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In relapsed or refractory follicular lymphoma, treatment with the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (axi-cel, Yescarta) was associated with better outcomes compared with currently available therapies, a comparative analysis of the ZUMA-5 and SCHOLAR-5 trials suggested.

Overall response rate (ORR) was higher, and both progression-free survival (PFS) and overall survival (OS) were longer in ZUMA-5, reported John Gribben, MD, DSc, of the Christie NHS Foundation Trust and University of Manchester in England, during a presentation at the virtual European Hematology Association congress.

In particular, Gribben observed that the substantial OS benefit seen with axi-cel "represents a significant improvement in treatment options for patients with relapsed/refractory follicular lymphoma."

While median OS was not reached with axi-cel in ZUMA-5 (as compared to 59.8 months in SCHOLAR-5), the 18-month OS rates in the trials were 88.3% and 67.1%, respectively (HR 0.42, 95% CI 0.21-0.83).

ZUMA-5 is an ongoing phase II, single-arm, open-label, multicenter trial evaluating 146 adult patients with indolent non-Hodgkin lymphomas, including follicular lymphoma, who received at least two prior lines of systemic therapy, including a combination of an anti-CD20 monoclonal antibody and an alkylating agent.

SCHOLAR-5 is an international external control cohort that was generated to provide comparative evidence in relapsed/refractory follicular lymphoma. This analysis included patients from seven institutions in five countries who had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 and had initiated a third- or later-line therapy after July 2014. Treatments in later lines of therapy included combinations of anti-CD20 monoclonal antibodies with bendamustine, fludarabine-based regimens, and CHOP-like chemotherapies; EZH2 inhibitors; PI3K inhibitor-based regimens; and immunomodulatory drug-based regimens. SCHOLAR-5 also included a group of patients with follicular lymphoma treated with idelalisib (Zydelig) from the .

ORRs were 94.2% in ZUMA-5 compared with 49.9% in SCHOLAR-5, while complete response rates were 79.1% and 29.9%, respectively.

"Experimental treatment options were commonly used in these centers in late-line follicular lymphoma treatment, and that is not at all surprising," Gribben pointed out.

Median PFS and OS were not reached with axi-cel in ZUMA-5, versus 12.7 and 59.8 months, respectively, with currently available treatments in SCHOLAR-5 (HR 0.30, 95% CI 0.18-0.49).

"What was very clear to us is that the treatment of follicular lymphoma is extremely heterogeneous in real-world clinical practice," Gribben said. "And this highlights the true lack of a uniform treatment option in this group of patients, making it also difficult to imagine what would have been the best comparator arm if the ZUMA-5 trial had been a randomized trial."

Since this analysis was potentially prone to bias and possibly difficult to interpret due to the cross-study nature of the comparison, the researchers compared follow-up data from 86 patients in ZUMA-5 (median 23.3 months) against a weighted sample of 85 patients in SCHOLAR-5 (median 26.2 months), balanced for patient characteristics through propensity scoring.

"Clearly, we believe these data strongly support the fact that there is an overall survival advantage for this very novel treatment in follicular lymphoma, but, of course, this requires verification in other types of prospective studies," Gribben said.

When asked about the prospect of a randomized trial, he pointed out that it would have been impossible in the setting of ZUMA-5, considering that the treatments available for follicular lymphoma in third or later lines meant "you're getting down to single numbers of patients being treated with individual treatments."

"We'll have to wait until we're able to advance this therapy to be considered in earlier lines of therapy for this particular disease group," he added. "But, even in the second-line setting, it's quite difficult to see exactly what the ideal comparator would be."

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