ASCO: BMS pitches Breyanzi as the first CAR-T for CLL. But will a single-arm trial persuade the FDA?

CAR-T therapies have been around for six years, but it was only in January that Bristol Myers Squibb unveiled the first positive readout for such a personalized immunotherapy in chronic lymphocytic leukemia (CLL), the most common form of leukemia, from a pivotal multicenter study.

In new data released Thursday, Bristol Myers Squibb said that Breyanzi eradicated signs of cancer in 18.4% of patients with heavily pretreated CLL or small lymphocytic lymphoma (SLL). The phase 1/2 trial coded TRANSCEND CLL 004 has therefore met its primary endpoint.

Among those who achieved a complete response, the median duration of response wasn’t reached after a median follow-up of 21.1 months. No patients in that group experienced disease progression or deaths by the data cutoff.

The results will be presented during the 2023 American Society of Clinical Oncology annual meeting on June 6. Bristol released the findings ahead of the meeting Thursday.

Breyanzi’s complete response data “are remarkable and represent a major step in bringing personalized, T-cell-based treatment approach delivered as a one-time infusion into clinical practice for a complex and historically incurable disease,” Tanya Siddiqi, M.D., lead investigator of the study and a lymphoma expert at City of Hope, said in a statement.

In a statement to Fierce Pharma, a BMS spokesperson said the company is completing a full evaluation of the data and look forward to discussing them with regulators. But how the FDA will perceive the results remains a question.

Breyanzi reached the 18.3% complete response rate in a group of patients who have tried a median five prior lines of therapy. Among that group, each patient failed on a BTK inhibitor such as AbbVie and Johnson & Johnson’s Imbruvica, plus AbbVie and Roche’s BCL2 inhibitor Venclexta. As BMS noted, existing treatments rarely provide complete, durable responses for these patients.

In a larger trial population, including patients who may not have tried Venclexta, Breyanzi registered the same 18.3% complete response rate.

But Breyanzi’s primary efficacy data came from just 49 patients. What’s more, the med’s overall response rate, at 42.9%, wasn’t statistically significant. Among the responders, the median duration of response was 35.3 months.

Noah Berkowitz, M.D., Ph.D., senior VP of hematology development at BMS, argued that compared with overall response, the rate of complete responses is more important. Gaining durable complete responses can allow doctors to “begin to start thinking about whether patients are really cured or not,” he said in an interview with Fierce Pharma.

The FDA’s recent crackdown on single-arm trials could pose another concern for Breyanzi’s regulatory pathway in CLL. As FDA’s oncology chief Richard Pazdur, M.D., has said at various occasions in the past year or so, single-arm trials can sometimes send misleading signals because they lack a comparator to help benchmark an experimental drug’s efficacy and safety.

The FDA has granted approvals to cancer therapies based on tumor shrinkage data from single-arm trials before, including for CAR-T therapies. After one such study, Breyanzi got its initial approval in third-line large B-cell lymphoma in 2021 based on a 73% response rate, including 53% of complete responses, derived from 256 patients.

But compared to those applications, Breyanzi’s current CLL data set is small and its magnitude of benefit is much less impressive.

On the flip side, according to Berkowitz, no drug can currently deliver a complete response in these patients. So, an 18.3% complete response rate—albeit coming from a small, single-arm study—might suffice for accelerated approval in a patient population that has run out of treatment options.

In a statement to Fierce Pharma, the BMS spokesperson noted that these heavily pretreated CLL/SLL patients have no standard of care, and that the T cell dysfunction in CLL/SLL has historically make it difficult to develop a T cell-based therapy.

In pretreated CLL, Breyanzi could end up facing competition from Eli Lilly’s oral, reversible BTK inhibitor Jaypirca. In the phase 1/2 BRUIN trial, Jaypirca induced a 79% overall response rate in 100 CLL/SLL patients who have failed a median five prior lines of therapy including both BTK inhibitor and BCL2 inhibitor. But the Lilly drug saw no complete responders.

Instead of filing for approval based on that phase 1/2 study, Lilly believes Jaypirca can vie for an approval in CLL/SLL based on a randomized phase 3 trial dubbed BRUIN CLL-321, a Lilly spokesperson told Fierce Pharma. That phase 3 study is testing Jaypirca against physician’s choice of combo therapies in patients who have failed on at least a BTK inhibitor.

Breyanzi is offering potentially a one-time treatment option for patients, and BMS has a “substantial study demonstrating outstanding benefit-risk” in patients with pretreated CLL, Berkowitz said. He suggested that there will be room for both CAR-T and oral therapies.

Editor's Corner: The story has been updated with additional comments from a BMS spokesperson.

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