Identifying the Barriers of Clinical Trial Access after CAR T-Cell Therapy in Relapsed/Refractory Large B-Cell Lymphoma
Authors: Kim Kunhwa , Ayers Amy , Ahmed Sairah , Claret Linda , Strati Paolo , Nair Ranjit , Nze Chijioke , Ramdial Jeremy , Torres Janet , Shpall Elizabeth J. , Fayad Luis E. , Nastoupil Loretta , Westin Jason R. , Flowers Christopher R. , Neelapu Sattva S. , Chihara Dai 
Published: December 2024

Background: Approximately 60% of patients with relapsed/refractory (r/r) large B-cell lymphoma (LBCL) experience progression after chimeric antigen receptor (CAR) T-cell therapy, which confers dismal outcomes and there is unmet need to improve clinical trial participation. However, former studies have shown that only less than 20% of patients are treated in trials after CAR T-cell therapy failures. Thus, understanding the barriers and characteristics of clinical trial participation is critical to improve the design of future trials and facilitate the accrual in this unmet need. Our study aimed to understand the factors associated with clinical trial access in patients with r/r LBCL after CAR T-cell therapy failure.

Methods: This is a single-center retrospective study that analyzed adult patients with r/r LBCL who received CAR T-cell therapy from 2018 to 2024. Baseline patient characteristics, clinical, and CAR-T variables were obtained from institutional databases, and further data were collected from chart review and clinical trial database for 3-time points: at diagnosis, at apheresis/CAR T-cell infusion, post-infusion at day 30, day 90, and relapse. The proportion of patients who were eligible for trials at the time of r/r disease post CAR T-cell therapy, factors associated with clinical trial screening or enrollment were analyzed using descriptive statistics.

Results: A total of 167 patients experienced r/r disease post CAR T-cell therapy during the study period. The median age at r/r disease after CAR T-cell therapy was 63 years (range 22-89). Patients had progression of disease at day 30 (n=36, 22%), between day 30 to day 90 (n=42, 25%), and post day 90 (n=89, 53%). Difference was seen in proportion of patients who were eligible for trials at the time of recurrence; 20% at day 30, 17% between day 30 to day 90, 34% post day 90 using eligibility criteria for pivotal glofitamab phase 2 trial (p=.095). At the time of r/r disease following CAR T-cell therapy, 66 (40%) and 46 (28%) patients were screened and enrolled for the clinical trial at MD Anderson Cancer Center, respectively. The median number of screened protocols was 3 (range 1-18). The common reasons for non-screening were cytopenia (38%), followed by deconditioning (22%) and rapid progression of disease (14%). The frequent types of clinical trial treatments were cellular therapy (22%), bispecific antibody (21%), targeted therapy (21%), and checkpoint inhibitors (21%). In the subsequent treatment in trial post CAR T-cell therapy, 70% of patients were taken off from disease progression but 20% are still in remission and the median days of treatment under the trial were 73 days (range 7-736 days).

The baseline characteristics of LBCL type (GCB or not, double-hit or not), and other disease characteristics at diagnosis were not associated with screening or enrollment rates. The mean number of lines of prior systemic therapies were comparable in screened patients to others, but lower in enrolled patients (p=.034). Younger age (age&lt;60) and good performance status (ECOG&lt;2) at CAR T-cell infusion were associated with more frequent screening (47% vs. 34% in age&gt;60 and 46% vs. 17% in ECOG ≥2) or enrollment (36% vs. 22% in age≥60 and 34% vs. 6% in ECOG ≥2). Also, advanced-stage disease and higher-IPI at CAR T-cell infusion was associated with lower enrollment rates. Patients with grade &lt;2 ICANS or CRS were more likely to undergo trial enrollment (ICANS: 36% vs. 17%, p=.008, CRS: 49% vs 27%, p=.005) than those with complications. Patients who achieved complete response after CAR T-cell therapy more frequently underwent screening (49% vs. 33% without CR, p=.035) and enrollment (36% vs. 22%, p=.050).

The median OS from relapse after CAR T-cell therapy for patients who underwent trial was 12.6 months (95% CI 9.3-21.3 months), and trial enrollment was associated with higher response rates (22% vs. 10%, p=.044) and improved overall survival (6-months: 55% vs 45%, p&lt;.001) post CAR T-cell failure.

Conclusion: Our study demonstrated the impact of various factors at the time of CAR T-cell infusion and at progression post CAR T-cell therapy for trial screening or enrollment. With the current trial eligibility criteria, more than half of patients are not eligible at the time of progression in real-world emphasizing the biased patient population in pivotal trials. Investigating feasible trial eligibility criteria post CAR T-cell therapy is unmet need to improve trial access.