For decades, the FDA has been offering accelerated approvals to open early access to new cancer drugs, but mostly for patients who’ve already tried several other regimens. FDA oncology chief Richard Pazdur, M.D., now plans to disrupt that longstanding practice with a new initiative.
Called “Project FrontRunner,” the new program will come online later this year, Pazdur, director of the FDA’s Oncology Center of Excellence, told Fierce Biotech in an interview. Although details are still in the works, the program’s theme is clear—to advance accelerated approval to earlier cancer treatment.
“We really want people to be looking at accelerated approval not in the most refractory populations,” Pazdur said, “but let’s move these drugs up to an earlier disease setting as their first approval in randomized studies.”
However, as Pazdur himself admitted, changing a well-established practice won’t be a cakewalk. Companies often rely on those later-line studies to gauge a drug’s potential, and those small trials offer a quick path to market to both help treat patients and give the drug a foothold against competitors, two industry experts said.
Accelerated nods saved for later
The accelerated approval pathway allows drugmakers to start selling medicines based on trials that show improvements in surrogate endpoints. In oncology’s case, those endpoints include tumor response rate and disease progression, rather than the gold standard of proof, which is a cancer drug’s ability to help people live longer. In many cases, this early data come from a single-arm trial without an active comparator.
No regulation dictates that accelerated approval must be saved for a drug in late-line treatment, Pazdur noted. In fact, the first new cancer drug approved under the accelerated pathway was for the chemotherapy docetaxel in advanced breast cancer just after anthracycline-based therapy. But that was 1996.
As more cancer drugs enter the market, though, late lines of treatment have been the fashion for accelerated approvals, and there’s a multipronged rationale for that practice.
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“It’s really a clinical regulatory perspective and tradition that, because oncology drugs are so toxic […] they are developed in the patients that have the biggest reward for [and] are most willing to take on toxicity,” said SVB Leerink analyst Daina Graybosch, Ph.D., who wasn’t commenting specifically on Pazdur’s proposal, but on oncology drug development steps.
Plus, later lines of therapy represent an urgent unmet need for patients who have exhausted all their other options, Mark Rutstein, M.D., vice president of Opdivo development at Bristol Myers Squibb, said in a separate interview about general oncology drug development strategies.
“Physicians, patients and regulators alike are often more willing to accept side effects in the later lines, where the alternatives are limited,” Rutstein said, echoing Graybosch.
“People want to take risks in oncology. I’ve been through this with family members and friends; it’s like ‘Doc, give it to me,’” Pazdur said.
But by Pazdur’s account, the regulatory component of that equation is shifting.
“It’s going to be harder and harder to define unmet medical needs as we have more and more therapies,” Pazdur said.
Delineating unmet needs is especially tricky in some diseases with long natural survival tails, such as indolent lymphomas or multiple myeloma, he noted, because patients often reuse some of the same therapies.
'Practical constraints' or a 'love affair'?
To Pazdur, the habit of starting with the most refractory patients has more to do with drugmakers’ “love affair” with single-arm trials. And dilly-dally with entrant into an earlier treatment line “may actually be doing harm to the field.”
Because many metastatic cancer patients don’t survive through all those therapies—and their deaths shrink the number of people eligible for later lines—a new drug for earlier treatment could benefit more people, Pazdur said. And an approval in earlier disease might obviate the need for that later-line indication because patients have already gotten the drug, he added.
The FDA oncology chief picked on Incyte’s PD-1 inhibitor retifanlimab, which lost its shot for an accelerated approval in previously treated squamous cell carcinoma of the anal canal. That application was based on tumor shrinkage data from a single-arm trial.
“There is no reason to do a phase 2 trial of 100 patients other than getting an approval by the FDA on accelerated approval,” Pazdur said of retifanlimab’s study. “After 30 patients [in a phase 1 trial], people should be moving to a randomized setting.”
By the time of the FDA rejection, Incyte was already running a phase 3 trial dubbed POD1UM-303 in chemo-naïve anal cancer patients. “Patients would have been served much better by having an earlier introduction of that PD-1 in an earlier disease setting, and that trial was postponed and delayed because of such an emphasis on this single-arm trial,” Pazdur said.
Drugmakers themselves often tout the benefits of using a therapy earlier in the treatment sequence to offer longer survival and potentially save lives. For example, BMS has pointed to a recent study showing that in patients with advanced BRAF-mutant metastatic melanoma, using the immunotherapy combination of Opdivo and Yervoy before Novartis’ targeted BRAF/MEK inhibitor cocktail of Tafinlar and Mekinist could help patients live longer than using the opposite treatment order.
Even when drugmakers start their medicines’ regulatory journeys in the late line, they almost always intend to move into earlier lines of treatment because of that larger patient pool and potentially longer durations of treatment. But cancer drug development often follows that “prolonged, stepwise” approach because there are “practical constraints” that prevent a rapid march into early lines as the regulatory steppingstone, BMS’ Rutstein said.
Compared with more advanced cancer, developing drugs in earlier settings comes with what Rutstein called a higher burden of proof, or as Graybosch put it, a less favorable balance of risk and cost.
In a late-line setting, a drug is often tested as a single agent, so the clinical trial sponsor doesn’t have to buy standard-of-care therapies. Buying those standard treatments is very costly because “nobody gives you a discount,” Graybosch said.
As both Rutstein and Graybosch pointed out, patients who are on treatment soon after diagnosis have longer life expectancies than those who’ve gone through cycle after cycle of treatment. That means a clinical trial must enroll more early-cancer participants to get a clear statistical signal on some “harder endpoints” like overall survival—and drugmakers likely will have to wait longer for the numbers to prove their candidates help people live longer.
“These later lines give you a faster, cheaper signal that then makes you more willing to spend a lot for longer […] and decide ‘should I combine this on top of standard care or is this so great I should just go head-to-head versus standard care?’” Graybosch said.
In later lines, “the ability to answer a question and to vet out whether or not we’re going to have an active drug and be able to help patients, we can get that answer sooner,” Rutstein said.
And time is crucial in drug development, especially when a competitor is in sight. A first mover is likely to enjoy a market share advantage and gain a strong foothold by getting physicians and patients familiar with its drug.
Moreover, for a drug that doesn’t have a novel biomarker to define a new patient population, accelerated approval has in reality been requiring that the drug find a niche where no other therapy has secured full approval, Graybosch explained.
Pushing for randomized trials
It remains to be seen what regulatory sweetener “Project FrontRunner” will offer, but Pazdur’s office appears open to disrupting the status quo by allowing accelerated approval based on an early signal as long as it’s from a randomized study. Such a move might help mitigate that concern over the development timeline.
Pazdur raised the example of HIV drugs, for which accelerated approval was originally designed. An HIV drug may first look at viral load at 24 weeks to earn a quick nod and then to confirm the benefit at 48 weeks.
“That they have the randomized study going in the same disease makes a lot of sense,” Pazdur said, “and that could be done in a much earlier phase of the disease [in cancer].”
“We’re really emphasizing the need to do randomized studies,” Pazdur said.
Recruiting patients shouldn’t be much of a problem, either, Pazdur said. From a patient perspective, a drug would already have some early clinical data before entering a randomized clinical trial. Besides, in earlier treatment settings, these new agents are often explored as add-ons to standard therapy. Most people are more than willing to do an add-on trial of a new drug plus conventional therapy because they realize they could get a chance to get something better, Pazdur argued.
“People want to take risks in oncology,” Pazdur said, pointing to his past experience as a practicing oncologist. “I’ve been through this with family members and friends; it’s like ‘Doc, give it to me.’”
Some drugs are already targeting earlier treatment with their initial registrational studies. Just a few days ago, BMS got a full FDA approval for its LAG-3 antibody relatlimab alongside its PD-1 drug Opdivo in a new, fixed-dose combo branded as Opdualag. For that drug’s pivotal study, a phase 2/3 dubbed Relativity-047, BMS went straight to previously untreated metastatic or unresectable melanoma.
Roche is exploring a similar strategy for its anti-TIGIT candidate tiragolumab in combination with PD-L1 inhibitor Tecentriq. In the phase 2 Cityscape trial, the immuno-oncology combo showed promise in chemotherapy-naïve patients with non-small cell lung cancer whose tumors have high expression of PD-L1. And Roche is targeting a front-line nod with the ongoing phase 3 Skyscraper-01 study.
Roche went front line first because the TIGIT mechanism doesn’t seem to work as single agents, Graybosch said. And if a randomized trial of a combination therapy is the way forward anyway, it might as well go directly to the front line. BMS developed Opdualag in the front line because of results from earlier studies, a company spokesperson said.
“Unfortunately, in oncology, we don’t have too many drugs that show themselves to have such a very strong benefit-risk profile early on that can trigger rapid entry into earlier lines,” Rutstein said.
Pazdur acknowledged that pushing for a paradigm shift would be an uphill fight, “however, if we don’t bring it forward, it won’t be done.”
Editor's Note: The story has been updated with additional comments from BMS.