CAR-T Cell Therapy in the FDA Spotlight.
FDA mandated boxed warnings for CAR-T cell therapies, this followed a 28 November 2023 communication that FDA was “Investigating Serious Risk of T-cell Malignancy Following BCMA-Directed or CD19-Directed Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies,” and a July — September 2023 Potential Signals of Serious Risks/New Safety Information Identified by the FDA Adverse Event Reporting System (FAERS).
On Friday 15 March 2024, FDA convened an Oncologic Drugs Advisory Committee panel and turned the spotlight on CAR-T cell therapy to review applications for two CAR-T therapies: Bristol Myers Squibb’s Abecma and Johnson & Johnson’s Carvykti. FDA prepared two documents, one on Carvykti and another on Abecma.
We can all agree that CAR-T cell therapy heralded a revolutionary approach in the battle against blood cancers with the first generation in 1993 and 2nd generation in 2002 (prostate cancer cells) and 2003 (leukemia, where CD-19 was shown as an effective target). With a unanimous thumbs-up, experts on the Committee seem to be rallying behind the expansion of this game-changing treatment, despite the whispers of concern regarding the risk of T cell malignancies, including CAR-positive lymphoma, among patients who received BCMA- or CD19-directed CAR-T cell immunotherapies. To be clear, the whispers are based on about 22 of so cases or 1/10 of 1% of total treated patients. In some cases, the onset was soon enough after the administration, suggesting a causal relationship.
There are now six FDA-approved versions of CAR T-cell therapy for different indications across leukemia, lymphoma, and myeloma. Having worked on Kymriah in 2010 at Penn and before the Novartis collaboration the same year, I have seen the changing regulatory landscape as FDA became more familiar with the treatment modality. This ODAC was one day after the FDA granted accelerated approval to Breyanzi — another CAR-T cell therapy made by Bristol-Myers Squibb for treatment of adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma who have received at least two prior lines of therapy, including a Bruton tyrosine kinase inhibitor (BTKi) and a B-cell lymphoma 2 inhibitor (BCL2i).
Enter Carvykti, a powerhouse collaboration between Johnson & Johnson and Legend Biotech, capturing the panel’s confidence with a solid 11–0 vote. The panel was convinced that for patients grappling with multiple myeloma after their initial treatments, Carvykti’s promise outweighs its risks. Not far behind, Abecma — birthed from the partnership of Bristol Myers Squibb and 2seventy Bio — garnered an 8–3 nod for patients who’ve marched through at least two prior therapies. As it stands, these therapies are the knights in shining armor for patients who’ve danced with four or more treatments.
The clinical trial stage painted a vivid picture: both drugs cast a shadow over standard therapy by significantly halting disease progression. Yet, a closer look revealed a concerning trend — early on, a higher tally of deaths in the CAR-T cell camps due to myeloma or its side effects compared to those on standard care. A red flag? Yes, but one that the panel believes is overshadowed by CAR-T cell therapy’s potential to offer patients a break from the relentless battle against cancer, with just a single dose.
Dr. Jorge Nieva, a panelist and oncologist, likened this to a “front-loaded risk,” a concept not alien to medicine. The key, he suggests, is in ensuring patients are fully briefed on what they’re signing up for.
Digging deeper, Carvykti’s trial spotlight shone bright, boasting a 59% reduction in the risk of disease progression or death over standard treatments. Abecma wasn’t far behind, offering patients a median of 13.4 months without disease progression, a significant leap from the 4.4 months seen with standard care.
As we edge closer to the FDA’s decision deadline for Carvykti on April 5, the anticipation is palpable. And while Bristol Myers plays its cards close to its chest regarding Abecma’s PDUFA action date, the potential for a wider embrace of CAR-T therapy looms large.
Imagine, for a moment, the impact. CAR-T isn’t just another treatment; it’s a beacon of hope for those caught in the relentless cycle of therapy after therapy. Yelak Biru, a voice for the multiple myeloma community, captured it best: this isn’t just about approval; it’s about offering a new lease on life.
The magic of CAR-T lies in its personal touch — tailoring treatment by reengineering a patient’s own immune cells to target and obliterate cancer cells. This process, though intricate, offers a glimmer of hope in what often feels like a dark tunnel for many.
Yet, it’s not without its hurdles. The patient treatment journey, spanning about a month, has its critical moments, particularly the bridging therapy intended to keep the disease at bay. This phase has been under scrutiny, as it could be the Achilles’ heel contributing to the early patient deaths observed in the trials.
With a price tag hovering between $370,000 — $530,000 for autologous treatments, the stakes are high. But the transformative potential of CAR-T cell therapy — especially if introduced earlier in the treatment crusade — could redefine the cancer care landscape. The question now is whether regulators and the medical community are ready to take this leap, broadening the horizon for CAR-T cell therapy from a last resort to a frontline beacon of hope.
