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Too many experimental drugs, too many trials, too few patients

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 New York Times reports that 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.

The report says in July, an expert panel of the US Food and Drug Administration approved a groundbreaking new leukaemia treatment, a type of immunotherapy. And companies are scrambling to develop other drugs based on using the immune system itself to attack cancers.

But, the report says, many of these experimental candidates in trials are quite similar and 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. The report says in a commentary, 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 – a patients.”

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, the report says, 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, the report says.

“How many PD-1 antibodies does Planet Earth need?” wondered Dr Roy Baynes, a senior vice president at Merck, which received approval for its first such drug in 2014.

The report says immunotherapy trials have proliferated so quickly that major medical centres are declining to furnish patients to them. The Yale Cancer Centre participates in fewer than 10% of the immunotherapy trials it is asked to join. The problem is that many of the trials are uninteresting from a scientific view, said Dr Roy Herbst, the centre’s chief of medical oncology. The companies sponsoring these trials are not addressing new research questions, he said; they are trying to get proprietary drugs approved.

And, the report says, 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 – so-called targeted therapies. The idea is that tumors can be reliant on certain gene mutations. Block those mutations and the tumors will die.

The problem is that the mutations can be extraordinarily rare – the report says patients who have cancers with the mutation in question have no idea; to find them, large groups of cancer patients must have their tumors genetically tested.

That’s expensive: Genetic sequencing costs about $5,000, and insurers rarely pay. Most cancer patients treated outside of academic centers do not have their tumors 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?

Also, the report says, 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 US, Japan, South Korea and Europe for 13 months just to find 59 patients whose tumors 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 senior 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. “We used to have trials not long ago that had 700 patients per arm,” Sharpless said, referring to the treatment groups in a study. “That’s almost undoable now.” Today, “trials can be eight patients.”

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, Bach of Memorial Sloan Kettering said. “That leaves some of us evidence geeks wondering if it works,” he said.

Some of the 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 markedly slowed the growth of tumors 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 is quoted in the report as saying. 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 favors.”

Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is required. Immunity is influenced by a complex set of tumour, host and environmental factors that govern the strength and timing of the anticancer response. Clinical studies are beginning to define these factors as immune profiles that can predict responses to immunotherapy. In the context of the cancer-immunity cycle, such factors combine to represent the inherent immunological status — or 'cancer–immune set point' — of an individual.

Daniel S Chen, Ira Mellman

[link url=""]The New York Times report[/link]
[link url=""]Nature commentary[/link]

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