Résumé
Background
Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have both demonstrated impressive clinical activity in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the pivotal JULIET trial, tisa-cel led to a best overall response rate (ORR) of 52% with a 40% complete response rate (CRR) and a median overall survival (OS) of 12 months. In the ZUMA-1 trial, axi-cel was associated with an 83% ORR, a 58% CRR and a median OS of 26 months. In the absence of a randomized comparison and given the large differences in trial design precluding a robust matched-adjusted indirect comparison, controversy exists as to whether there are significant differences regarding both efficacy and safety between the two products.
Methods
We conducted a propensity score (PS)-matched comparison of axi-cel and tisa-cel in a large cohort of R/R DLBCL patients treated outside of clinical trials. All data were collected through the French DESCAR-T registry designed by the LYSA/LYSARC which aims to collect real-life data. The PS was calculated for each patient by using multiple logistic regression analysis against treatment category (axi-cel v tisa-cel) entering the following variables (assessed at time of lymphodepletion for most): age, ferritin, time from last treatment to CAR T-cell infusion, sex, histological diagnosis, LDH level, CRP, ECOG status, stage, number of previous treatment lines, use of a bridging therapy, response to bridging therapy if any, previous stem cell transplant, diameter of the largest tumor involved (with a cut-off set up at 5 cm), time from first commercial CAR T-cell order (of any type) of the center to CAR T-cell order for the patient (as a correlate for center experience for CAR T-cell practice), and treatment center. For all categorical variables, missing values (which were marginal for most parameters and balanced between CAR T-cell subtypes) were considered as a category to reduce the number of patients not included in the analysis. Of note, patients with primary mediastinal B-cell lymphoma were not included since approval has been granted for axi-cel only. The primary endpoint was OS. The following secondary endpoints were analyzed: best ORR and CRR (according to Lugano 2014 classification), progression-free survival (PFS) and duration of response (DoR). All time-to-event analyses used time of CAR T-cell infusion as the origin. PS-matching of the two patient cohorts was then conducted using PS rounded to one decimal place.
Results
An initial cohort of 504 patients with DLBCL (NOS, high grade or transformed from indolent lymphoma) and treated with axi-cel (n=321) or tisa-cel (n=183) was considered. Among others, patient characteristics were imbalanced regarding ECOG, and prior transplant rate with worse prognosis for patients receiving tisa-cel. After a 1:1 ratio PS-matching, outcome was compared between 144 patients treated with axi-cel and 144 patients treated with tisa-cel with no residual significant difference in baseline patient characteristics according to CAR T-cell type. After a median follow-up of 6.6 months (95% CI, 6.1-10.4 months), OS was not significantly different between axi-cel and tisa-cel (78% v 70% at 6 months respectively, P=0.44). Best ORR and CRR were significantly higher with axi-cel compared with tisa-cel (73% v 60%, P=0.02 and 56% v 36%, P<0.001, respectively). There was no difference in DoR. PFS was significantly longer with axi-cel than tisa-cel (53% v 32% at 6 months respectively, P=0.011).
Regarding toxicity, there was no significant difference in incidence of cytokine release syndrome (CRS) but axi-cel was associated with significantly more frequent and higher-grade immune effector cell-associated neurotoxicity syndrome (ICANS) (30.6% v 18.1% for grade 1-2 and 10.4% v 2.1% for grade ≥3 for axi-cel compared with tisa-cel, respectively, P< 0.001).
Conclusion
In this study, after stringent PS-matching on a large patient population treated with CAR T-cell in real-life, there was no OS difference between axi-cel and tisa-cel. Axi-cel yielded higher ORR and CRR and significantly prolonged PFS compared with tisa-cel. However, greater efficacy came at the cost of higher neurotoxicity with axi-cel. These data could help in refining CAR T-cell subtype choice for different patient populations, with young and/or fit patients benefiting most from axi-cel while tisa-cel being most advantageous to elderly and/or unfit patients.
Figure 1 Figure 1.