Diagnosed with advanced lung cancer over a year ago, Gabe Tartaglia was loath
to undergo the kind of harsh chemotherapy that had devastated his sister before
her death three years earlier from pancreatic cancer.
He decided to enter a clinical trial for a new drug designed to trigger the
immune system to fight cancer. The results were better than anyone expected.
"Everything has shrunk," said the 62-year-old contractor from Wolcott,
Connecticut, who still goes for treatment every two weeks and has regular scans
to keep tabs on his progress. "Some of the tumours you can't even see."
Just a few years ago, nobody believed it was possible to harness the immune
system to respond to cancer, but drugs like nivolumab, the experimental
Bristol-Myers drug Tartaglia receives, are showing promise, even in some
patients who have never tried any other treatments.
The drugs will be a main focus of this year's American Society of Clinical
Oncology five-day meeting in Chicago beginning on May 31. Much of the attention
will be trained on agents that disable a protein called programmed death 1, or
PD-1, that enables tumours to evade the immune system.
In addition to nivolumab, experimental drugs in the class include Merck's
lambrolizumab and Roche's MPDL3280A, which work by blocking a partner protein
known as PD-L1 (the L is for ligand). PD-L1 in turn works within cancer cells to
shut down the immune response.
Analysts and investors will be parsing the ASCO data for clues to the market
potential for the drugs, which are expected to generate billions of dollars in
annual sales. Nivolumab alone is forecast to have sales of $1.2 billion in 2017,
according to Wall Street analysts tracked by Thomson Reuters Pharma.
'I get to come home and eat'
Part of the excitement comes from a Phase 1 study last year of nivolumab,
which showed lasting response rates among 20% to 30% of a group of patients with
multiple cancers, including lung cancer, a leading cause of cancer death that so
far has shown limited response to immune system therapies.
The trials are still in the early stages. Researchers are working to
understand why most patients do not respond and are exploring combining
immunotherapies with other treatments.
Aside from the nuisance of frequent blood draws, Tartaglia has had few
complaints. "The best part is, I get to come home and eat. I'm all set. Other
people are throwing up," he said of patients at Yale Cancer Center in New Haven
who are still getting conventional chemotherapy.
Normally, experimental cancer drugs are only used in patients who fail other
treatments, said Dr Scott Gettinger, Tartaglia's doctor and an associate
professor of medical oncology at the center.
"Now we are starting to use immunotherapy drugs as first-line treatments I
know what first-line chemotherapy can do for lung cancer, and it's not
Patients with non-small-cell lung cancer, the most common form of lung
cancer, who are treated with the current standard of care - chemo and Roche's
Avastin - have a median survival of about a year, Gettinger said, noting that
some of his patients have been on nivolumab for more than three years.
"We haven't really realised the potential of this therapy," he said. "As we
learn how to use this drug, we are going to see higher response rates."
Another of Gettinger's patients, 68-year-old Bruce Leonard, tried
chemotherapy, but his lung cancer returned after two years, prompting a decision
to enter the nivolumab study. "I felt at the time that by just doing chemo
again, at best I would see the same result," the retired commodity buyer
"About two months after I started (the trial), there was a 30 percent
improvement and it has gotten progressively better, to the point that with my
last scan they found absolutely nothing."
Many patients do not respond to the treatments, but for those who do, the
responses have been extraordinary; some patients have lived for years. Yervoy,
Bristol-Myers' breakthrough melanoma treatment, only benefits about 10% to 15%
of patients. Newer agents, such as nivolumab, have shown response rates ranging
from 20% to 40%.
A small study released earlier this month looking at a combination of the two
drugs showed 53% of patients had their tumours shrink by at least half after 12
weeks. In 18% of patients on the dual therapy, tumours were no longer
Bristol-Myers has three late-stage clinical trials of nivolumab in melanoma,
two late-stage trials in lung cancer and one in kidney cancer.
Last November, interim results from an early-phase trial of Merck's
lambrolizumab in patients with advanced melanoma showed that it shrank tumours
in 51% of patients after 12 weeks, compared with a typical response rate of
about 5 percent for similar patients given conventional treatment.
Merck plans to present an update of this study on June 2 at the ASCO meeting.
The company also is studying its anti-PD-1 drug in so-called triple-negative
breast cancer, a hard-to-treat form of the disease, as well as head and neck
cancer, bladder cancer and lung cancer.
Last month, lambrolizumab won designation from the US Food and Drug
Administration as a breakthrough therapy, which could speed its approval.
"It's clear now that these medicines do have activity across a broader
spectrum of tumours, and they seem to be remarkably potent in very challenging
clinical oncology settings," said Dr Gary Gilliland, a senior vice president who
heads the oncology franchise at Merck Research Labs.
In April, Roche reported results of a small safety study of its anti-PD-L1
drug MPDL3280A that showed anti-tumour activity against a variety of cancers
including lung, kidney, colon and gastric cancers. Roche plans to start a Phase
III study in lung-cancer patients.
The findings are driving enthusiasm for immunotherapies.
"It tells us these are poised to be the most important agents in oncology,"
said Dr Antoni Ribas of the University of California Los Angeles' Jonsson
Comprehensive Cancer Center.
Citigroup research analyst Andrew Baum expects immunotherapies to form the
backbone of treatments for up to 60%of cancers over the next decade, up from
less than 3% today, transforming the treatment of cancer from a desperate
struggle with death into a chronic disease, in which treatments keep patients
alive for years. Baum estimates that would generate annual sales of $35
"The current explosion in all ongoing approaches to utilise the immune system
to seek and destroy cancer cells marks a watershed, analogous to the impact of
HIV drugs transforming life expectancy in (patients infected with) HIV," Baum
said in a recent note to investors.
Years, not months
Doctors have been trying for decades to get the immune system to fight cancer
with limited, sporadic success. But the disease has developed wily defenses that
camouflage tumour cells.
"The tide really turned in 2010 with the first presentation of pivotal data
about ipilimumab," said Dr Jedd Wolchok of Memorial Sloan Kettering Cancer
Center of the drug now sold as Yervoy.
In 2011 ipilimumab became the first immunotherapy drug to help extend the
lives of patients with advanced melanoma.
"We're very pleased that Yervoy prolongs survival in one out of five
individuals, but there is still room for growth," said Michael Giordano, senior
vice president of global development for oncology and immunology at
"Our goal here is to have very long-term durable responses. We're not just
trying to increase the patient's disease-free survival for a few months," said
Nils Lonberg, senior vice president of discovery biologics at Bristol-Myers.
Lonberg envisions a day when immunotherapy will be as important a tool for
oncologists as surgery, radiation and chemotherapy.
Wolchok says the promise for immunotherapies is treatment responses that
last. "The immune system is a dynamic organ. It remembers things," he said.