Immunotherapy Clinical Tests Spur Hope, and Plenty of Headaches

Xconomy National — 

Thanks to remarkable results in a small group of patients, including former U.S. President Jimmy Carter, cancer immunotherapy has spurred talk of once impossible-to-imagine cures and has gained its share, perhaps more than its share, of hype.

But immunotherapy is also creating new challenges and exacerbating old ones for doctors, patients, and researchers. These new treatments, which recruit patients’ own immune systems to the fight against tumor cells, are forcing re-assessments of the standards used to gauge a patient’s condition, and complicating clinical trial designs.

Doctors and researchers around the country are worried that patients who want access to a treatment that’s in the headlines will sign up for a clinical trial but drop out if they are assigned to the control group—which usually receives a form of chemotherapy that, until something better is proven out, remains the standard of care.

Trials for cancer drugs are more often “open label” than trials for other kinds of drugs, meaning that volunteers know whether they’re receiving the experimental drug or the control treatment. Blinding many studies is futile, say clinicians. Savvy patients who have done their homework know the telltale side effects of various drugs, and experimental immunotherapies are administered differently than standard chemotherapies.

“A number of patients are sick and tired of chemo, so they’ll roll the dice, knowing they won’t stay on the study” if they are assigned to take chemo, says Andrew Ko, a gastrointestinal cancer specialist at the University of California, San Francisco. “They’re coming from far distances to do something experimental. Patients enter trials with preconceived biases, and I can understand it.”

Ko has seen the problem firsthand. He had patients take part in a pancreatic cancer trial, dubbed ECLIPSE, which compared two kinds of experimental immunotherapy from the Berkeley, CA-based Aduro Biotech (NASDAQ: ADRO) against chemotherapy. Aduro reported in May that more dropouts than expected scuttled the trial. Aduro CEO Steve Isaacs says the design—assigning about a third of the patients to one of several chemotherapy options—was an FDA requirement. “We didn’t have much choice,” he says.

Some doctors aren’t just sympathetic to patients. They actively encourage patients to leave a trial if they don’t get the cutting-edge cancer drug. “I only put patients on trials that may help them, and sometimes the only access to a specific drug is through a trial,” says oncologist Steve Perkins, who sees patients with a wide variety of cancers in Dallas, TX. “I tell them the control arm won’t help you, so if you get randomized to a control arm, drop out and try something else.”

It doesn’t happen often—about once a year, says Perkins—but his practice, staffed by seven oncologists and not affiliated with a large research center, only places about 20 patients in trials per year.

Because so many of the immunotherapy trials currently underway are testing drugs, called “checkpoint inhibitors,” that work in a similiar fashion—a concern that the FDA’s top cancer regulator Richard Pazdur voiced earlier this year—patients in some locations can shop around.

Mary Tagliaferri, vice president of clinical development at Nektar Therapeutics (NASDAQ: NKTR) in San Francisco, agrees with Pazdur. She says companies have an obligation to develop a wider variety of immunotherapy agents—as Nektar is doing—“just as patients and doctors are beholden to ethically complete clinical trials and adhere to what they’ve consented to.”

Perkins has a different view. “My only obligation is to the patient, not to the trial,” he says.

(As part of the Obama administration’s “cancer moonshot” initiative, a panel of experts is weighing in today with recommendations for changes in cancer research and treatment. One recommendation is for a clinical trial network dedicated to immunotherapy.)

Dropouts are not a new problem for clinical trials. But the problem could be starker with some immunotherapies because the gap between their performance and that of the old standard of care is extraordinary for some patients, and others don’t want to be denied the chance at a similar result. “People are coming to get those new drugs, which could be lifesaving even in a Phase 1 setting,” says Scott Lippman, director of the Moores Cancer Center at UC San Diego.

Just how often are patients dropping out of immunotherapy trials after being assigned to the control group? No hard data have emerged yet, but a top cancer statistician says to watch for data from ongoing or recently completed studies of approved drugs like nivolumab (Opdivo) or pembrolizumab (Keytruda) in new types of cancer, or in new combinations. (Pembrolizumab is the drug that knocked out President Carter’s melanoma; the FDA has also approved it for certain lung and head-and-neck cancers.)

“Now that these agents are approved, it might be harder to get people to stay” in trials if they don’t get the immunotherapy, says Brad Hirsch, who at Duke University studied cancer clinical trials with Rob Califf, now the FDA commissioner. Hirsch practices medicine in the same Dallas group as Steve Perkins, and he is also senior medical director at Flatiron Health, a cancer data analysis firm in New York City.

Hirsch speculates that the dropout problem could abate as more trials start to compare one immunotherapy to another, instead of an immunotherapy to chemotherapy. But until then, one way to assuage some patients when faced with a randomized trial is more flexibility within the trial itself—perhaps letting patients cross over from the control arm to the experimental immunotherapy arm when the control is clearly having no effect. But crossover trials are much harder to design if the main outcome being measured is how long a drug can extend people’s lives—which is often the case when testing drugs to treat aggressive cancers, like pancreatic or brain tumors.

Crossover trials can work better when measuring a different outcome, the length of time a drug holds a tumor in check (or shrinks it), called progression-free survival. “There are challenges to that, too, but we have to have smarter trial design,” says Paul Sabbatini, a gynecological cancer specialist at Memorial Sloan Kettering Cancer Center in New York who also helps steer the center’s clinical standards and practice.

One of those challenges, for clinical trials and regular medical practice, is a direct product of the new immunotherapy drugs. They can create an effect called “pseudo-progression” or “tumor flare”—meaning the immune boost from the drug makes the tumor, measured with scans, look bigger—as if it were growing unchecked. “There’s discomfort watching something grow and wondering if it will respond to the treatment,” says Sabbatini. He notes that doctors have to be confident not only that the treatment will kick in, but that patients will be strong enough to stay on what might be a longer course of therapy before it takes effect.

The old standard for measuring tumor progression, known by the acronym RECIST, is “archaic,” says Perkins. New standards to measure the immune system’s effectiveness in fighting cancer are necessary.

For these two clinical immunotherapy problems—patients dropping out of trials and the need to rethink the measurement of tumor response—there is, generally speaking, one solution: Better diagnostics.

Doctors nervously watching a tumor expand after immunotherapy would feel a lot more confident, Sabbatini says, if the treatment was reserved for patients identified ahead of time as highly likely to respond, perhaps because of an underlying genetic mutation. Pembrolizumab and others like it seem to work better in patients whose tumors carry a high amount of the protein PD-L1 on their surfaces, for instance, but it’s not that simple. Even among “high-expression” patients those drugs don’t work all the time.

As more is understood about the intricate dance between tumor cells, the immune system, and other factors, researchers hope to create diagnostics to better predict which of the available therapies stand the best chance of fighting each individual patient’s cancer.

Researchers and doctors would also like to use diagnostics to make big, randomized trials less necessary. New experimental drugs would need to be tested for safety, of course. But if those drugs are well designed to match the complicated profiles of a subset of patients, could those Phase 1 tests provide enough evidence of a drug’s efficacy without having to do larger comparisons to older treatments, like chemotherapy? “I think we’re moving to a place where you’re looking for great effects in Phase 1b, or Phase 2 nonrandomized trials,” says Gary Gilliland, president and director of the Fred Hutchinson Cancer Research Center in Seattle, who oversaw development of pembrolizumab while a top oncology executive at Merck (NYSE: MRK).

What about drugs that don’t show big early “signals” that they are head and shoulders above the standard of care? Will drug developers want to keep spending R&D dollars on them? If a drug needs to be compared in a randomized trial to a standard treatment, is it likely only to show an incremental benefit? Will insurers want to pay for it? Will doctors want to prescribe it, or patients want to take it?

“We have more drugs and combinations than we can possibly test,” says Gilliland. “It’s OK to leave some stuff on the shelf.” He argues that choosing patients more wisely for trials, combined with more sophisticated statistical analysis, will allow everyone in the field to make decisions based on smaller trial sizes.

If the current “gold standard” is to compare two types of cancer treatment in a randomized trial, perhaps a future gold standard would be to compare a new treatment to the historic performance of the standard of care. Pembrolizumab was first approved—to treat advanced metastatic melanoma that other drugs had failed to halt—without an active control arm. (The 173 patients were randomized to either a low dose or a high dose of pembrolizumab.) The large Phase 1b trial showed enough of an advance over the historical record that the FDA gave the green light, upon condition that Merck follow up with a randomized trial that included the standard of therapy.

A world of new, powerful cancer drugs that, on early blush, seem remarkable and are conditionally approved without randomized testing makes some practitioners nervous. Once a drug is approved, says UCSD’s Scott Lippman, it’s difficult to reel it back, even with safety surveillance systems like the FDA Sentinel program.

“Traditional clinical trials aren’t going anywhere,” says Sabbatini of Memorial Sloan Kettering. “How many times have we done Phase 1 trials that look great, then in Phase 2 you get a 50 percent response, then in Phase 3 it’s a failure?”

New FDA commissioner Rob Califf has encouraged discussion about the use of real-world historical data to supplement clinical data, but keeping the “gold standard” of randomization in large, late-stage trials.

In June, he told the crowd at a conference on big data and healthcare that ultimately he’d like to see a mix of historical and up-to-the-minute clinical data in the evaluation of a drug or medical device. But he delivered that assessment with a generous dose of caution: “If we compromise safety in the interest of innovation it will set us all back.”