
diminished over the course of the study. No new safety signals for
Avastin were observed."

At the Genentech ASCO press briefing, the lead investigator, Carmen Allegra noted that six events separated the study from meeting the early-stopping rule at one year.  It was that close.  The one year data showed plenty of hints of significant survival but by the pre-specified three-year endpoint, when there were 603 events,
disease-free survival had ceased significance. The end result
for Avastin was 77.4% versus 75.5% for standard chemotherapy alone.

The difference between taking a look at the interim data and the final analysis clearly shows the benefit of long term follow up in the adjuvant setting because things may not always be as they seem.  It will be interesting to see futher analyses to see if any particular subsets responded better to the combination treatment with Avastin.

Meanwhile, VEGF as a pathway has had a somewhat chequered history since Judah Folkman first elucidated angiogenesis as a potentially important pathway in how tumours grow and survive.  Numerous compounds have entered the clinic with great fanfare, but successfully navigating the treacherous R&D waters through to phase III/IV has proved problematic.  The latest interesting molecule is AstraZeneca's Zactima (vandetanib, ZD6474), a dual-acting TKI that targets VEGF receptor-2 (KDR) and EGFR.  It is currently in phase III development for lung cancer and phase I/II trials are ongoing in colorectal cancer, medullary cancer and others.

The big news with this agent at ASCO earlier this month was the ZODIAC, ZEAL and ZEST trial data in advanced NSCLC. 

ZODIAC is a randomised, double-blind, placebo-controlled Phase III
study evaluating the combination of vandetanib 100mg with docetaxel
versus docetaxel alone.  The study enrolled 1391 patients previously
treated with one prior anti-cancer therapy for advanced NSCLC.  Results presented by Roy Herbst et al., showed that the study met its primary endpoint and the addition of vandetanib to docetaxel resulted in a
statistically significant improvement in progression-free survival
(PFS), the length of time a patient lives without their cancer growing:

PFS 14.0 weeks vs. 17.3 weeks (HR 0.79; P<0.001) in favour of vandetanib. 

An update on the survival data is expected be available later this year.

ZEAL (ZACTIMA Efficacy with Alimta in Lung cancer) is a randomised, double-blind, placebo-controlled Phase
III study evaluating the combination of vandetanib 100mg with
pemetrexed versus pemetrexed alone in patients with locally advanced or
metastatic NSCLC, treated with one prior anti-cancer therapy.  It
enrolled 534 patients at 160 centres across 23 countries.

The data from ZEAL followed the same trend of ZODIAC, although the primary endpoint
did not reach statistical significance in the study, despite median PFS of 11.9 weeks vs.
17.6 weeks in favour of the  vandetanib plus pemetrexed arm (HR 0.86, P=0.108).

Secondary endpoints in the ZODIAC and ZEAL studies were also reported.  They showed
that addition of vandetanib to chemotherapy significantly improved
objective response rate, a measurement of tumor shrinkage:

ZODIAC: 17.0% vs. 10.0%, P<0.001

ZEAL:     19.1% vs.  7.9%, P<0.001

The studies also demonstrated that adding vandetanib to standard chemotherapy resulted
in a significantly longer time to deterioration of disease related

ZODIAC: HR 0.78, P=0.002

HR 0.61, P=0.004

Overall survival in both
studies showed a positive trend, although they had not yet reach
statistical significance:

ZODIAC: HR 0.91, P=0.196

ZEAL:     HR 0.86, p=0.219

Adverse events reported in both studies was consistent with previous studies with vandetanib in
NSCLC. The most common adverse events associated with vandetanib
included rash, diarrhea and hypertension (ZEAL); rash, diarrhoea and
neutropenia (low white blood cell count) (ZODIAC). Incidence of
protocol-defined QTc prolongation was <2.0 percent in both studies
and was not associated with symptoms.

The ZEST (ZACTIMA Efficacy Study versus Tarceva) trial
is a Phase III randomised, double-blind, multi-centre study to assess
the efficacy of vandetanib 300mg versus erlotinib 150mg in patients with
locally advanced or metastatic NSCLC after failure of at least one
prior anti-cancer therapy.  It enrolled 1240 patients at 171 centres
across 22 countries.

Results from the ZEST phase III study were also presented at ASCO.  Again, the primary objective of demonstrating a
statistically significant prolongation of PFS for vandetanib was not
met in this study.  In a pre-planned non-inferiority analysis,
vandetanib was shown to have similar efficacy to erlotinib for PFS and

PFS: HR 0.98, P=0.721

1.01, P=0.830.

The objective response rate (ORR) and
symptom control were also similar for both treatments ie ORR was 12% in both arms.  The most common adverse events observed in the ZEST study were rash,
diarrhoea and hypertension. Incidence of protocol-defined QTc
prolongation was 5.1 percent in the vandetanib arm.

On the basis of these results, AstraZeneca are expected to file with the FDA in the first half of 2009.  Other trials ongoing include ZEPHYR and ZETA.  Results from ZEPHYR (300mg monotherapy study in EGFR failures in
advanced NSCLC) and ZETA (300 mg monotherapy in advanced
medullary thyroid cancer) phase III studies are expected be available during
the second half of 2009.

Overall, aside from the Avastin data in glioblastoma following on from the recent FDA approval, I thought this batch of trial results with VEGF inhibitors rather dispiriting, but it may be the almost constant rain in New Jersey over the last 8-10 days that has influenced that sentiment.

 VEGF update from ASCO 2009