Mark your calendars, oncology drug and CAR-T therapy developers. The FDA has decided on a date for a highly anticipated advisory committee meeting to discuss applications for Bristol Myers Squibb’s Abecma and Johnson & Johnson’s Carvykti.

The FDA will convene its Oncologic Drugs Advisory Committee (ODAC) for a full-day meeting March 15 to review the applications for BMS and 2seventy bio’s Abecma and J&J and Legend Biotech’s Carvykti in earlier treatment of multiple myeloma, a government filing (PDF) shows.

External experts invited by the FDA will review clinical data from Carvykti’s CARTITUDE-4 trial and Abecma’s KarMMa-3 study. In both cases, overall survival data will be the focus of the discussions.

The meeting is expected to carry a lot of weight in the oncology community. For one, industry watchers are trying to take the FDA’s pulse around the benefit-risk profile of CAR-T cell therapies amid an investigation into a new safety signal of secondary T-cell cancers.

In an even broader implication, the gathering offers cancer drug developers a chance to understand the FDA’s view around the impact of control arm crossovers on final patient survival.

BMS first announced the FDA’s intention to hold an ODAC meeting for Abecma’s label expansion bid in November. According to Friday’s government filing, BMS is seeking an indication covering multiple myeloma patients who have received three different classes of drugs: an immunomodulatory agent such as BMS’ Revlimid; a proteasome inhibitor such as Takeda’s Velcade; and an anti-CD38 antibody such as J&J’s Darzalex. Typically, patients have used those classes of drugs in at least two prior lines of therapy.

That’s the patient population enrolled in Abecma’s KarMMa-3 study. In that trial, data shared in December confirmed a striking 51% reduction in the risk of progression or death for Abecma against traditional combination regimens. But when it came to overall survival, the analysis pointed to no benefit for Abecma, which was linked to a 1% increased risk of death.

To explain the lackluster survival showing, BMS and the trial investigator pointed to the fact that 56% of patients in the control arm received Abecma after relapsing on their originally assigned standard treatment. After adjusting for those crossovers, Abecma was associated with a 31% reduction in the risk of death.

During BMS’ fourth-quarter earnings call Friday, Chief Medical Officer Samit Hirawat, M.D., again noted the clear impact crossovers had on the survival benefit among control patients in KarMMa-3.

BMS remains confident in Abecma’s profile and looks forward to having that discussion with the FDA, Hirawat said.

As for Carvykti, the CARTITUDE-4 trial previously showed that the J&J/Legend CAR-T drug slashed the risk of disease progression or death by a whopping 74% compared with standard treatment in multiple myeloma patients who had tried one to three lines of therapy. When the data were shared in June, Carvykti conferred a preliminary 22% reduction in the risk of death.

It’s not clear whether the FDA has received updated data since then or whether agency reviewers have spotted any concerning survival signs with respect to Carvykti.

J&J looks forward to reviewing the updated overall survival and safety data with the FDA ODAC, J&J CEO Joaquin Duato said during the company’s fourth-quarter earnings call last week.

“Overall, we remain confident in two things: both the risk-benefit of Carvykti in the indication that it’s being studied, and at the same [time] on the potential of Caryvkti to be a $5 billion-plus asset at peak-year sales,” Duato said.

The FDA’s close attention to overall survival has been well documented in recent decisions where the agency either rejected drugs—or limited approvals—based on negative survival trends.

Still, as novel agents strive to move into earlier lines of treatment, the FDA is asking drug developers to incorporate crossover designs into their clinical trials, allowing control patients to receive the new drugs later. Such crossovers, especially when happening at high rates, could confound the final survival readouts, biopharma companies have argued.

In those cases, a drug is basically being evaluated as an earlier treatment against itself in a later-line setting, even though its trial isn’t designed to test that scenario.

The crossover problem has already affected Novartis. The Swiss pharma recently delayed an FDA filing for its prostate cancer radiotherapy Pluvicto because of a preliminary negative trend in overall survival that was caused by an 84% patient crossover rate.

“Overall, as an industry, we’ll learn more with some of the upcoming adcomms from other competitor medicines on how the FDA is thinking about OS crossover and how to manage this,” Novartis CEO Vas Narasimhan, M.D., said on the company’s fourth-quarter earnings call. “And I’m hopeful that overall patient benefit is what ultimately rules out over some of the pure statistical considerations given that we’re encouraged to utilize crossover in our studies to be patient-friendly.”

Source:
https://www.fiercepharma.com/pharma/fda-sets-date-high-profile-car-t-adcomm-bristols-abecma-jjs-carvykti
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