FDA "Project FrontRunner" - to advance accelerated approvalsFor 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. The program’s theme is clear—to advance accelerated approval to earlier cancer treatment. 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. 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-nave 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.
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.
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.
BMS and Roche went front line first because the LAG-3 and TIGIT mechanisms don’t seem to work as single agents.
And if a randomized trial of a combination therapy is the way forward anyway, it might as well go directly to the front line.
https://www.fiercebiotech.com/biotech/fda-oncology-chief-eyes-accelerated-approval-earlier-cancer-treatment-under-planned-project