Tecartus (brexucabtagene autoleucel)

P2, N=40, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

Among possible determinants of CD4+ T cell recovery, we recognized infusion of a 4-1BB product (tisagenlecleucel, TSA) in comparison with a CD28 (axicabtagene/brexucabtagene, AXI/BRX) (hazard ratio [HR] [95% CI]: 5.79 [1.16-24.12] p = 0.016). We conclude that a faster CAR- CD4+ T cell recovery is associated with TSA as compared to AXI/BRX. Month-1 CAR- CD4+ T cell subset recovery could represent a "red flag" for CAR-T cell therapy failure in DLBCL patients.

P2, N=90, Recruiting, Kite, A Gilead Company | Trial completion date: Dec 2027 --> Mar 2025 | Trial primary completion date: Dec 2027 --> Mar 2025

P2, N=700, Enrolling by invitation, Kite, A Gilead Company | Trial completion date: Mar 2041 --> Dec 2040 | Trial primary completion date: Mar 2041 --> Dec 2040

Findings suggest that brexu-cel may offer clinically and statistically significant benefits regarding objective response, complete response, and progression-free survival compared to pirtobrutinib among patients with R/R MCL after prior cBTKi therapy. Given the short follow-up and high degree of censoring in BRUIN, an analysis incorporating updated BRUIN data may provide more definitive overall survival results.

P=N/A, N=144, Active, not recruiting, Masonic Cancer Center, University of Minnesota | Recruiting --> Active, not recruiting | N=240 --> 144 | Trial primary completion date: Jun 2028 --> Feb 2024

P1/2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

With the simultaneous detection of the CAR-T cells and the B cell malignancy in patient peripheral blood, the HDSCA-HemeCAR workflow may be considered for risk monitoring and patient management.

P1, N=20, Recruiting, Stanford University | Phase classification: P1b --> P1

P2, N=21, Recruiting, Kite, A Gilead Company

Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton's tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma...Pharmaceutical co-targeting of HSP90 and CDK9 synergistically diminished MYC activity, leading to potent anti-MCL activity. Collectively, our study revealed that HSP90-MYC-CDK9 network is the primary driving force of therapeutic resistance.

P2, N=40, Not yet recruiting, M.D. Anderson Cancer Center

P1/2, N=116, Recruiting, Kite, A Gilead Company

P2, N=60, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Nov 2026 --> Nov 2028

P2, N=90, Active, not recruiting, Kite, A Gilead Company | Trial primary completion date: Jul 2024 --> Nov 2023

P2, N=28, Not yet recruiting, Peking University People's Hospital; Fosun Kite Biotechnology Co., Ltd

Introduction: Fludarabine and cyclophosphamide (Flu/Cy) lymphodepletion (LD) prior to chimeric antigen T-cell (CAR T) infusion favorably impacts CAR T expansion and efficacy...Three deaths (2 Cla/Cy) occurred before day 100, all due to refractory fungemia post anakinra... Cla/Cy LD prior to brexu-cel is feasible in ALL and MCL patients with comparable efficacy. Toxicity rates including CRS, ICANS and early infections were similar to those seen with Flu/Cy, but there was a trend towards earlier recovery of neutrophils, B-, and T-cells with Cla/Cy. The trend was demonstrable even in patients at high risk of prolonged post-CAR T neutropenia as identified by the HS.

While many therapies are under investigation including the addition of a tyrosine kinase inhibitor or ruxolitinib to conventional chemotherapy, a standardized and molecularly-based approach to treating patients with Ph-like ALL is not yet defined. There also remain questions about the efficacy of integrating inotuzumab ozogamicin or blinatumomab into first-line therapy for these patients...1 patient received Car T cell therapy with Brexucabtagene autoleucel following relapse after allogeneic stem cell transplant... We identified 9 patients who met inclusion criteria. All 9 patients self-identified as either ‘American Indian or Alaska Native’ or ‘Hispanic or Latino. ‘ The median age at diagnosis was 34 and the mean BMI at diagnosis was 34.

P2, N=60, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1/2, N=125, Completed, Kite, A Gilead Company | Active, not recruiting --> Completed | Trial completion date: Nov 2034 --> Nov 2023

The main goals of the symposium are: to share the benefits of Yescarta in 3/2L of LBDCL in the elderly patient setting share the benefits of Tecartus in MCL, a disease with major incidence in older patients. Target audience: Hematologists, geriatricians, nurses and other healthcare professionals in contact with geriatric cancer patients.

Background: Cytokine release syndrome (CRS) is a potentially life-threatening, supraphysiologic response following immunotherapy resulting in the activation or engagement of endogenous or infused T cells and/or other immune effector cells. Table 1 summarizes data by indication. Incidence of CRS ranged from 56% (104/185) in DLBCL to 72% (66/92) in MCL. Excluding categories with small numbers of cases (<15), CRS incidence also varied by individual CAR-T therapy and underlying indication and ranged from 35% for idecabtagene vicleucel in MM to 73% for brexucabtagene autoleucel in MCL.

While acknowledging the inherent limitations of an unanchored indirect comparison, our findings suggest that brexu-cel offers clinically and statistically significant efficacy benefits in terms of ORR, CR, and PFS compared to pirtobrutinib in patients with R/R MCL after prior cBTKi therapy. Both treatments were not statistically different in terms of OS and DOR although the estimated hazard ratios indicated a favorable trend for brexu-cel; however, given the relatively shorter follow-up and the high degree of censoring in BRUIN, an updated analysis incorporating longer follow-up data with more events from BRUIN could provide more reliable results. Although efforts were made to ensure a robust approach to the selection of prognostic factors for inclusion in the model, the possibility of some residual confounding variables cannot be completely ruled out.

Preceding CAR-T, median number of treatments was 3 (range 1-9), all patients had prior Rituximab and Ibrutinib, 62 patients (56%) had received autologous stem cell transplantation (SCT) and 11 patients had received an allogeneic SCT. 111 patients have been identified: median age at diagnosis was 64.3 years (range 42.3-79.5; 19/99 patients ≥ 70), 18% female (not known (nk) 2.7%); ethnicity 66.7% Caucasian (nk 30.6%). Disease characteristics: 80/88 had stage 3/4 (91%), histology was classical in 34/57 cases (60%) and blastoid in 19/57 (33%), respectively. MIPI score was low 14/53 (26%), intermediate 17 (32%), high 21 (40%).

Pts received a median of 4 prior lines of therapy (range 1-13); 46% had prior inotuzumab and 58% had prior blinatumomab...Treatment for CRS and/or ICANS consisted mainly of tocilizumab (67%) and corticosteroids (51%)...Updated data with longer follow-up will be reported at the time of presentation. *First and second authors are equal contributors

Similarly, with brexucabtagene autoleucel (brexu-cel), ICANS also occurred in approximately 60% with ≥ G3 occurring in 26-31% of patients...Tocilizumab (8 mg/kg) was administered to 11 patients (73.3%) with the median number of doses being 1 (range 1 to 4)...One patient with Richter's had progressive disease at day 30, 4 patients had partial remission, and 10 patients had a complete remission for an ORR of 93%. Conclusions Preliminary results show that simvastatin and intrathecal dexamethasone appear to be feasible, safe, and effective in reducing the incidence and severity of ICANS in patients receiving axi-cel and brexu-cel.

ALC data for 84 pts who received CD19 CAR-T (77 pts with axicabtagene ciloleucel and 7 pts with brexucabtagene autoleucel) for non-Hodgkin lymphoma (NHL) were included as a comparison...Furthermore, ALC dynamics differed by BCMA CAR-T product, with cilta-cel exhibiting later CRS with higher max-ALC peaking at a later day when compared to ide-cel. Furthermore, higher max-ALC and absolute ALC increase were associated with deeper response (VGPR/CR) and sustainable response on follow up. Our findings suggest that peripheral lymphocytosis after CAR-T is disease specific (NHL vs MM) and post CAR-T lymphocytosis in peripheral blood is a potential biomarker for clinical outcomes and toxicity.

INTRODUCTION: Over 40% of patients with mantle cell lymphoma (MCL) will progress within 1 year after treatment with brexucabtagene autoleucel (Brexu-cel)(Michael Wang et al... Evidence from the ZUMA-2 study and our study highlights the significance of early post-CAR-T MRD as an independent prognostic marker for predicting disease recurrence and durable remissions in MCL. Combining MRD measurements with PET-CT at months 1, 3, and 6 after CAR-T therapy can effectively identify high-risk patients for disease progression, offering promising potential to improve outcomes in MCL.

With 4 years of median follow-up in ZUMA-2, patients continued to benefit from brexu-cel with a median OS of almost 5 years in patients with CR. Consistent with ZUMA-2 findings, brexu-cel demonstrated a high level of efficacy in patients with R/R MCL in ZUMA-18, with an ORR of 87% and median OS not yet reached at 33.5 months of follow-up. Additionally, no new safety signals were detected in ZUMA-18.

Pts with Ki-67 PI ≥ 50% were more likely to receive Bruton's tyrosine kinase inhibitor (BTKi) (92% vs 81%) and bridging therapy (52% vs 37%), but less likely to receive bendamustine (47% vs 62%). These real-world findings with 12 mo of follow-up suggest that outcomes of brexu-cel treatment are largely consistent, including a high CR rate, regardless of ZUMA-2 eligibility or the high-risk feature subgroups analyzed. Although pts without deletion of TP53/17p appeared to have longer OS than pts with deletion of TP53/17p, the data further support brexu-cel as the standard of care across pts with R/R MCL, including those with high-risk features. An updated dataset is planned to be analyzed and results can be presented at the conference.

P2, N=105, Completed, Kite, A Gilead Company | Active, not recruiting --> Completed | Trial completion date: Jun 2025 --> Sep 2023

P2, N=90, Recruiting, Kite, A Gilead Company | Trial completion date: Nov 2029 --> Dec 2027 | Trial primary completion date: Nov 2029 --> Dec 2027

P1b, N=20, Recruiting, Stanford University | Not yet recruiting --> Recruiting

We analyzed 110 patients with relapsed/refractory B-cell non-Hodgkin lymphoma (n = 105) or acute lymphoblastic leukemia (ALL) (n = 5), treated with Axicabtagene-Ciloleucel (39%), Tisagenlecleucel (51%), or Brexucabtagene autoleucel (10%). Lastly, sequential analysis showed a modest VAF increase of 1.3% and acquisition of novel mutations within 100 days postinfusion. CH was frequent in large B-cell lymphoma/ALL patients receiving CAR T-cells but did not affect toxicity nor treatment response or outcome.

In this multi-institutional study, pts receiving BRT prior to CAR T therapy for BCL frequently had bulky disease yet experienced favorable PFS and OS. There were no serious toxicities attributable to BRT, and the rates of CRS and ICANS are comparable to those after CAR T alone. Comprehensive BRT associated with superior PFS.

Among 44 B-NHL pts, 24 received axicabtagene ciloleucel (Axi-cel) and 16 tisagenlecleucel (Tisa-cel). Four mantle cell lymphoma pts received brexucabtagene autoleucel (Brexu-cel)... Assessing T-cell phenotypes has implications for predicting clinical outcomes of CAR T-cell therapy and suggests that apheresis at earlier treatment segments might improve the CAR product quality. Our data highlight the importance of CAR T-cell/immune monitoring for improved clinical management of treatment-associated side effects and may help to optimize CAR T-cell therapy in the future.

The establishment of the role of Bruton tyrosine kinase led to the development of ibrutinib, a first-generation BTK inhibitor, and its successors...Brexucabtagene Autoleucel, the only approved CAR T-cell therapy, has proven advantageous for relapsed/refractory MCL in both children and adults. This article reviews certain therapies that could help update the current approach and summarizes a few miscellaneous agents, which, seldom studied in trials, could alleviate the regression observed in traditional therapies. DATA AVAILABILITY: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

In ZUMA-3, adults with R/R B-ALL benefited from brexu-cel, regardless of prior therapies and subsequent alloSCT status, though survival appeared better in patients without certain prior therapies and in earlier lines of therapy. Additional studies are needed to determine the impact prior therapies and subsequent alloSCT have on outcomes of patients who receive brexu-cel.

But at MD Anderson, rather than using intensive chemotherapy followed by autologous stem cell therapy, we used Hyper-CVAD rituximab alternating with rituximab plus methotrexate-cytarabine. For elderly patients over 65 years old, we formerly used R-CHOP, but now the international standard is bendamustine-rituximab...In the past 20 years, the FDA has approved many therapies for relapsed mantle cell lymphoma, including the protease inhibitor bortezomib, the cereblon-binding immunomodulator lenalidomide, the first-ever Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, and the second-generation BTK inhibitors acalabrutinib and zanubrutinib...The FDA also approved brexucabtagene autoleucel, a CD19-targeted CAR-T cell therapy and, in January 2023, approved the novel non-covalent reversible BTK inhibitor pirtobrutinib...These included our Window approach, the acalabrutinib-venetoclax-rituximab trial,3 and the acalabrutiniblenalidomide-rituximab (ARL) trial.4 We now have many clinical trials employing rational combinations with targeted agents...We work closely with patients and their families, industry, NIH, and many collaborators within and outside of our institution. We are in the process of saving many lives from mantle cell lymphoma.

In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.

P1b, N=20, Not yet recruiting, Stanford University

These four products differ in the costimulation domains, with axicabtagene ciloleucel (Yescarta) and brexucabtagene autoleucel (Tecartus) both utilizing the CD28 costimulation domain whilst tisagenlecleucel (Kymriah) and lisocabtagene maraleucel (Breyanzi) both utilizing the 4-1BB costimulation domain. Additionally, while in vitro and preclinical in vivo studies have compared CARs with different costimulation domains, it remains a challenge to extrapolate differences observed in this biology across different experimental systems to the overall product performance. While there has been extensive preclinical and clinical work looking at CARs with a variety of targeting domains and architectures, this review will focus on the differences between the four marketed anti-CD19 CAR-Ts, with an additional focus on the impact of hinge and transmembrane domain on CAR activity and interaction with the target cell as well as other proteins on the surface of the T-cell.