Lisocabtagene maraleucel

New CAR-T treatments for cancer will need to prove that they’re better than existing therapies to win FDA approval, the agency’s biologics chief Vinay Prasad said in a journal article Monday, raising the bar on the data that will be required for the products. Prasad co-authored the article in JAMA with other top FDA officials in the Center for Biologics Evaluation and Research. Developers of new CAR-T treatments will need to take into account existing CAR-T therapies when developing a control group for trials, and generate evidence showing “superiority of the investigational CAR T-cell therapy compared with control.” There are seven CAR-T products approved for cancer on the market, all of which reached patients based on single-arm trials without a control group. Others are running single-arm trials for CAR-Ts in rare or late-line cancers to win full approvals. Going forward, that won’t be sufficient for full approvals, but may still be enough for accelerated approvals in cancers that lack options, the FDA officials said, who along with Prasad include CBER hematology branch chief Upendra Mahat, CBER’s Director of the Office of Clinical Evaluation Asha Das, and CBER Deputy Director Vijay Kumar. “The response rate supported by durability from a single-group trial will generally be considered for an accelerated approval,” the officials wrote. “Traditional approval will generally require evidence of effectiveness on a direct clinical end point such as overall survival from an RCT.” The change in standard could be a challenge for companies that have committed to single-arm trials, though it’s unclear whether this policy will apply to trials already underway or whether it will apply to future studies. Gilead and Arcellx, for instance, are developing an anti-BCMA CAR-T therapy for multiple myeloma. They said in June that their pivotal, single-arm trial showed their therapy had potentially better safety than Legend Biotech and Johnson & Johnson’s blockbuster CAR-T Carvykti, with comparable efficacy in multiple myeloma patients who have already tried three or more previous treatment regimens. But Carvykti has shown an overall survival benefit in patients who have attempted two or more therapies for multiple myeloma. Gilead and Arcellx can likely still win accelerated approval of their cell therapy based on the iMMagine-1 study, rather than the full approval the companies previously said they are seeking. In a June note predicting changes that may be brought by Prasad, Leerink analyst Daina Graybosch wrote, “Even if CBER decides to review iMMagine-1 for AA [accelerated approval], we are more confident anito-cel meets ‘meaningful advantage’ criteria.” However, Gilead and Arcellx’s randomized Phase 3 trial called iMMagine-3, which began last year, does not currently include CAR-T treatment in the control arm. Gilead and Arcellx didn’t immediately respond to a request for comment on the JAMA publication. Meanwhile, Lyell Immunopharma appears to be running a program that aligns with what the FDA officials outlined. Lyell is running a single-arm study of its large B-cell lymphoma cell therapy ronde-cel in third-line and later patients, and a head-to-head Phase 3 trial of ronde-cel versus Breyanzi and Yescarta in second line patients. “The onus is on sponsors to justify what aspect of the unmet need their product would address if approved,” the FDA officials wrote. That could include “either lack of available therapies or, when there are available therapies, based on improved effect on serious outcome of the condition, improved safety, or other clinically meaningful therapeutic advantage over available therapies.” They also offered the example of an off-the-shelf allogeneic CAR-T cell therapy that doesn’t have a manufacturing delay as potentially providing an advantage over approved autologous CAR T-cell therapies “by decreasing the risk of progression and obviating the need for bridging therapies.” The FDA has made other efforts to boost access to the therapies as in June they eliminated a safety monitoring program for all CAR-Ts. Editor’s note: This story was updated throughout with additional details.