It isn’t often that a single company has an advisory committee meeting for one product and an FDA decision for another in the same week. Even more unusual is when the two drugs are of the same therapeutic class.

That’s what’s happening this week for Bristol Myers Squibb, though, as the regulator approved the company’s CAR-T treatment, Breyanzi, late on Thursday for chronic lymphocytic leukemia and small lymphocytic leukemia ahead of Friday’s meeting about Abecma, another CAR-T therapy, which will be discussed alongside Johnson & Johnson’s Carvykti for use as earlier lines of treatment in multiple myeloma.

With Thursday’s announcement, Breyanzi, a CD19-directed CAR T cell therapy, is approved for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who have already received treatment with a Bruton tyrosine kinase inhibitor (BTKi) and B cell lymphoma 2 inhibitor (BCL2i).

BTKi and BCL2i therapies are the most common and most effective treatment options for CLL, said David Porter, director of Cell Therapy and Transplantation at Penn Medicine’s Abramson Cancer Center. “When patients have failed both of those, the prognosis is terrible,” he told BioSpace. “They have truly very few effective treatment options at that point. This will offer one of the best, most potent, effective options for patients who have failed the more conventional therapy.”

But the outcome for Abecma may not be so positive, according to briefing documents released earlier this week. Specifically, the FDA raised concerns about the “higher rate of early deaths” in the clinical trials of both Abecma and Carvykti.


A ‘Manageable’ Safety Profile

In TRANSCEND CLL 004, Breyanzi showed a “manageable safety profile,” according to BMS. “I think that’s probably good wording,” Porter said. “CAR T cells do have potentially life-threatening toxicity. They have to be managed by caregivers with expertise in managing CAR T cells.”

For CLL and SLL, the FDA attached a boxed warning for cytokine release syndrome, neurologic toxicities and secondary hematological malignancies. The first two risks have occurred with Breyanzi specifically, while the third pertains to BCMA- and CD19-directed CAR-T therapies, including Breyanzi.

It’s those risks and others that the FDA is evaluating carefully when it comes to this class of therapies. In November, the regulator launched an investigation into the “serious risk” of secondary malignancies, leading to a boxed warning added to all six commercial CAR-T therapies at the time.

Rosanna Ricafort, vice president and head of late development hematology and cell therapy, noted that the field has come a long way in terms of toxicity management guidelines “and an understanding of how to manage CAR T-associated toxicities that are well characterized.”

Porter said that when considering CAR-T therapy, there must be a “very favorable” risk-benefit profile. “Patients with new diagnosis, early diagnosis, patients who may have low-risk disease, don’t necessarily need CAR T cells with its own set of toxicities.” However, he said that for patients with high-risk disease who are unlikely to have long-term benefit from standard therapies, “there’s a lot of logic to consider moving up into earlier lines of treatment,” as BMS and J&J seek to do with Abecma and Carvykti, respectively.

Ricafort agreed. “Multiple myeloma is a disease that is marked by multiple relapses and remissions,” she said. “When you have a transformational therapy, such as a CAR-T cell therapy that’s able to deliver a depth and durability of response, we know that employing those treatments earlier in treatment course will improve outcomes for patients.”


CAR-T Options Continue to Expand

Despite the FDA’s actions over the past several months, oncologists say the therapeutic class can be lifesaving, and analysts are confident the future of the CAR-T market is bright. And with Thursday’s approval of Breyanzi in CLL and SLL, the FDA is clearly open to expanding CAR T therapy into more oncology indications.

In the pivotal TRANSCEND 004 trial, 18.4% of patients with CLL or SLL followed for 21.1 months saw a complete response (CR) to treatment with Breyanzi, and an overall response rate (ORR) of 42.9%, BMS reported in May 2023. On Thursday, the company released updated results from the trial, showing that Breyanzi elicited a CR rate of 20% and an overall response rate (ORR) of 45%, with responses lasting more than 35 months.

Porter said that when the initial CR was first reported, he was disappointed. “It’s lower than I would have anticipated. It’s lower than we’ve seen in clinical trials that we’ve done here at Penn,” he noted. “That said, it certainly is better than the alternatives.”

Ricafort emphasized the significance of even the 20% CR rate. “With current available therapies, complete responses are basically unheard of in this patient population, with relapsed/refractory CLL,” she told BioSpace.

Porter further suggested that the CR rate might be an “underestimate of the activity of the cells.” There are very strict criteria to score a complete response in CLL, he explained. In several clinical trials, he said, patients have had “significant improvements,” but the lymph nodes may not shrink down to a level that meets this CR criteria.

Next up for Breyanzi, BMS hopes to bring the therapy to market for patients with relapsed or refractory follicular lymphoma and relapsed or refractory mantle cell lymphoma who have been treated with a BTKi therapy. The company has a PDUFA date of May 23, 2024 and May 31, 2024, respectfully.

“Cell therapies are a significant focus of our research,” Ricafort said. “This is a big year for Breyanzi for label extensions as we strive to deliver this transformative cell therapy to more patients.”

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