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 Bristol's Opdivo and Merck's Keytruda are both therapies designed to
block a protein known as Programmed Death receptor (PD-1) that
tumors use to evade the body's natural defenses. Competitors Roche
Holding, AstraZeneca and Pfizer also have similar drugs in an
earlier stage of development. The drugmakers are conducting clinical
trials that test patient tumors for a related protein called PD-L1.
The new drugs are mainly aimed at patients with so-called solid
tumors suffering from diseases including lung cancer and liver
cancer. Lung cancer, the most common type, claims 1.8 million new
cases each year worldwide. Sales of drugs to block PD-1 could reach
$33 billion a year by 2022, according to Morningstar.
New data published on Friday showed that Opdivo was most helpful to
lung cancer patients with the highest levels of PD-L1 in their
tumors, adding to evidence of a link. That would suggest that
doctors routinely test for the protein before giving a patient
Opdivo. The approach is already used for some cancer drugs that are
prescribed only if a patient has a specific genetic mutation.
Cancer experts interviewed by Reuters at the American Society of
Clinical Oncology meeting in Chicago, however, said that use of
protein levels in a tumor as a guide for treatment cannot be counted
on in the same way as a genetic variation.
Test results can vary depending on which part of the tumor was
biopsied and the degree to which the cancer has spread. In addition,
tests developed by drugmakers don't follow the same standards.
So while clinical trials show that drugs like Opdivo and Keytruda
work best in people who test positive for PD-L1, some patients who
test negative have benefited from the treatment.
"We shouldn't withhold immunotherapy from patients based on a
biomarker yet," said Dr Roy Herbst, chief of medical oncology at
Yale Cancer Center in New Haven, Connecticut, referring to Opdivo.
"We don't even know if PD-L1 is the right biomarker."
Dr. Richard Pazdur, the U.S. Food and Drug Administration's oncology
chief, also cautioned that there is still a great deal of
uncertainty about how to best measure for PD-L1.
"The key issue is whether the biomarker is essential for safe and
effective use of the drug," Pazdur said. "If not, then it is
probably not going to be an essential element in the indications for
the drug. But it would be useful information."
WHO GETS A COSTLY DRUG?
Health insurers would also be keen to have a surefire test of when a
novel, and expensive, cancer drug is most likely to work. Treatment
with Opdivo or Keytruda alone costs about $12,500 a month in the
United States, or $150,000 a year.
Pfizer's Xalkori, another new, expensive drug, is approved by the
FDA only for patients with a mutation of the ALK gene. A diagnostic
test must be used to identify the estimated 4 percent of patients
with non-small cell lung cancer who are likely to improve using
Xalkori.
Current approvals for PD-1 drugs do not require tumor testing.
Bristol's Opdivo, or nivolumab, was approved by the FDA in December
to treat advanced melanoma. In March, it was cleared to treat a form
of lung cancer, giving Bristol an early advantage in the much larger
market. Merck's Keytruda, or pembrolizumab, has been approved for
advanced melanoma since September and is awaiting approval as a lung
cancer treatment.
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Another confounding factor is that drugmakers are combining Opdivo
and Keytruda with other treatments to boost their effect, from
well-established medications like chemotherapy to experimental
compounds.
In a small trial of patients with advanced lung cancer,
AstraZeneca's experimental PD-L1 antibody, MEDI4736, was given in
combination with tremelimumab, which targets a different immune
system inhibitor. Nearly half of patients who were negative for
PD-L1 responded to the treatment.
"It seems like the PD-L1 negative patients are now responding as
well," said Bahija Jallal, executive vice president at AstraZeneca's
MedImmune unit. "That was the whole point of doing the combination."
A Bristol-Myers trial found melanoma patients whose tumors contained
PD-L1 fared just as well with Opdivo alone as with a combination of
Opdivo and a second immunotherapy, Yervoy. But patients without
PD-L1 detected in their tumors lived more than twice as long without
their disease getting worse when treated with both drugs.
Around 80 percent of melanomas test positive for PD-L1, compared
with around 50 percent of lung cancers, said Eric Rubin, Merck vice
president, global clinical oncology. At the same time, levels of
PD-L1 are not static.
"If I check it today, it might change tomorrow. It might be
different in one area of the tumor than in another area," said Dr.
Richard Carvajal, director of melanoma service at Columbia
University Medical Center in New York.
Drug companies are working to refine and standardize their PD-L1
testing, as well as exploring other ways to identify which patients
will benefit from immunotherapies.
Data presented at ASCO showed that Opdivo helped patients with
certain cancers, including colon cancer, whose tumors exhibited an
uncommon defect in genes needed for DNA repair. Drugmakers are also
trying to discover if there are any "negative" biomarkers to
indicate which patients should not be treated with immunotherapies.
"We are taking account of how the immune system is interacting with
the tumor. It's a completely different type of biomarker and
understanding," said Sandra Horning, chief medical officer at
Roche's Genentech unit.
(Reporting by Deena Beasley; Editing by Michele Gershberg and John
Pickering.)
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