R&D
W
ith somewhere between a quarter different mechanisms of action, they have yet GlaxoSmithKline formed an oncology research
and a third of all drugs in to prove their worth in large clinical trials. and development organisation.
development being investigated High-profile failures this year included Pfizer’s
for oncology, and more than 1,200 companies anti-CTLA-4 monoclonal antibody
NSCLC
involved in producing cancer drugs, there was tremelimumab in melanoma, which the
Lung cancer remains the biggest cancer killer,
no shortage of news in this cutting-edge company discontinued after Phase III failure.
due to its high incidence combined with the
medical field in 2008. Sanofi-Aventis/Oxford BioMedica’s gene-
fact that it is often detected at an advanced
In addition to being the most explored therapy based immunotherapy Trovax also
stage, and the failure of many drugs to improve
therapeutic area, cancer also continues to be stumbled in Phase III in kidney cancer, although
upon standard doublet-based chemotherapy.
the area where the most novel drugs are it continues to be explored in this and other
Among this year’s successes in non-small cell
being tested. There is a mind-boggling array indications. Dendreon’s cellular therapy
lung cancer (NSCLC), which comprises about
of targets and mechanisms, spurred by the Provenge (sipuleucel-T) failed to meet a
75% of all lung cancer, were Erbitux, Iressa,
rapidly increasing knowledge of molecular statistical interim hurdle in Phase III and must
Tarceva, and Lilly’s Alimta (pemetrexed).
biology and the realisation that patients need wait until 2009 to see if it shows a survival
Erbitux became the second targeted drug after
to be treated according to the underlying benefit in the pivotal trial in hormone-
Avastin to lengthen overall survival in the
genetics of their disease rather than simply refractory prostate cancer. Cell Genesys
disease in the Phase III first-line FLEX trial, and
their basic tumour type. discontinued GVAX for prostate cancer after
it was subsequently filed for this indication in
As a result, cancer is the disease at the the failure of two Phase III trials. It may be that
the EU, with imminent plans for a US filing.
forefront of the “personalised medicine” investigating immunotherapy in earlier rather
However, last year the drug failed in another
revolution, with targeted anticancers continuing than late stage disease proves more fruitful,
Phase III first-line trial, BMS CA225-099, to
to generate the most excitement in the something GlaxoSmithKline is doing with its
meet its primary progression-free survival
oncology community. The personalised MAGE-A3 vaccine in a large adjuvant Phase III
(PFS) endpoint on top of another
medicine approach was arguably best trial in lung cancer.
chemotherapy doublet. Moreover, the increase
illustrated this year with the KRAS story, with
in median survival in FLEX was only one
major studies confirming this well-known
Even pharma companies
month, leading some experts to question
oncogene to be a negative predictor of
whether the high cost of the drug was worth
response to EGFR-targeted drugs in colorectal
intent on developing the this modest benefit, and highlighting the need
cancer, such as ImClone Systems/Bristol-Myers
next blockbuster drug realise
to further refine the patient population which
Squibb/Merck KGaA’s Erbitux (cetuximab) and
may benefit most. If approved, Erbitux would
the necessity to subdivide
Amgen’s Vectibix (panitumumab). Both drugs
provide an option to squamous cell patients,
were approved in Europe only for advanced
patient populations based on
who comprise about 25-40% of NSCLC –
colorectal cancer patients whose tumours are
underlying disease genetics
Avastin is not used in these patients because
EGFR-positive and who have a wild-type KRAS
of the risk of fatal pulmonary bleeding.
gene.
The large IPASS trial of AstraZeneca’s
Positive predictors of response to targeted In addition to testing targeted therapies on
EGFR-targeted Iressa (gefitinib) in non-smoking
therapies appear to be more difficult to their own, some were tested in combination,
Asian patients with adenocarcinoma was the
discover, but even pharma companies intent on where the greatest promise of such drugs is
first in the first-line metastatic setting to show
developing the next blockbuster drug realise thought to lie. However, the high-profile failures
a benefit (in terms of PFS) of the product
the necessity to subdivide patient populations of some combinations – such as Roche/
compared with standard doublet
based on underlying disease genetics and are Genentech’s anti-angiogenic Avastin
chemotherapy. These selected patients have a
hard at work to find appropriate biomarkers (bevacizumab) with Erbitux in colorectal
higher rate of EGFR-sensitising mutations
that would allow them to do this. This would cancer, and Avastin and Roche/Genentech’s
which make it easier for Iressa to bind to the
also lead to greater success in clinical trials and EGFR-targeted Tarceva (erlotinib) in second-
EGFR receptor and block it. Iressa is not
greater likelihood of drug approval, which is of line NSCLC – illustrated the need to rationally
licensed anywhere in the first-line setting,
great importance in an area where attrition design combinations of targeted drugs, a
including Asia, and AstraZeneca said it was in
remains a major issue. necessity as more and more reach the market.
consultation with relevant health authorities
In 2008, there were both high-profile late- While some novel drugs reported Phase III
regarding the IPASS data. In 2008, AstraZeneca
stage clinical successes and failures. Some results in 2008, far more candidates are still in
also filed for EU approval for Iressa in pre-
successes included drugs that were previously Phase III, Phase II, or earlier clinical or preclinical
treated NSCLC on the basis of the INTEREST
used in non-cancer indications, such as development, hinting at even more news to
trial, presented in 2007, in which the drug
Novartis’s bone drug Zometa (zoledronic acid; digest in years to come. Moreover, some
showed equivalent survival to docetaxel
approved for osteoporosis and to treat bone targeted drugs, such as Avastin, are in late-stage
chemotherapy.
complications in cancer) which showed trials in the adjuvant setting, where the greatest
Tarceva, which is approved as a second-line
promise in adjuvant breast cancer, and possible benefit, a cure, is a potential.
therapy in NSCLC based on a survival benefit
Novartis’s mTOR inhibitor RAD001 The tremendous interest in oncology was
in that setting, could find use earlier in the
(everolimus; approved as Certican for the highlighted in the corporate world by battles
treatment of the disease. Roche/Genentech
prevention of organ rejection in a different to acquire major cancer drug developers, such
said that it had met its primary PFS endpoint
dosing) in kidney cancer. Drugs already as Roche’s so-far unsuccessful bid for
in its first Phase III trial testing it as a first-line
approved for cancer, such as Erbitux, showed Genentech and Bristol-Myers Squibb’s and
maintenance therapy in advanced NSCLC, and
a benefit this time around in other major Lilly’s battle for ImClone, eventually won by
Roche plans to discuss filing a new indication
oncology indications (lung cancer in the case Lilly. Additionally, Pfizer, the world’s largest
for the drug with regulators.
of Erbitux). pharma company, has now shifted its major While the major interest might lie with
While immunotherapies harbour significant investment from cardiovascular disease to targeted anticancers, Lilly’s Alimta proved that
potential in cancer, and companies large and cancer, Schering-Plough underlined cancer as a additional benefit may still be derived from
small remain dedicated to exploring numerous key part of its future product pipeline, and chemotherapies. The drug received FDA
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