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The first batch of targeted
therapies featured breakthrough drugs, a new drug/diagnostic paradigm, and the
rapid evolution of both resistant mutations and new treatments for them. Now,
Part II in this drama is already promising more eye-openers.
Many targeted drugs are being
tried with standard chemotherapy, but an even bigger question is whether
targeted-drug-only combinations will be more effective and reduce cancer
treatment side effects. Early trials suggest that’s true. If this promise
holds up, it could impact many aspects of cancer care, ranging from cure rates
through the cost of therapy.
“Targeted combinations will
move quickly, and it is an area we want to get into more and more,” says
Charles Baum, head of Pfizer’s clinical oncology. “There’s a lot of
excitement that there could be synergies, but even additive effects would be
good if the side effects are less.” Greg Plowman, head of angiogenesis
research at Genentech, agrees: “There are many exciting possibilities.”
Already, Genentech’s Avastin
(bevacizumab) and Tarceva (erlotinib) delivered encouraging results in a Phase
II non-small-cell lung cancer trial. Preclinical data from xenograft models had
suggested this might be a powerful combination for this extremely tough-to-treat
disease. Avastin inhibits angiogenesis by targeting vascular endothelial growth
factor (VEGF), while Tarceva inhibits the epidermal growth factor receptor (EGFR).
Eight of 34 patients who received the full Phase II dose in this study had
partial responses, while 26 had stable disease. (See Clin Cancer Res 12,
4421s-5s; 2006.) Now the combination will be studied in Phase III.
“That study shows that
combinations [of targeted drugs] are making an impact even in the absence of
chemotherapy,” says Plowman.
Intriguing results are also
starting to come out of Phase I trials combining Genentech/Roche’s Herceptin (trastuzumab)
and Genentech’s Avastin (bevacizumab) in advanced breast cancer. In this case
again, researchers are looking at patients who have undergone surgery but are
not getting chemotherapy. Those trials were prompted by evidence that
HER2-positive patients, who are the ones receiving Herceptin, also have elevated
levels of VEGF.
“We’re looking at Avastin
with just about everything,” says Plowman. Because the drug makes cancers more
sensitive to chemotherapy, it is being studied with standard treatment as well.
But in other protocols, Plowman says, it is being combined with “Kinase
inhibitors, mTOR inhibitors, hormonals, all the major classes of drugs.”
Pfizer, meanwhile, will be
looking at Sutent in combination with its own new MEK inhibitor (PD0325901) as
well as with other companies’ drugs, such as Genentech’s Tarceva. With so
much still unknown, study design questions remain. “We need to be creative
about how we do the trials to be successful,” says Baum.
Target Information Boom
The trend is being fueled by
two key factors — the availability of approved targeted therapies and the
explosion in knowledge about them. But not all combinations are equally well
planned. “At this point, the pairings are partly rational,” says Baum. “As
we get more knowledge about the biology of each mutation driving individual
tumors, it will become even more so.” In particular, he says, new targets from
colorectal and non-small-cell lung cancer are feeding into this process.
Drugs such as Pfizer’s Sutent
(sunitinib) and more recently Bristol-Myers Squibb’s Sprycel (dasatinib) have
already demonstrated the advantages of individual drugs that hit multiple
targets. “In GIST, Sutent works mainly by targeting the c-Kit mutations, and
in renal cell cancer its activity is more related to angiogenesis inhibition,”
Baum explains. As a growing armamentarium of targeted drugs becomes available,
scientists can learn more about exactly how these drugs add up.
One of the major questions is
whether researchers should try to hit a single mechanism on multiple fronts, or
instead, hit multiple mechanisms at once. The answer to that could vary from
cancer to cancer. Researchers also want to know whether targeted drugs might
also show synergistic toxicity. “Efficacy rules in cancer research,” Plowman
says, “but you have to be careful for overlapping toxicities.”
Finally, questions about cost
have been dogging targeted therapy developers since the field’s inception.
These drugs are top sellers for their makers: Gleevec (imatinib), for example,
netted Novartis more than $2 billion in 2005. Makers argue that these treatments
are R&D intensive, and thus cost a lot to develop. All these drugs cost
payers tens of thousands of dollars or more, however, so in doubling them up,
researchers will need to show either real benefits for patients or other cost
savings, such as less need for chemotherapy.
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