Colorectal
cancer, which affects the colon or rectum, is the second
leading cause of cancer-related deaths in the US for
both sexes, behind lung cancer. It has a higher mortality
than either prostate or breast
cancer, which have
arguably garnered more media and scientific attention.
In the 21st century, however, high-profile sufferers
such as Sharon Osbourne and the late husband of television
presenter Katie Couric have led to increased discussion
of the disease, and since 1999, March has been dedicated
National Colorectal Cancer Awareness Month in the US,
particularly to highlight the importance of screening.
In
2004, there was extra reason to celebrate: on February
26 the FDA approved Genentech's Avastin (bevacizumab).
Not only was it the first anti-angiogenesis cancer drug
approved by the agency (and a month before its decision
deadline), but unusually, Avastin was cleared for use
in the first-line treatment of metastatic colorectal
cancer, in combination with 5-fluorouracil-based chemotherapy;
frequently, the FDA initially approves novel cancer therapies
for second-line use only.
After
a number of setbacks in the development of biotech oncology
products, Avastin looks like being at the vanguard of
a new wave of options for patients and physicians.
Costly but effective
Avastin was launched almost immediately. It will cost
$46,600 for a typical treatment course ($4,400 per month),
a higher price than had been forecast, but Avastin has
a demonstrable impact on survival - increasing patients
lifespan by four-five months compared with the Saltz regimen
of 5-FU, leucovorin and irinotecan (Yakult Honsha, Aventis
and Pfizer's Campto/Camptosar) alone. It was less
successful when irinotecan, a highly toxic drug, was omitted
from the regimen; however, the broad label for Avastin,
which specifies only 5-FU, means physicians have some flexibility
in their treatment approach.
The antibody
inhibits the action of VEGF (vascular endothelial growth
factor), suppressing angiogenesis (the process through
which tumour cells promote the development of new blood
vessels to support their growth and spread, or metastasis)
and thus tumour growth. The FDA official who oversaw the
review of Avastin, Patricia Keegan, commented: "Seeing
a survival advantage of this magnitude is unusual. This
is actually very exciting. In every subset analysis of
the trial, every patient regardless of gender, age, extent
of disease - all of them responded."
Genentech's majority owner Roche has
rights to the product outside the US and Japan, and the
two are collaborating on the study of Avastin in further
tumour types, including breast, lung, pancreatic and
renal cell (kidney). At the time of writing, Avastin
was pending approval for colorectal cancer in the EU,
Switzerland, Canada and Australia.
While Genentech has maintained
a cautious stance on Avastin's potential, the successful
marketing of its breast cancer antibody Herceptin (trastuzumab),
also in conjunction with Roche, had led industry observers
to predict blockbuster status for Avastin - particularly
as Herceptin is only suitable for approximately 30% of
patients. Many analysts believe Avastin will easily exceed
$1.5 billion in annual sales, especially if it receives
marketing clearance for use in other cancers.
Erbitux also finally approved
Only two weeks earlier, on February 12, the FDA had also
approved ImClone Systems' Erbitux (cetuximab), which
will be marketed by Bristol-Myers Squibb in the US (through
a $2 billion agreement) and Merck KGaA in Europe. The trial
data submitted for Erbitux's BLA did not demonstrate a
survival benefit, though the monoclonal antibody was shown
to shrink tumours in 23% of patients when used in combination
with standard chemotherapy.
Survival trials are ongoing with Erbitux, which blocks
the epidermal growth factor receptor. Currently, it is
approved as a second-line treatment in metastatic EGFR-expressing
colorectal cancer that has proved refractory to irinotecan;
EGFR is expressed in more than 70% of advanced colorectal
cancers. Unlike Avastin, Erbitux can be used in combination
with irinotecan or on its own (monotherapy) in patients
who cannot tolerate irinotecan; as a single agent, Erbitux
has an 11% response rate.
The news came as welcome relief for ImClone, which was
in the news for all the wrong reasons thanks to the trial
of Martha Stewart, the US 'domestic guru' who had sold
ImClone stock just before the FDA rejected Erbitux's initial
BLA in December 2001. Erbitux was first approved in Switzerland,
a Merck KGaA territory, in December 2003; EU clearance
is expected in mid-2004. Despite the narrower label compared
with Avastin, some analysts think Erbitux could achieve
sales of at least $1 billion; it is also being tested in
other cancers, including lung.
Late-stage biological therapies for colorectal cancer
|
Compound |
Type
of action |
Developers |
Phase
(colorectal cancer) |
|
ABX-EGF |
MAb, EGFR |
Abgenix, Amgen |
III |
|
Canvaxin |
therapeutic vaccine |
CancerVax |
III |
|
IGN101 |
MAb, EpCAM vaccine |
igeneon |
III |
|
Genasense (oblimersen) |
bcl-2 antisense inhibitor |
Genta, Aventis |
II |
|
Oncophage |
personalised therapeutic
vaccine |
Antigenics |
II |
|
Theratope |
mucin vaccine |
Biomira, Merck KGaA |
II |
Source: IMS
LifeCycle R&Dfocus
As can be seen
from the selection listed in the table above, behind
Avastin and Erbitux there are a number of
other biotech products for colorectal cancer waiting in
the wings. The importance of having a range of treatment
options is growing as researchers begin to realise that
colorectal cancer is not a single biological entity, but
several different subtypes that have their own individual
sets of biomarkers.
In parellel with its approval of Erbitux, the FDA also
cleared an EGFR pharmDx kit from DakoCytomation,
used to identify patients eligible for treatment with Erbitux.
As David Parkinson, head of clinical oncology at Amgen,
notes: "We know that patients are not all the same. What
we're trying to do now is define the differences." Like
Erbitux, Amgen and Abgenix's ABX-EGF is a MAb targeting
EGFR. ABX-EGF, however, is fully humanised, whereas Erbitux
is chimaeric - a difference Abgenix believes may make its
product safer, for example causing fewer allergic reactions
and possibly thus being suitable for higher or longer-term
dosing.
Traditional drugs also improving outlook
While the biotech industry's efforts have perhaps gained
more exposure, there have also been advancements in traditional
chemotherapies for colorectal cancer. Camptosar, launched
in the US in 1996, was the first new product for colorectal
cancer in decades, after 5-FU. Debiopharm and Sanofi-Synthelabo's Eloxatin (oxaliplatin),
not launched in the US until 2002, has gained a 40% share
of the US market and its global sales doubled in 2003 to
reach € 824 million; it has become a treatment mainstay
as part of the FOLFOX regimen, which combines Eloxatin,
5-FU and leucovorin.
Roche reported a 29% increase in sales in 2003 for Xeloda (capecitabine),
its oral, tumour-activated prodrug of 5-FU, which trials
have demonstrated is superior to a combination of 5-FU
and leucovorin in previously treated patients. It is now
testing a combination of Xeloda and Eloxatin, with or without
Avastin, against FOLFOX. Launched for use in breast cancer
in 1998, Xeloda received FDA approval for colorectal cancer
in 2001.
Altogether, pharmaceutical and biotechnology companies
are demonstrating that slow, steady advancements in research
and development can lead to an incremental improvement
in patient survival and quality of life, even in diseases
as severe as metastatic colorectal cancer.
This article was written by Selena Class, Deputy Executive
Editor of IMS
Company Profiles. For more information on how IMS can help you understand the
colorectal cancer market, please contact IMS
Global Consulting's Fil
Manuguid via e-mail or call +44 207 393 5713. |
