The 86 cancer patients were a disparate group, with tumors
of the pancreas, prostate, uterus or bone. One woman had a cancer so rare there
were no tested treatments. She was told to get her affairs in order.
Still, these patients had a few things in common. All had
advanced disease that had resisted every standard treatment.
All carried genetic mutations that disrupted the ability of
cells to fix damaged DNA. And all were enrolled in a trial of a drug that helps
the immune system attack tumors.
The results, published on Thursday in the journal Science,
are so striking that the Food and Drug Administration already has approved the
drug, pembrolizumab, brand name Keytruda, for patients whose cancers arise from
the same genetic abnormality.
It is the first time a drug has been approved for use
against tumors that share a certain genetic profile, whatever their location in
the body. Tens of thousands of cancer patients each year could benefit.
“This is absolutely brilliant,” said Dr. José Baselga,
physician in chief at Memorial Sloan Kettering Cancer Center in New York, which
has just hired the study’s lead investigator, Dr. Luis A. Diaz Jr.
After taking
pembrolizumab, 66 patients had their tumors shrink substantially and stabilize,
instead of continuing to grow. Among them were 18 patients whose tumors
vanished and have not returned.
There was no
control group, which meant the results had to be absolutely compelling to be
convincing. The study started in 2013 and is funded by philanthropies; the
drugmaker’s only role was to supply the drug. The study is continuing.
The drug,
made by Merck, is already on the market for select patients with a few types of
advanced lung, melanoma and bladder tumors. It is expensive, costing $156,000 a
year.
A test for
the mutations targeted by the drug is already available, too, for $300 to $600.
Just 4
percent of cancer patients have the type of genetic aberration susceptible to
pembrolizumab. But that adds up to a lot of patients: as many as 60,000 each
year in the United States alone, the study’s investigators estimated.
Clinicians
have long been accustomed to classifying cancers by their location in the body
— patients are diagnosed with lung cancer, for example, or brain cancer.
Yet
researchers have been saying for years that what matters was the genetic
mutation causing the tumors. At first, they were certain they would be able to
cure cancers with drugs that zeroed in on the mutations, wherever the tumors
were lodged.
But cancers
were more complicated than that, said Dr. Drew M. Pardoll, director of the Johns
Hopkins Bloomberg-Kimmel Institute and an author of the new paper.
A mutation that appeared in half of all melanomas, for
example, turned out to be rare in other cancers. And even when scientists
pinpointed that mutation in 10 percent of colon cancers, the drug that worked
for melanoma patients did not work for other cancer patients.
“It was a
great dream,” Dr. Pardoll sighed.
The new
study was based on a different idea. The immune system can recognize cancer
cells as foreign and destroy them. But tumors deflect the attack by shielding
proteins on their surface, making them invisible to the immune system.
Pembroluzimab is a new type of immunotherapy drug
known as a PD-1 blocker, which unmasks the cancer cells so that the immune
system can find and destroy them.
The drug is
the happy result of a failed trial. A nearly identical drug, nivolumab, was
given to 33 colon cancer patients, and just one showed any response — but his
cancer vanished altogether.
What was
special about that one patient? Dr. Diaz, a geneticist at Johns Hopkins until
now, and lead author of the new study, found the answer: a genetic mutation
that prevented the tumor from repairing DNA damage.
As a result,
the man’s cancer cells contained a plethora of mutated genes, which produced
thousands of strange-looking proteins on the surfaces of the cells. Once the
tumor’s cloaking mechanism was short-circuited by the drug, the man’s immune
system had no trouble targeting the foreign proteins on the cancer cells.
That led to
the idea for the Dr. Diaz’s new study. He and his colleagues sought patients
whose tumors had the same genetic defect, which can arise in any of four genes
in a pathway that repairs damaged DNA. They gave these patients a PD-1 blocker
and were surprised by the results.
The drug’s
effects have been so durable that the investigators do not know how long the
results should be expected to persist or how long these patients might expect
to survive. That kind of result, Dr. Baselga said, “is insane.”
One patient
in the study, Adrienne Skinner, 60, of Larchmont, N.Y., had an extraordinarily
rare and deadly cancer, ampullary cancer that arises at the end of the bile
duct. There is no standard treatment, and the prognosis is dire.
Her doctors scheduled her for a drastic surgery that
removes part of the pancreas, part of the small intestine, and the gall
bladder. But her surgeon canceled the operation when he discovered her cancer
had invaded her liver.
She tried
chemotherapy instead — six months of one kind, then six months of another; Neither
worked.
Then she
qualified for Dr. Diaz’s clinical trial at Johns Hopkins. On April 15, 2014,
Ms. Skinner had her first dose of the drug.
In July, her
doctor inserted an endoscope for another biopsy. He turned to Ms. Skinner and
said, “If someone hadn’t told me you have ampullary cancer, I would not have
known.” The tumor was gone.
The trial
involved giving patients the drug for two years, so Ms. Skinner continued to
take the drug as a sort of insurance. Last year, she stopped, and her cancer
has not returned.
“In effect, I
was cured within months,” she said. “I have a great life.”
But even this
promising trial has left a thread dangling: Why didn’t all of the patients
respond?
There is now a fervid search for the answer. “Multiple labs are
looking like crazy,” Dr. Balsega said.
source:nytimes.com
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