New cancer drugs face unusual problem

With the arrival of two revolutionary treatment strategies, immunotherapy and personalised medicine, cancer researchers have found new hope — and a problem that is perhaps unprecedented in medical research.

There are too many experimental cancer drugs in too many clinical trials, and not enough patients to test them on. The logjam is caused partly by companies hoping to rush profitable new cancer drugs to market, and partly by the nature of these therapies, which can be spectacularly effective but only in select patients.

In July, an expert panel of the Food and Drug Administration approved a ground-breaking new leukemia treatment, a type of immunotherapy. Companies are scrambling to develop other drugs based on using the immune system itself to attack cancers.

Many of these experimental candidates in trials are quite similar. Yet each drug company wants to have its own proprietary version, seeing a potential windfall if it receives FDA approval. As a result, there are more than 1,000 immunotherapy trials underway, and the number keeps growing. “It’s hard to imagine we can support more than 1,000 studies,” said Dr Daniel Chen, a vice president at Genentech, a biotechnology company.

In a commentary in the journal Nature, he and Ira Mellman, also a vice president at the company, wrote that the proliferating trials “have outstripped our progress in understanding the basic underlying science.”

“I think there is a lot of exuberant rush to market,” said Dr Peter Bach, director of the Centre for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Centre. “And we are squandering our most precious resource — patients.” Take melanoma: there are more than 85,000 cases a year in the United States, according to Dr Norman Sharpless, who was recently named director of the National Cancer Institute.

Most melanomas are cured by surgery, leaving about 10,000 patients who have had relapses and could be candidates for an experimental treatment. But nearly all will be treated by doctors outside of academic medical centres, who are not part of the clinical trials network and so do not offer patients experimental treatments.

Companies therefore must compete for the few patients with relapsed melanoma who are at centres offering clinical trials. Many end up struggling to find enough subjects to determine whether a treatment actually works — and if so, for whom. And these drugs often are not so different from one another. Immunotherapy drugs that attack a protein known as PD-1 are approved for treatment of lung cancer, renal cell cancer, bladder cancer and Hodgkin’s disease, noted Dr Richard Pazdur, director of the FDA’s Oncology Centre of Excellence.

Yet many pharmaceutical companies want their own anti-PD-1. Companies are hoping to combine immunotherapy drugs with other cancer drugs for added effect, and many do not want to have to rely on a competitor’s anti-PD-1 drug along with their own secondary drugs.

So, in new trials, additional anti-PD-1 drugs are being tested all over again against the same cancers — a me-too business strategy taken to multibillion-dollar extremes.

If the struggle to find patients for immunotherapy trials is challenging, finding patients for another new type of cancer treatment can be next to impossible. These are drugs that attack mutations that tumours need to grow and thrive — targeted therapies. The idea is that tumours can be reliant on certain gene mutations. Block those mutations and the tumours will die.

The problem is that the mutations can be extraordinarily rare. Most patients who have cancers with the mutation in question have no idea; to find them, large groups of cancer patients must have their tumours genetically tested. That’s expensive: Genetic sequencing costs about $5,000, and insurers rarely pay. Most cancer patients treated outside of academic centres do not have their tumours sequenced.

So, what to do if you’re a company with a drug that seems to be dramatically effective, but only in a few patients? You may be forced to undertake a worldwide search for subjects that can last for years.

To test a two-drug combination against lung cancer, GlaxoSmithKline searched the United States, Japan, South Korea and Europe for 13 months just to find 59 patients whose tumours shared a rare mutation. It took Pfizer three years to locate 50 lung cancer patients who carried a rare aberration called ROS1, found in just 1% of patients.

Clinical trials with patient searches like these are “not for the faint of heart,” said Dr Mace Rothenberg, a vice president at Pfizer. It helps that the FDA has not insisted on large trials with control groups in instances of targeted therapies with few who qualify. Instead, the agency is looking for drugs with effects so powerful there is no question that they work — studies in which patients went into remission, for example, when all evidence suggested they would die.

Rare mutations

To test a drug that attacks a tumour with a mutation found in just 1% of cancer patients, researchers at Memorial Sloan Kettering fanned out to the non-academic medical centres where the majority of patients are treated, offering to pay for most of the cost of genetic testing.

That is how Bruce Fenstermacher, 67, a retired long-distance truck driver who lives in Allentown, Pennsylvania, discovered he had the rare mutation that the drug’s manufacturer, Loxo Oncology, had been looking for.

He had been receiving immunotherapy for his melanoma, but it had stopped working and his cancer was spreading again. Discovering that mutation was like hitting the jackpot for Fenstermacher, said Dr Suresh Nair, an oncologist in private practice in Lehigh Valley, Pennsylvania.

The experimental drug seems to be working for Fenstermacher. But since so few patients have tumours that might respond, oncologists wonder how they will find them. Is it worth it? Is it even possible? “If I had a family member with cancer, I would insist on this type of testing,” said Dr David Hyman, chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Centre. “But I don’t know what the rate has to be for society to say, ‘We can’t afford to miss these people.’”

And trials involving limited numbers of patients can be perilous. The smaller the study and the shorter its duration, the more likely that what looks like an effect in a trial might simply be a result of chance. “That leaves some of us evidence geeks wondering if it works,” Bach of Memorial Sloan Kettering said.

Some new cancer drugs have had such impressive results that their effectiveness was not in doubt, said Dr Vinay Prasad, an oncologist at Oregon Health and Sciences University. But, there also were drugs approved without control groups that did not provide such stunning benefits, and others that slowed the growth of tumours but did not extend life.

In tiny studies, serious side-effects can be missed, said Dr Scott Ramsey, an oncologist at the Fred Hutchinson Cancer Research Centre. He worries about the expense of the new drugs, including out-of-pocket costs to patients. They may want the new cancer drugs reaching the market, he said, “but you wonder if you are doing them any favours.”