The National Cancer Institute’s announcement Monday that it will soon begin a nationwide trial to test treatments based on the genetic mutations in patients’ tumors, rather than on where the tumors occur in the body, highlights a profound shift taking place in the development of cancer drugs.
Researchers increasingly are using DNA sequencing, which has become far faster and cheaper over time, to identify molecular abnormalities in cancers. That technology is allowing them to develop drugs they hope will prove more effective in specific sets of patients and to design clinical trials that get the most promising drugs to market more quickly.
“We are truly in a paradigm change,” James H. Doroshow, director of the division of cancer treatment and diagnosis at the NCI, said in announcing the initiative Monday. He called the project “the largest and most rigorous precision oncology trial that’s ever been attempted.”
Traditionally, drug trials have focused on cancers in specific organs, such as the lungs or prostate. But that model is being upended by newer approaches such as basket trials, which group together patients with similar genetic mutations, regardless of the location of their cancers.
Whether these new kinds of trials will prove more beneficial over time remains uncertain, but basket trials already have helped patients such as Bruce Maxwell, a 63-year-old Dublin man diagnosed with bladder cancer in 2012.
Maxwell underwent surgery and chemotherapy, but the disease returned. He had few treatment options left when, in early 2014, he flew to New York and enrolled in a basket trial at Memorial Sloan Kettering Cancer Center. The experimental drug he received had been designed to treat a certain type of breast cancer, but doctors began testing it in patients with other cancers, all of which had a particular genetic mutation.
Nearly 18 months later, Maxwell’s cancer has not advanced.
The NCI project announced Monday comes amid a push by the Obama administration to promote “precision medicine.” Beginning July 1, the institute will begin screening several thousand patients at 2,400 sites around the country, from large academic hospitals to community medical facilities. Those who meet certain criteria will be sorted into nearly two dozen treatment arms of 30 to 35 patients each, based on the genetic mutations of their cancers.
For example, a patient with a kidney tumor might be assigned to a group being treated with a drug traditionally used for a different form of cancer, as long as tests show the drug might work on the tumor’s particular makeup. Each group will receive a different drug provided by pharmaceutical companies that are part of the effort. Drugs may be added to or dropped from the research as the project continues in coming years.
“Certainly, this is where oncology is going,” said Barbara Conley, associate director of the institute’s cancer diagnosis program.
The effort is the latest in a series of trials that federal researchers and others have launched to match the right patients with the right therapies and to streamline regulatory approval. The American Society of Clinical Oncology, for instance, announced this week that it is starting a comparable project that will provide patients with drugs targeted at similar molecular abnormalities and collect the data from oncologists providing their care, to better understand the effectiveness of the treatments.
“The rules of engagement have changed,” said Jose Baselga, physician in chief at Sloan Kettering, which genetically sequences the tumors of every patient and has helped pioneer the use of basket trials.
On a weekday morning, the computer screen in Baselga’s office, high above the East River, offered a glimpse of the changing landscape of cancer trials in the United States. He called up images from one of the numerous basket studies at the hospital. The scans showed historically hard-to-fight tumors in the brain, lungs and other organs melting away in many, though not all, patients with specific genetic mutations. Seldom in the past have cancer drugs yielded such dramatic results.
“That’s the promise of precision medicine,” said Baselga, who worked on one of the first targeted cancer therapies, Herceptin, decades ago. “You [now] have the capability to identify what’s driving the particular tumor and then to devise methodologies that result in a better understanding of the disease and the development of better therapies. That’s where the optimism resides.”
Like Sloan Kettering, some other institutions routinely sequence the tumors of patients, looking for “actionable” mutations that might respond to existing drugs and using the data to create basket trials to test new targeted therapies.
For patients, the evolution means access to experimental drugs that, at least in theory, should prove more effective than previous generations of treatments. In addition, because the trials tend to involve smaller numbers of patients and move rapidly, the most promising drugs could reach the market years earlier than they otherwise might.
This transformation would matter little without the support of the Food and Drug Administration. But the FDA in recent years has embraced an array of novel trial designs and shown a willingness to approve drugs rapidly if they show unmistakable benefits in early trials.
“We’re seeing better drugs, with increased activity of the drug very much from the get-go,” Richard Pazdur, director of the FDA’s Office of Oncology Drug Products, said in an interview. “We have a better understanding of the diseases and also the molecular pathways of these drugs.”
That’s a notable departure from what Pazdur calls the “roulette wheel” model of drug development, in which researchers often try a new drug on various cancers and hope for the best. These days, some targeted drugs are showing response rates of 50 percent or higher in early trials — not nearly as high as researchers would like, but unheard of compared with many drugs in the past.
“You’re homing into a population that is going to have benefits, so the clinical trials are going to be different,” said Pazdur, whose office has sped approval of numerous “breakthrough” therapies in the past several years. “You [often] don’t need huge, randomized trials, because when the effect size is big, you can use a smaller sample size to demonstrate the difference.”
For all the optimism, Pazdur and other experts are wary of hyping the new trials or the novel drugs they are designed to test. Despite their historically high response rates, targeted drugs simply have not worked for many patients or their benefits have been short-lived. In other cases, patients’ tumors don’t contain mutations for which there are treatments.
Oncologist David Hyman has experienced both elation and exasperation while leading one of the current basket trials at Sloan Kettering. “There are failures; not everybody responds,” he said. “Even among patients who respond, the duration of that response is not as long as we would like.”
Still, when a patient does respond, the benefit can be remarkable. Hyman pointed to Maxwell’s case, saying he had “probably a couple months” to live when he started the basket trial in early 2014.
“It has completely arrested his cancer,” Hyman said. “This is a dramatic departure from how he would have done.”
On a recent morning in New York, Maxwell once again had crossed the Atlantic for his latest scan and to pick up another batch of pills for the trial. The images showed that his cancer remained at bay, and he sighed with relief.
Maxwell and his wife began planning a trip to mark their 35th wedding anniversary. He said he looked forward to more time babysitting his granddaughter, who recently turned 1. And he talked about being grateful for good timing, knowing that the trial he’s participating in might not have been possible much before now.
“I’m lucky in the sense I’m living in these times rather than five years ago or even three years ago,” Maxwell said. “I can only be thankful for it. Long may it last.”