Bristol Myers' Abecma wins FDA nod in earlier multiple myeloma with updated boxed warning on secondary cancer

After a short period of doubt, the FDA has followed the opinion of its advisers and moved Bristol Myers Squibb’s CAR-T therapy Abecma into the earlier treatment of multiple myeloma.

The BCMA-targeted CAR-T is now approved for multiple myeloma patients who have tried two or more prior lines of therapy, BMS announced Friday. The cell therapy was previously cleared as a fifth-line treatment.

In a positive development for the New Jersey pharma and its partner 2seventy bio, the new approval does not require that patients be refractory to three classes of drugs—namely an immunomodulatory agent such as BMS’ Revlimid, a proteasome inhibitor such as Takeda’s Velcade and an anti-CD38 antibody such as Johnson & Johnson’s Darzalex—only that they have tried those therapies. Those meds are typically used in combinations.

The triple class-exposed description is the same as the indication Abecma scored from the European Commission a few days ago.

Simultaneously with the label expansion, the FDA added an expected new item to Abecma’s boxed warning section, which states that “T cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T cell immunotherapies, including Abecma.”

The language of the boxed warning is nearly identical to what the FDA previously demanded for all marketed CAR-T therapies, except for one important difference. The Abecma version now spells out that the secondary cancer cases have emerged from treatment of “hematologic malignancies.” This differentiation could be viewed as a win for drug developers working on CAR-T therapies for autoimmune diseases and solid tumors.

Although the boxed warning effectively exonerates potential autoimmune disease candidates for now, there’s no guarantee that a cautious FDA wouldn’t still slap a similar boxed warning on any future CAR-T products—even if the approved indication falls outside of “hematologic malignancies,” or blood cancers. After all, the mechanism of action that triggered the FDA’s concern—the possibility of CAR integration into the genome—also theoretically exists for non-cancer patients.

The FDA green light for Abecma came late as the agency was originally expected to rule in mid-December.

Meanwhile, Johnson & Johnson and Legend Biotech’s rival CAR-T therapy Carvykti is awaiting an FDA decision today for an even earlier multiple myeloma treatment setting.

Both BCMA CAR-T therapies faced scrutiny during an FDA advisory committee meeting three weeks ago. The FDA was wrestling with the risk of early deaths observed in the two meds’ phase 3 trials. Patients on the CAR-Ts appeared to be more likely to die than traditional drug combinations in the first few months of their respective studies. However, the external experts backed both drugs, persuaded by their massive benefit in slowing tumor progression and, in Abecma’s case, no apparent detriment to patient survival after a longer-term follow-up.

However, the vote tallies showed that the committee members were more convinced by Carvykti than Abecma.

In the phase 3 KarMMa-3 trial, Abecma reduced the risk of disease progression by 51% versus standard combinations. Patients in the Abecma arm lived a median 13.3 months without disease progression, versus 4.4 months in the control group, according to data presented in December.

When it came to overall survival, Abecma showed a negligible 1% increased risk of death before adjusting for any patient crossovers. BMS and the trial’s investigators have attributed the lack of an overall survival showing to the 56% of patients in the control arm who later received Abecma following disease progression. After accounting for those crossovers, Abecma was linked to a 31% reduction in the risk of death.

By comparison, J&J and Legend’s Carvykti is gunning for an approval after a minimum of just one prior line of therapy, which if approved would be one line earlier than Abecma. At an interim analysis of the CARTITUDE-4 trial in that second-line-plus treatment setting, Carvytki showed a preliminary 43% reduction in the risk of death, which widened from the 22% in a previous analysis.

Thanks to Carvykti’s stellar efficacy data, analysts have argued that Abecma will have a hard time capturing market share in the later lines of treatment, especially when supply constraints are no longer a problem.

Also in the latest label update, the FDA cleared a wider recommended dose range for Abecma, allowing up to 510 x 106 CAR-positive T cells, compared with up to 460 x 106 in the original approval. The lower boundary remains the same at 300 x 106