Real-world CAR T-cell therapy as safe, effective as in clinical trial setting
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Axicabtagene ciloleucel administered as standard of care appeared as safe and effective as when given during the agent’s pivotal clinical trial, according to study results published in Journal of Clinical Oncology.
The retrospective study — conducted by the 17-member U.S. Lymphoma CAR T Consortium, comprised of institutions that provide cellular therapies — examined the use of the chimeric antigen receptor T-cell therapy axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead) among patients with relapsed or refractory large B-cell lymphoma.
“The issue with clinical trials is that they often are very highly selective,” Michael D. Jain, MD, PhD, assistant member in the department of blood and marrow transplant and cellular immunotherapy at Moffitt Cancer Center, told Healio.
When the consortium pooled its data, the subsequent analysis showed axicabtagene ciloleucel given as standard of care in a real-world setting induced similar responses to those seen in a clinical trial setting, Jain said.
“The number of patients in a durable remission tracked quite well with what the original clinical trial described,” he said. “The take-home message from this study is that patients who receive this therapy in a real-world setting will do just as well as patients who receive it in a clinical trial.”
The investigators retrospectively collected data from 17 participating U.S. centers on patients who underwent leukapheresis as of Sept. 30, 2018, for an axicabtagene ciloleucel infusion intended as standard-of-care therapy for relapsed or refractory large B-cell lymphoma.
Researchers assessed responses according to Lugano 2014 criteria, and they graded and managed toxicities per each member intuition’s guidelines.
The study included 298 patients (51.7% 60 years; 64% men); the majority (n = 275; 92%) received CAR T-cell therapy and were eligible for the safety and efficacy analyses.
Median follow-up was 12.9 months after CAR T-cell infusion.
Results showed 129 patients (43%) who received axicabtagene ciloleucel as standard-of-care therapy would have been ineligible for treatment using the criteria established in the agent’s pivotal ZUMA-1 trial.
The safety analysis showed grade 3 or greater cytokine release syndrome occurred in 7% of patients treated with axicabtagene ciloleucel, whereas 31% of patients experienced some form of neurotoxicity. The nonrelapse mortality rate was 4.4%.
The efficacy analysis showed an overall response rate of 82% (95% CI, 77-86) and complete response rate of 64% (95% CI, 58-69).
Researchers observed median PFS of 8.3 months (95% CI, 6-15.1). Median OS had not been reached.
Both univariate and multivariate analyses showed patients with poor ECOG performance status (2-4) and elevated lactate dehydrogenase levels before therapy achieved shorter PFS and OS.
The large portion of patients in the study who would not have met the ZUMA-1 clinical trial criteria shows that clinicians have far greater discretion in the standard-of-care setting, Jain said.
Although clinicians have more leeway outside the rigid restrictions of clinical trials, some payers will not provide coverage for the therapy unless patients adhere to the clinical trial criteria, Jain said.
“Our work is important because it shows that even those patients who don’t strictly adhere to clinical trial inclusion and exclusion criteria can still benefit from this therapy,” he told Healio. “Therefore, it’s not a good idea to base coverage on clinical trial criteria.”
The results should give referring physicians confidence about the treatment’s safety and efficacy when contemplating CAR T-cell therapy as a standard-of-care choice, Jain said.
“Because the U.S. was the first to approve CAR T-cell therapy, we have developed a vast amount of knowledge from our early experience with the treatment that can be informative as it expands across the country and around the world,” Jain said. “It gives clinicians more confidence to provide this treatment to patients outside the confines of a clinical trial.”
Perspective
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Lee Greenberger, PhD
The findings by Jain and colleagues are promising. The data suggest axicabtagene ciloleucel is safe and effective for a wide scope of patients with advanced-stage lymphomas, such as diffuse large B-cell lymphoma and other aggressive large-cell lymphomas. The OS of patients who received axicabtagene ciloleucel is impressive, suggesting that some will experience the benefit of long-term disease control. It also indicates the possibility of cures — although this won’t be known until the analysis is conducted for a longer period of time.
Not surprisingly, patients with poorer performance status had worse outcomes than those with better performance status, similar to what researchers observed in the ZUMA-1 registration trial. Performance status defines the level of the patient’s function in terms of self-care and daily activities such as walking. ZUMA-1 included only patients with an ECOG performance status of 0 or 1; in this analysis, 19% of patients had a status greater than 1 and would have been disqualified from ZUMA-1.
This analysis suggests eligibility criteria for future studies with axicabtagene ciloleucel, and possibly other CD19 CAR T-cell therapies, should be broadened. High-grade cytokine release syndrome and neurotoxicity continue to be serious toxicities with autologous CD19 CAR T-cell therapy among patients with large cell lymphoma, but they are transitory.
Leukemia & Lymphoma Society supported the initial development of axicabtagene ciloleucel through our Therapy Acceleration Program, and continues to make further investments in improvements in CAR-T.
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