R&D
approval in the first-line setting for patients targeted agents. This was shown to be the case
with non-squamous histology, after it showed in 2008 with Erbitux. When a KRAS biomarker
an approximate one-month survival advantage analysis was conducted on evaluable tumour
for this group compared with Lilly’s older samples in the pivotal CRYSTAL trial, it was
chemotherapy drug Gemzar (gemcitabine), shown that patients with a mutated KRAS
both used in combination with cisplatin. oncogene did not benefit from the addition of
Although the benefits of the lung cancer Erbitux to chemotherapy in terms of PFS or
successes might be termed marginal, they response rate. On the other hand, patients
appear larger next to the numerous failures. with wild-type KRAS had improved PFS with
Bayer/Onyx’s multi-targeted kinase inhibitor Erbitux (32% reduction in the risk of
Nexavar (sorafenib), approved in liver and progression or death during the period of
kidney cancers, failed a Phase III first-line trial observation). There was also a trend towards
when added to carboplatin and paclitaxel improved overall survival (a non-significant
chemotherapy, the common US doublet benefit of approximately four months) for
chemo regimen, although it is still being tested patients with a wild-type KRAS gene. Other
in a second study evaluating it in combination studies with Erbitux in CRC showed similar
low to intermediate risk of disease recurrence,
with a different chemotherapy regimen. results, as did a KRAS analysis of Amgen’s
compared with hormone therapy alone (with
AstraZeneca said that a Phase II/III study of Vectibix in previously treated patients
five-year disease-free survival of 94% vs 91%,
its new experimental anti-angiogenic Recentin presented last year.
respectively).
(cediranib; AZD2171) in first-line NSCLC However, the presence of a wild-type KRAS
While some experts said the result was “not
would not continue into Phase III development gene does not predict a sure response to
yet practice changing”, the potential anticancer
due to toxicity. However, it also said that a new EGFR-targeted agents, and therefore the
benefit of Zometa could soon be confirmed in
Phase II/III first-line trial would commence in search is underway for other biomarkers to
other trials. AZURE (Adjuvant Zoledronic acid
2009 testing a lower dose of the drug. further refine the population most likely to
to reduce Recurrence), which completed
Meanwhile, AstraZeneca’s most advanced respond to these drugs. There are thoughts to
enrolment in 2006, is evaluating the impact of
new anticancer Zactima (vandetanib), an oral combine EGFR inhibitors with inhibitors of
a more intensive schedule of Zometa in
inhibitor of VEGFR-2, EGFR and RET kinase, downstream components of the KRAS
reducing the risk of cancer recurrence in 3,360
prolonged PFS in one Phase III trial in pre- pathway to overcome resistance, but most of
pre-menopausal and postmenopausal women
treated NSCLC and failed do to so in two these have not yet reached late-stage
with stage II/III breast cancer (therefore at
others. development.
higher risk of recurrence than those in
Amgen was forced to temporarily suspend The other biggest story in CRC this year
ABCSG-12) when added to chemotherapy
enrolment in its Phase III trial of motesanib may have been the Phase III failure of the
and/or hormonal therapy. In targeting higher-
testing its anti-angiogenic drug candidate as a Avastin plus Erbitux combination. From a cost
risk women, the trial is more in line with
first-line treatment for advanced NSCLC after perspective, such a combo would have difficult
clinical practice.
higher mortality rates were observed with the to afford. However, there were hopes that
Avastin secured accelerated approval in the
drug compared with placebo in an interim combining two targeted agents which have US, a surprise and controversial decision that
analysis. Treatment was discontinued in patients shown efficacy in the disease would lead to an came after the drug’s failure to show a survival
with squamous cell NSCLC based on an added benefit. Instead, in the large first-line benefit in its pivotal study, E2100, and the
observation of a higher incidence of CAIRO2 trial, the outcome (in terms of PFS) FDA’s advisory committee voting against
pulmonary bleeding in these patients, the same was actually worsened with the two agents approval in a panel meeting. A full review of
issue as with Avastin. when added to chemotherapy versus the other trials with Avastin, including the first-line
Avastin failed to improve overall survival in a Avastin plus chemo control arm. Experts Phase III AVADO and RIBBON-1 studies, is
second Phase III pivotal trial, AVAIL, testing it concluded that the understanding of the VEGF required for accelerated approval to be
on top of gemcitabine and cisplatin. This led and EGFR pathways was incomplete. converted into a full approval. Like E2100,
some experts to say it was not a mandatory AVADO met its primary endpoint of
standard in lung cancer despite its showing an
breast cancer
extending PFS (although by a much more
approximate two-month survival benefit on
Breast cancer remains one of the biggest
modest margin, with median PFS extended by
top of chemotherapy in its first pivotal trial
cancer killers, despite a relatively high survival
less than one month). Overall survival results
which led to its approval in NSCLC.
rate when compared with many other tumour
from AVADO are expected by mid-2009, but
The combination of Avastin and Tarceva
types, as a result of its high incidence and not
given the modest PFS benefit observed, as well
failed their first Phase III trial in NSCLC, in the
always being caught early.
as the crossover allowed in the study, there is
second-line setting, but they are still being
Novartis’s bisphosphonate Zometa provided
some chance that a survival benefit may not
tested together as first-line maintenance
one of the biggest clinical success stories this
be seen. Roche and Genentech said that
treatment.
year. The 1,803-patient ABCSG-12 trial was RIBBON-1, which tested Avastin in
the first large-scale study to demonstrate the combination with other chemotherapies,
colorectal cancer significant anti-tumour benefit of zoledronic succeeded in meeting its primary PFS
Colorectal cancer (CRC) remains the second acid, which so far is known only for its endpoint, but overall survival data are not yet
biggest cancer killer in the West. The biggest beneficial effects on bone. However, preclinical available.
story of 2008 was that of the KRAS biomarker. studies have suggested that the drug may have In the largest study of two targeted agents
KRAS is a well-known oncogene, which is anticancer effects, and research over the next in HER2+ metastatic breast cancer, the synergy
mutated to different levels in different tumour several years may help further elucidate its of Roche/Genentech’s HER2-targeted
types (35-45% in CRC). The KRAS protein is mechanism. Herceptin (trastuzumab) and GlaxoSmithKline’s
downstream of EGFR, and when locked in the In the trial, Zometa reduced the risk of newer dual-targeted Tykerb (lapatinib) was
“on” position as a result of a mutation in the breast cancer recurrence on top of hormone demonstrated in a Phase III trial in patients
KRAS gene, confers resistance to EGFR- therapy by 36% in pre-menopausal women at who had received prior chemotherapy.
42
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