As the growing wave of excitement over immunotherapies has swept through the cancer field, a concern has followed in its wake: Are there now too many clinical trials for these novel treatments, which enlist the immune system to battle tumors? One recent tally found more than 1100 studies combining a popular new class called checkpoint inhibitor drugs, which unleash suppressed immune cells, with other treatments. That’s up from about 100 trials testing these combos through 2014.
Some academic researchers, pharma executives, and other cancer experts have decried this explosion of trials as a counter-productive glut motivated more by the race for money than by good science. They worry that many of these efforts may not finish because of a lack of participants. Even if these trials do meet enrollment targets, many duplicate other trials and are diverting resources that could go to novel drugs, Richard Pazdur, director of the U.S. Food and Drug Administration’s (FDA’s) Oncology Center of Excellence in Silver Spring, Maryland, has warned.
“The trials have to be smarter,” says Yale University lung cancer researcher Roy Herbst.
One influential patient advocacy group, although eager to see preclinical research translated into treatments, is also concerned about the skyrocketing number of combination trials. “It’s very exciting to have options, but we’re somewhat worried that it will take too long to find these patients and get answers,” says Ellen Sigal, chairperson of Friends of Cancer Research in Washington, D.C.
Some cancer researchers, however, think the competition is healthy—and the best studies and combos will prevail. “It’s not surprising to me that there are more and more trials,” says David Feltquate, head of oncology early clinical development at Bristol-Myers Squibb (BMS) in Princeton, New Jersey, which markets two checkpoint inhibitor drugs and is developing others. “We are in what I would call the golden age of oncology drug development.” Antoni Ribas, a melanoma immunotherapy researcher at the University of California, Los Angeles, also sees no reason to worry. “I basically disagree with the common notion that we have too many trials open.”
In a trial at MD Anderson Cancer Center in Houston, Texas, bladder cancer patient David Wight received two immunotherapy drugs known as checkpoint inhibitors.
Checkpoint inhibitors, which block cell-surface proteins that enable a cancer to hide from the immune system’s T cells, have become big business thanks to the impressive medical outcomes they sometimes produce. In patients with metastatic disease, the drugs have wiped out tumors for years. Since 2011, six checkpoint inhibitors have been approved for melanoma, lung cancer, and some other cancers—all targeting a protein called CTLA-4 or PD-1 on immune cells or PD-1’s binding partner, PD-L1, on cancer cells. But only about 20% of patients overall respond to these drugs, and the race is on to learn whether combining them with other treatments can push that figure higher.
That excitement and the commercial potential of checkpoint inhibitors—a year’s course of the approved PD-1 inhibitors sold by Merck and BMS costs about $150,000—explains the unprecedented growth in trials. At least 1105 combination studies are now testing drugs targeting PD-1 or PD-L1, according to the Cancer Research Institute (CRI), a nonprofit in New York City, which reported its findings online in December 2017 in the Annals of Oncology. That is out of a larger universe of 3042 active trials testing immunotherapy treatments. The PD-1/PD-L1 inhibitor combination trials alone started in the past 3 years are seeking more than 138,000 patients, including 52,539 for trials launched in 2017.
Feltquate says BMS, which has about 225 trials underway globally with its two approved checkpoint inhibitors, has not noticed a lag in patient recruitment. “If anything, enrollment is actually faster than we had seen historically.”
Indeed, it’s hard to find checkpoint inhibitor trials that have been stymied by competition, partly because the U.S. database ClinicalTrials.gov doesn’t include patient accrual data. But by examining a database of National Cancer Institute (NCI)-sponsored trials, which posts enrollment data, Science identified a few examples of trials that may be having trouble recruiting subjects within the planned time frame. (NCI-funded trials sometimes struggle more than company-led efforts because the firms pay more to participating institutions per patient and can recruit patients globally.)
Yet the principal investigators of those trials often expressed no concerns about patient accrual when contacted. Jonathan Schoenfeld of the Dana-Farber Cancer Institute in Boston, for example, says his trial of a checkpoint inhibitor–radiation combo for lung cancer initially attracted few patients because of competing trials, but is picking up steam.
One leader of an NCI trial at a major cancer center did attribute slow enrollment to competition, but asked that the trial details not be identified because its funding is coming up for renewal. The trial combines a drug that targets a specific flaw in the cells of some cancer patients with a checkpoint inhibitor. The investigators will extensively analyze tumor biopsies to see whether the added drug helps T cells recognize cancer cells.
But 16 months after the trial was launched, only eight people have enrolled, far fewer than the four per month projected. Elad Sharon, a senior investigator with NCI’s Cancer Therapy Evaluation Program in Bethesda, Maryland, which oversees the trial, blames other studies seeking the same small pool of patients with the rare cancer type targeted. “It’s a little frustrating. A better designed trial is getting crowded out by less well-designed trials,” Sharon says. NCI plans to make changes to boost enrollment and finish the trial, he adds.
In the worst case, lagging enrollment might force investigators to cancel a trial, says Richard Schilsky, chief medical officer of the American Society of Clinical Oncology in Alexandria, Virginia. “If the trials don’t complete, there really is a rift of the ethical obligation that we have with patients who are willing to participate as research subjects,” he says.
The rush to test combination therapies may also have taken a toll on rigor. As a cost-saving measure, many trials don’t contain control, or comparator, arms, Schoenfeld notes. Others are launched despite a lack of a hypothesis or animal data providing a mechanistic rationale, says Ira Mellman, Genentech’s vice president for cancer immunology in San Francisco, California. “Many seem to be tried simply because they are possible to do or the agents are available,” he says.
Even those who lament the proliferation of trials note that taming it won’t be easy. FDA has no authority to rein in immunotherapy trials as long as they pass certain standards. “Everybody does the study they want to do as long as they can get it funded and get it through the system … there’s no oversight,” Schilsky says.
As a first step, some are calling for better coordination. Groups like CRI, the Parker Institute for Cancer Immunotherapy set up by tech billionaire Sean Parker, NCI, Friends of Cancer Research, and FDA are encouraging companies to share their drugs as part of multicenter, innovative clinical trial designs that have several treatment arms and a single control group. “We cannot do one-off [single site] trials anymore. It will take too long and will ravage the patient population,” Sigal says.
And the NCI-managed cancer moonshot started by former Vice President Joe Biden has launched a 5-year effort in which academics and 11 companies are working together to find biomarkers revealing why some patients respond better to immunotherapies than others do. “There’s no doubt we could focus more if people got together in a precompetitive way,” Herbst says. “It is happening. We just need more of it.”