Promising New Cancer Drugs Empower the Body’s Own Defense System
By ANDREW POLLACK
Published: June 3, 2013
CHICAGO — The early success of a new class of cancer drugs, revealed in test results released here over the last several days, has raised hope among the world’s top cancer specialists that they may be on the verge of an important milestone in the fight against the disease.
Scott Morgan/ASCO
“If you look five years out, most of this meeting will be about immunotherapy,” said Dr. Mario Sznol.
Scott Morgan/Asco
“We’re so used to failure, we get excited very easily,” said Dr. Kim Margolin, a melanoma expert.
The excitement has spread to Wall Street. Shares of Merck and Bristol-Myers Squibb, which are developing such drugs, rose more than 3 percent on Monday after data from their studies was presented over the weekend at the meeting of the American Society of Clinical Oncology.
The drugs, still generally in early testing, work in an entirely new way, by unleashing the immune system to attack cancer cells much as it attacks bacteria. That could be an alternative to often-debilitating chemotherapy.
Finding ways to use the body’s own defenses has been a goal since the late 1800s, when a New York surgeon named William B. Coley noticed that cancer disappeared in a patient who had a severe bacterial infection.
He then began injecting bacteria into cancer patients to rev up their immune systems. His claims of success were disputed and most attempts since then to harness the immune system have not worked.
The new drugs work by disabling a brake on the immune system called the programmed death 1 receptor, or PD-1. And although the data presented at the meeting was from the earliest stage of testing only, the drugs were the center of attention here, with some doctors predicting that cancer treatment was about to shift.
“If you look five years out, most of this meeting will be about immunotherapy,” said Dr. Mario Sznol, a professor of medical oncology at Yale.
Analysts, who predict billions of dollars in sales, are trying to determine which of the three front-runners — Merck, Bristol-Myers and Roche — have the best drug and how soon the drugs could reach the market. Some think it could be as early as a year and a half from now.
“I think all of you recognize this is a very special moment in oncology,” Dr. Roger M. Perlmutter, head of research and development at Merck, told analysts Sunday at a standing-room-only meeting.
Harnessing the immune system is appealing for several reasons. It might be applicable to many different types of cancer. It might produce longer lasting remissions than can be achieved by chemotherapy or the newer targeted drugs. And it seems somehow more natural and holistic.
“It seems the right thing to do to stimulate our body’s defense rather than take some kind of poison,” said Therese Bocklage, a cancer patient and pathologist from Albuquerque.
Dr. Bocklage thought she had bruised her leg moving a Christmas tree in late 2011. It turned out to be the return of the melanoma she thought had been successfully eradicated by surgery 20 years earlier.
She has been taking Merck’s experimental PD-1 inhibitor, lambrolizumab, as part of a clinical trial since January 2012, and her tumors have disappeared. “If I had had this turn up not last year but six years ago, most likely I’d be dead,” she said.
But there are reasons to be cautious. This is cancer, after all. Many other hoped-for miracles have failed to materialize. This is a conference that has hailed drugs that extend lives by only a few weeks as breakthroughs.
“We’re so used to failure, we get excited very easily,” said Dr. Kim Margolin, an expert on melanoma and immune therapies at the Seattle Cancer Care Alliance.
Most of what is known about the PD-1 drugs is that they shrink tumors significantly in 15 to 50 percent of patients. It is still not clearly established, though there are some hints, that the drugs will let people live longer.
And results seen in trials, under idealized conditions, do not translate perfectly to the real world. One poster presented here looked at use in Britain of Yervoy, a melanoma drug approved in 2011 that disables a different immune system brake. Median survival has been only about half of what was seen in clinical trials.
Moreover, just because the immune system is involved does not make something safe. Ask anyone with lupus, multiple sclerosis or other diseases caused by an aberrant immune system.
Yervoy, made by Bristol-Myers, has some serious side effects caused by overstimulation of the immune system. The newer PD-1 drugs seem remarkably well tolerated so far, though lung inflammation is seen in some patients.
For the last decade or so, the emphasis in oncology has been so-called targeted therapy, in which drugs counteract particular genetic mutations that drive tumor growth. These were supposed to displace conventional chemotherapy, which tends to poison fast-growing cells, both cancerous and healthy ones, causing serious side effects.
Targeted therapy has had some great successes, particularly the leukemia drug Gleevec. But cancer cells, which tend to mutate rapidly, can develop resistance to the targeted therapies. And it is becoming more difficult to develop drugs for each narrow population of patients with a particular tumor mutation.
The PD-1 drugs are in a sense a return to a one-size-fits-all approach. And it might be harder for the tumor to become resistant to the immune system, which can adapt, than to a single drug.
In fact, what most excited researchers here this weekend was “the tail.” When researchers plot on a graph how many patients remain alive over time, the curves tend to drop to near zero for metastatic cancer. A successful drug slows the rate of decline, but eventually almost all patients die from the cancer.
But with Yervoy and, experts hope, with the PD-1 drugs, there appears to be fraction of patients who do not die of the disease, at least for a long time. The curve levels out in a plateau.
Dr. Sznol said that of five patients treated at Yale with the Bristol-Myers PD-1 blocker, nivolumab, two had no evidence of recurrence even two years after stopping the drug.
Over all, 133 melanoma patients at various clinics took nivolumab in the Phase 1 trial. Median survival was 16.8 months, with 62 percent of patients alive at one year and 43 percent alive after two years. There was no comparison group in the study, but with the existing melanoma drugs, about 24 to 33 percent of patients are alive after two years, Dr. Sznol said.
So if the immune system is so effective, why doesn’t it cure cancer on its own? One reason is that cancerous cells are the body’s own cells, though mutated, and might not be recognized by the immune system as foreign. Another is that the tumors act to suppress the immune system.
Much of the previous attempts at cancer immunotherapy have focused on the first problem — trying to train the immune system to recognize the tumor and attack it.
The PD-1 drugs tackle the second problem of immune system suppression. How many cancers this will work for is still unclear. Much of the early work has been in melanoma, which is known to be more susceptible than many other tumors to immune system attack. There are cases, though rare, in which the immune system vanquishes melanoma on its own.
What is encouraging doctors is that the drugs can shrink some lung cancer tumors, which have not been considered particularly susceptible to immune attack. There are sporadic reports of cases with other cancers as well, like colorectal cancer.
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