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Higher Efficacy, But Also More Toxicity of Axicabtagene Ciloleucel Compared to Tisagenlecleucel in Relapsed/Refractory DLBCL

Findings from an individual patient data based matched comparison of efficacy and safety between two commercial CAR T cell products
27 Sep 2022
Cancer Immunology and Immunotherapy;  Haematologic malignancies

Given the lack of an adequate comparison for efficacy and safety between tisagenlecleucel and axicabtagene ciloleucel, a group of researchers led by Dr. Emmanuel Bachy of the Hematology Department, Hospices Civils de Lyon in Lyon, France embarked on an individual patient data based matched comparison concerning all patients in France with diffuse large B cell lymphoma (DLBCL) treated with commercial chimeric antigen receptor (CAR) T cells and included in the DESCAR-T registry. Although only a randomised study could allow for an undisputable comparison between the two CAR T cell products, this matched comparison showed a higher efficacy, but also a higher toxicity of axicabtagene ciloleucel compared to tisagenlecleucel in third and further line of treatment for patients with relapsed/refractory DLBCL. The findings are published on 22 September 2022 in the Nature Medicine.

Since 2019, the French Health Authorities have required extensive data collection for each patient with a theoretical indication for CAR T cells treatment. Reimbursement is conditional on data comprehensive completion by the local investigator. The DESCAR-T registry has been set up by the Lymphoma Study Association and the Lymphoma Academic Research Organization to fulfil this regulatory request and to allow for comprehensive real-world evidence studies.

In the present study, 809 patients for whom a CAR T cells treatment order was obtained outside of a clinical trial setting for DLBCL in second or subsequent relapse were analyzed. All patients treated in France with axicabtagene ciloleucel or tisagenlecleucel from December 2019 to October 2021 and retrospectively included in the DESCAR-T registry were considered. Data export from the registry was set on 18 October 2021.

Tisagenlecleucel is a 4-1BB co-stimulatory domain-based second-generation CAR T, whereas axicabtagene ciloleucel is CD28 based. They have both demonstrated impressive clinical activity in relapsed/refractory DLBCL. Approvals were granted after the results of the JULIET and ZUMA-1 pivotal studies. The recent updated follow-up of ZUMA-1 after 5 years suggested that approximately 40% of patients might be cured with CAR T cells in this setting.

In the last 2 years, many publications based on real-life data from various countries worldwide have confirmed the high response rates, prolonged response duration and survival achieved with CAR T cells in DLBCL. Efficacy in the non-trial setting seems to parallel results obtained in pivotal studies, and toxicity appears significantly lower in real life.

The authors explained that many parameters can impact efficacy and safety of CAR T cells treatment, such as the use of a bridging therapy to control for disease progression during product manufacturing, the tumour bulk or the delay between leukapheresis and infusion. Therefore, the need for real-world evidence studies to apprehend this fast-moving field has never been so high.

Several matching-adjusted indirect comparisons have been attempted to compare different CAR T cell products. Matching-adjusted indirect comparison uses individual patient data from one study and trial-level data from another to form a population-adjusted indirect comparison between treatments. One of these recently reported matching-adjusted indirect comparisons suggests that axicabtagene ciloleucel is superior to tisagenlecleucel for disease control, but is associated with significantly more side effects. Furthermore, many biases remain with such statistical methods.

In this study, after 1:1 propensity score matching in 418 patients, the best overall response rate (ORR) and complete response rate (CRR) were 80% and 60% versus 66% and 42% for patients treated with axicabtagene ciloleucel compared to tisagenlecleucel (p < 0.001 for both ORR and CRR comparisons). These findings mirror the response rates in the two pivotal clinical studies, JULIET and ZUMA-1.

After a median follow-up of 11.7 months, the 1-year progression-free survival was 46.6% for axicabtagene ciloleucel and 33.2% for tisagenlecleucel (hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.46–0.79; p = 0.0003).

Overall survival (OS) was also significantly improved after axicabtagene ciloleucel infusion compared to after tisagenlecleucel infusion with 1-year OS rate of 63.5% versus 48.8% (HR 0.63, 95% CI 0.45–0.88; p = 0.0072). Median OS was 11.2 months with tisagenlecleucel, whereas median OS was not reached with axicabtagene ciloleucel, echoing the 11.1 months and 25.8 months of median OS in the recent updates of the JULIET and ZUMA-1 studies. Similar findings were observed using the inverse probability of treatment weighting statistical approach.

Grade 1–2 cytokine release syndrome was significantly more frequent with axicabtagene ciloleucel than with tisagenlecleucel, but no significant difference was observed for grade ≥3. Regarding immune effector cell-associated neurotoxicity syndrome (ICANS), both grade 1–2 and grade ≥3 ICANS were significantly more frequent with axicabtagene ciloleucel than with tisagenlecleucel.

The authors concluded that this matched comparison study supports a higher efficacy, but also a higher toxicity of axicabtagene ciloleucel compared to tisagenlecleucel in the third or further treatment line for relapsed/refractory DLBCL. These results need to be confirmed by other large real-world evidence studies with similar statistical methods to account for imbalance between patient characteristics. The findings from this study could help in refining the choice of CAR T cells product for a specific patient based on safety and efficacy.

The DESCAR-T registry was partly funded by Gilead and Novartis. 

Reference

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