The six CAR-T therapeutics with U.S. approval have transformed blood cancer treatment, eliminating cancers in some patients or preventing recurrence. But the FDA is now requiring these therapies to include a black box warning on the label after 22 patients went on to develop secondary T-cell cancers.
The FDA sent letters out on Jan. 19 to Bristol Myers Squibb, Gilead Sciences’ Kite Pharma, Johnson & Johnson and Novartis, spelling out the changes companies will need to make following an investigation into cancers that occurred in patients treated with five of the six approved BCMA- and CD19-directed genetically modified autologous T cell immunotherapies. Post-marketing surveillance identified the cases, which represent a small portion of the 27,000 patients treated with FDA-approved CAR-T therapies — although it’s unclear if it flagged all cases.
All six treatments — Abecma, Breyanzi, Carvykti, Kymriah, Yescarta and Tecartus —will carry the warning. However, the FDA sent a revised letter to Kite for its therapy, Tecartus, removing the requirement to state that secondary cancers have occurred in patients who took the therapy because it hasn’t identified any cases. It’s unclear how or if the newly identified risk will affect the burgeoning CAR-T market, which is poised to expand beyond oncology and may generate $35.9 billion by 2032.
Drugmakers weigh next steps
Some of the companies affected by the FDA decision said they are now determining how to proceed.
“Bristol Myers Squibb has received the letters from the FDA and is evaluating next steps on the labels for Abecma and Breyanzi,” the company said in an emailed statement. “Bristol Myers Squibb has treated more than 5,000 patients with hematologic malignancies across clinical and commercial settings with Abecma and Breyanzi. To date, BMS has not observed any CAR-positive T-cell malignancy cases and therefore, we have not found a causal relationship between our products and secondary T cell malignancies.”
Even so, the company said it will continue to focus on patient safety.
“We remain confident in the safety profile and clinical value of our cell therapies and are committed to ongoing transparency with all stakeholders,” BMS said.
Johnson & Johnson officials said it’s clear the benefits of CAR-T, and its treatment, Carvykti, outweigh the risks.
“We remain focused on the clinical development of Carvykti in our commitment to improving outcomes for patients living with multiple myeloma, a disease where unmet needs continue to persist,” Johnson & Johnson officials said in an emailed statement. “While the FDA determined that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD-19 directed CAR-T therapies, it’s important to note that the agency did communicate that the overall benefits of these products continue to outweigh their potential risks.”
To date, more than 2,000 patients have been treated with Carvykti worldwide.
While the risk/benefit profile remains in favor of CAR-T products, it’s unclear how the safety warning will impact FDA reviews of expanded approvals for the therapies as earlier line treatments. Last June, J&J submitted a supplemental BLA seeking approval of Carvykti for patients who’ve received just one prior line of therapy rather than four. A decision on the application will be taken up by the FDA’s Oncologic Drugs Advisory Committee at a still undetermined date. BMS is similarly slated to face the same adcomm for its bid to expand the use of Abecma into earlier lines of care. For patients who have undergone CAR-T treatment, experts suggest ongoing monitoring to identify new cases.
“It is important for clinicians caring for people who have received CAR-T cells to report the occurrence of any new cancer,” states a NEJM perspective. “At this time, we recommend that patients and clinical trial participants who receive treatment with these products be monitored for new cancers throughout their lives, since — owing to the relatively recent widespread introduction of CAR-T products into clinical care — we don’t yet know how long after treatment people remain at risk for these adverse events.”