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HEALTH INDUSTRY JUNE 5, 2011
Major Shift in War on Cancer
Drug Studies Focus on Genes of Individual Patients; Testing Obstacles Loom
By RON WINSLOW
(See Correction & Amplification below .)
CHICAGO—New research is signaling a major shift in how cancer drugs are developed and patients are
treated—offering the promise of personalized therapies that reach patients faster and are more effective
than other medicines.
At the heart of the change: an emerging ability for
researchers to use genetic information to match drugs
to the biological drivers of tumors in individuals.
Studies released at the annual meeting of the American
Society of Clinical Oncology here are helping to support
previous findings that personalized medicine—
introduced more than a decade ago—is closer to being
realized as a weapon to fight cancer.
"A pattern is developing at an accelerated pace where
The Washington Post / Getty Images
we are able to match genetic information about a tumor
Studies show gains from targeting cancer patients
more individually. Work at a breast-cancer clinical to a new agent and get results," says John Mendelsohn,
trial at George Mason University. president of Houston's MD Anderson Cancer Center.
Despite the progress, researchers stress, most
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successful therapies to come onto the market. Another
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issue is cost. The targeted drugs already available run
into the tens of thousands a year.
One study led by doctors at Memorial Sloan Kettering, for instance, found that among skin-cancer
patients with a mutation in a gene called BRAF, 48% responded to a targeted treatment, compared with
just 5% who responded to the current standard treatment.
The report was published online Sunday by the New England Journal of Medicine. Another study, from

2. researchers at Massachusetts General Hospital, suggests that lung-cancer patients with a specific
mutation lived significantly longer when treated with a targeted therapy from Pfizer Inc. than a matched
group of similar patients who didn't get the drug.
Both drugs are now on a fast-track review at the U.S. Food and Drug Administration, reaching in the
agency in about half the time it takes more conventional medicines to get there.
"We've never had more insight into genetic pathways and the genetics of tumors than we do now," says
Gary Gilliland, head of cancer research and development at Merck & Co. These insights are driving "an
end-to-end change in the way we develop new drugs for cancer patients and the way we do business."
By targeting mutations, researchers say fewer patients will be needed to prove the efficacy of new drugs,
hastening their path to the market. In addition, fewer people will be enrolled in trials of drugs that
provide them little hope of benefit.
But the use in drug development of specific genetic traits in tumors, called biomarkers, poses a maze of
challenges. Many tumors are complex organisms fueled by multiple pathways. When one is disrupted
even by a potent single agent, others compensate to help tumors develop resistance to treatment. Target
therapies will likely be more effective when given along with similar agents or as some are used now,
with existing conventional drugs.
Researchers and drug companies are already working to
test combinations of targeted agents. In some cases,
they are collaborating with rivals. Combining agents
risks increasing side effects and the cost of therapy,
researchers and regulators say, and will likely require
changes to current procedures for approving drugs.
In addition, companies developing any drug that targets
a specific mutation must also develop a valid
companion diagnostic test to identify patients who
would be candidates for the treatment. Diagnostic tests
are reviewed by part of the Food and Drug
Administration that is separate from drug approval,
complicating the need to develop the test and drug in
tandem, says Mace Rothenberg, senior vice president of
clinical development for Pfizer's oncology business unit.
Janet Woodcock, director of the FDA's Center for Drug
Evaluation and Research, says the agency also sees the potential for targeted drugs and is working to
change regulatory policies to help accommodate these scientific advances. At a recent cancer symposium
in New York Dr. Woodcock said, "We are on the tipping point of a whole new game in how we develop
drugs [for cancer]."
The targeted skin-cancer drug featured at the ASCO meeting is called vemurafenib and is being
developed by Roche Holding AG and Daiichi Sankyo's Plexxikon unit. It inhibits a mutated form of a
gene called BRAF found in more than half of patients with advanced melanoma and has been shown to
have hardly any treatment effect on patients with a normal version of the gene.
Data from a 675-patient trial showed that those taking the drug were 63% less likely to die over a six-
month period compared to those taking chemotherapy called dacarbazine. The median time before
disease progressed for patients on the drug was 5.3 months compared with 1.6 months on
chemotherapy. As a side-effect, the drug caused a benign form of skin cancer in nearly one-fifth of

3. patients that researchers said was easily treated.
The Pfizer drug reported on at the meeting is called crizotinib and it blocks a mutated gene called ALK
that is found in up to 7% of patients with a form of lung cancer called non-small-cell lung cancer. In the
first report on survival rates benefit from the drug, Alice Shaw, a researcher at Massachusetts General,
said 74% of 119 patients treated with the drug were alive after one year and 54% after two years. The
study wasn't randomized, but Dr. Shaw said survival for a comparable set of patients who weren't
treated with crizotinib was 44% after one year and 12% after two years.
Another report featured results from an initiative at MD Anderson Cancer Center involving several
experimental drugs in initial, or phase I, testing. Typically, phase I studies of cancer drugs test a single
agent in patients to determine a maximum tolerable dose with the hope that a treatment effect might be
seen in a couple of patients.
The MD Anderson program pooled 1,144 patients in a phase I study after profiling their tumors for
mutations that might be targets of the tested drugs. Apostolia Tsimberidou, the researcher who led the
study, reported that 40% had mutations in 10 molecular pathways that were targeted by the
experimental compounds.
Tumors in 27% of those given agents that targeted their mutations responded to treatment compared to
5% for those with unmatched therapies.
Other researchers said such a high response rate in a phase I study was highly unusual and could help
prompt other academic and corporate researchers to change their protocols to help speed the early-
phase trials.
Such testing of patients is also moving into clinical practice thanks to plummeting costs of performing
DNA sequencing that researchers use to identify patients' mutations.
Massachusetts General Hospital and MD Anderson Cancer Center are among institutions beginning to
offer routine genetic profiling of tumors for every patient, moving into clinical practice a strategy
reserved only for research just a year or two ago and unheard of a decade ago.
Write to Ron Winslow at ron.winslow@wsj.com
Correction & Amplification
Daiichi Sankyo's Plexxikon unit is developing a targeted skin cancer drug with Roche Holding AG.
Plexxikon was misspelled in a previous version of this story.
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