Yescarta in the Real-World Setting: How Did the Results Compare With ZUMA-1 Outcomes?

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Inferior patient outcomes from treatment with axi-cel were linked to poor performance status and increased tumor bulk in patients.
Inferior patient outcomes from treatment with axi-cel were linked to poor performance status and increased tumor bulk in patients.
The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.

SAN DIEGO — A multicenter, retrospective study of Yescarta, also known as axicabtagene ciloleucel or axi-cel, revealed that the real-life response rates of the CD19 chimeric antigen receptor T-cell (CAR-T) therapy in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (r/r B-cell NHL) were somewhat consistent with those that were calculated in the ZUMA-1 trial when investigators were testing the medication in a controlled manner.

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“Results support the use of axi-cel outside of strict clinical trial criteria, although the outcomes may be slightly inferior,” the research group reported during a presentation at the 2018 American Society of Hematology (ASH) Annual Meeting, in San Diego, California.

Presenter Caron Jacobson, MD, department of medical oncology, Dana Faber Cancer Institute, Boston, Massachusetts, noted that the rates of cytokine release syndrome (CRS) and neurotoxicity (NT) linked to the real-life use of axi-cel were on par with the rates observed in the ZUMA-1 trial.

The numbers for overall response rate (ORR) and complete response (CR) in real-life settings, though, were not as high as principal investigators reported in ZUMA-1. ORR and CR rate in ZUMA-1 were 82% and 54%, respectively, but in the current trial of 95 evaluable patients conducted between December 2017 and October 2018 across 6 academic medical centers, the best rates (at 5.6 months median follow-up) were 71% and 44%, respectively, and by intention-to-treat analysis (108 individuals), the ORR was actually closer to 62%. The real-word results compared “favorably” to ZUMA-1, according to the research group.

In the real-world analysis, the median progression-free survival rates for patients with complete responses and partial responses have not been reached; median overall survival for all patients has not yet been reached.

At 6-month follow-up, 43% of patients had a complete response; this was because 50% of patients with “an initial partial response for whom there is longer follow-up went on to have a complete response,” Dr Jacobson noted. The other 50% of this group went on to have progressive disease.

Notably, 13 patients (11%) who were apheresed were ultimately not treated, which the investigators explained was because of 6 cases of progressive disease, 2 infections, and 3 instances (3%) where there where manufacturing issues: patients had nonconforming cells or the product was out of specification. One patient was not treated because of another malignancy, and another participant had a complete response to bridging.

A univariate analysis for response showed that there was no correlation between patient response to axi-cel with International Prognostic Index, cell of origin, double/triple hit cytogenetics, prior lines of therapy, bridging therapy, eligibility for ZUMA-1, high-grade CRS or neurotoxicity, or tocilizumab or steroid use. However, inferior patient outcomes were linked to poor performance status and increased tumor bulk.

The median time to onset of serious reactions was 5 days. Thirty percent of patients in the real world ended up in the intensive care unit after infusion of axi-cel, and neurotoxicity of any grade was seen in 76% of patients. Of those who experienced neurotoxicity, 39% saw a reaction of grade 3 or higher. The nonrelapse mortality rate was 7%, and the causes were CRS, neurotoxicity, infection, and cardiac issues.

Low day zero c-reactive protein (CRP) levels and high ALC at apheresis were also determined to be predictors of response to axi-cel, and low day zero CRP and low peak ferritin were “highly predictive” of patient groups with “significantly superior survival,” said Dr Jacobson.

What's more, said the researchers, was that time of progression biopsies unveiled potential resistance mechanisms that could be at play in this study. The abstract prior to the presentation had suggested potential reasons for resistance, and included the loss of target antigen or an inhibitory tumor/tumor microenvironment as potential explanations for this phenomenon. When an audience member asked if there was any correlation with resistance and lack of CAR-T cell tumor infiltration — another potential reason the researchers had suggested in the initial abstract, but said during the presentation that one resistance mechanism was still unknown — Dr Jacobson replied, “We haven't formally analyzed enough patients to say that … we are actively compiling patients and going through our samples to be able to answer those questions in the future.”

Disclosure: The investigators disclosed various ties to pharmaceutical companies in this abstract. For a full list of disclosures, please refer to the original abstract.

Read more of Cancer Therapy Advisor's coverage of the ASH 2018 meeting by visiting the conference page.

Reference

  1. Jacobson CA, Hunter B, Armand P, et al. Axicabtagene ciloleucel in the real world: outcomes and predictors of response, resistance, and toxicity. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 92.

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