CAR-T ‘definitively’ superior as second-line therapy for large B-cell lymphoma
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Key takeaways:
- Axi-cel conferred significantly longer OS than standard therapy.
- Investigators recommend a CAR-T-first approach for those who relapse within 1 year of initial therapy.
CHICAGO — Second-line therapy with axicabtagene ciloleucel conferred a significant increase in OS compared with the current standard of care among adults with relapsed or refractory large B-cell lymphoma, results of the randomized phase 3 ZUMA-7 study showed.
Treatment with the chimeric antigen receptor T-cell therapy reduced the risk for death by 27.4% compared with standard care, updated findings presented at ASCO Annual Meeting and published in The New England Journal of Medicine showed.
“This definitively establishes axi-cel as a superior treatment strategy among those who do not respond to first-line chemotherapy,” Jason Westin, MD, MS, director of lymphoma clinical research and section chief for aggressive lymphoma at The University of Texas MD Anderson Cancer Center, told Healio. “Axi-cel as a second-line treatment should be a standard approach.”
Background and methods
Axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead Sciences) — commonly called axi-cel — is an autologous, gene-edited, CD19-directed CAR-T.
FDA approved axi-cel last year as initial treatment for relapsed or refractory large B-cell lymphoma based on data from the ZUMA-7 trial.
ZUMA-7 examined the safety and efficacy of axi-cel vs. standard of care among 359 adults with relapsed or refractory large B-cell lymphoma at 77 centers worldwide. Standard of care consisted of a platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy and autologous hematopoietic stem cell transplantation for those who responded to chemoimmunotherapy.
Investigators randomly assigned patients 1:1 to preconditioning chemotherapy plus a single infusion of axi-cel (n = 180) or standard therapy (n = 179).
EFS served as the primary endpoint. Key secondary endpoints included objective response rate and OS.
The ZUMA-7 investigators previously reported interim OS data at the time of the primary EFS analysis. At ASCO, researchers presented data from a prespecified primary OS analysis to be conducted after 210 deaths or no later than 5 years after random assignment of the first patient in the trial.
Median follow-up was 47.2 months, with a data cutoff date of Jan. 25 for the OS primary analysis.
Key findings
A primary analysis showed significantly longer median OS among patients treated with axi-cel than standard therapy (31 months vs. not yet reached; HR = 0.72; 95% CI, 0.54-0.97).
Notably, 57% of patients treated in the standard therapy arm received subsequent off-protocol treatment with cellular immunotherapy, Westin said.
Investigators reported superior median PFS among those treated with axi-cel compared with standard therapy (14.7 vs. 3.7 months; HR = 0.51; 95% CI, 0.38-0.67). Likewise, they noted a significantly higher estimated 4-year PFS rate for the axi-cel group (41.8% vs. 24.4%).
Treatment-related toxicities remained consistent with those previously reported in the ZUMA-7 trial, Westin said.
Cytokine release syndrome occurred among 92% of patients in the axi-cel group, with 6% of events being grade 3 or higher. Meanwhile, 80% of those in the standard care group developed cytopenia, with 75% being grade 3 or higher.
Clinical implications
The results thus far show axi-cel to be superior second-line therapy for large B-cell lymphoma across all subgroups in the trial, Westin said.
“The results signal the need for a paradigm shift,” he added. “Based on these data, the paradigm should no longer be a [chemotherapy]/transplant strategy but instead a CAR-T.”
The previous paradigm resulted in curative treatments for only approximately 10% of those who went on to receive HSCT as second-line therapy, Westin said.
Based on the current second-line indication for axi-cel, the new paradigm should be dictated by the time to relapse from initial therapy, Westin said. If that time is less than 1 year, he advised clinicians to pursue CAR-T provided their patient is eligible.
“This will increase the number of people who go on to receive definitive therapy, while also improving overall survival,” Westin told Healio.
References:
- Westin J, et al. Abstract LBA107. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
- Westin J, et al. N Engl J Med. 2023;doi:10.1056/NEJMoa2301665.
Perspective
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Saad Z. Usmani, MD, MBA, FACP
One of the things that has become clear after seeing the latest data from ZUMA-7 is the changing role of autologous stem cell transplantation as second-line therapy for patients who have progressed within 12 months of receiving induction therapy.
The primary analysis from ZUMA-7 already demonstrated superior PFS for axi-cel among adults with relapsed or refractory disease, including those who had less than 12 months of PFS benefit from their first-line treatment. This used to be the group of patients who would go on to receive an autologous HSCT.
Extremely encouraging PFS data showing a plateau in the survival curve among the axi-cel arm of ZUMA-7 has led to a change in clinical practice. There is now an increasing trend toward offering CAR T-cell therapies instead of auto-HSCT across transplant and cell therapy programs.
This latest ZUMA-7 analysis also demonstrates an encouraging OS benefit for axi-cel compared with standard of care. With a follow-up of approximately 4 years, there is a roughly 9% difference in 4-year OS between the two groups favoring axi-cel.
As a result of this OS data readout, few doubts should remain about the role of CAR-T in this setting. These results augment the clinical practice changes that many transplant and cellular therapy centers have adapted for patients with lymphoma.
Memorial Sloan Kettering Cancer Center
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Westin J, et al. Abstract LBA107. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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