Key Takeaways From Long-Term Follow-Up of Early CAR T in LBCL

The 2 currently approved chimeric antigen receptor (CAR) T-cell products in large B-cell lymphoma (LBCL) have advanced to the second line of therapy based on distinct clinical trial approaches that established the efficacy and safety of axicabtagene ciloleucel (axi-cel; Yescarta) or lisocabtagene maraleucel (liso-cel; Breyanzi). In a Community Case Forum event held in Denver, Colorado, Matthew Lunning, DO, assistant vice chancellor of clinical research and associate vice chair of research of the department of internal medicine at the University of Nebraska Medical Center, discussed the differences between the pivotal trials and what the long-term outcomes mean for managing patients who receive CAR T-cell therapy.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: How was axi-cel investigated in patients with early relapsed or primary refractory LBCL?

Matthew Lunning, DO: ZUMA-7 [[NCT03391466]…was a 1:1 randomization of axi-cel vs standard of care [SOC]. [Patients] had to relapse within 12 months or have primary refractory disease and had to have the intent to proceed to transplant. An 82-year-old [patient], if they got randomly assigned to platinum plus transplant, wouldn’t go on the trial. The [SOC arm]…was investigator-selected platinum-based chemotherapy. What is different between ZUMA-7 and TRANSFORM [NCT03575351] is that this was not an intent-to-CAR study, meaning that if you had an event in the SOC arm, you could get CAR T cells, but that CAR T-cell [therapy] had to be obtained off of the clinical trial, either with commercial product or a different product that was experimental. The primary end point here was event-free survival [EFS], with key secondary end points of overall response rate [ORR] and overall survival [OS].

What were the findings from ZUMA-7 with long-term follow-up?

At 4 years of follow-up, in the axi-cel arm 39% [of patients] were event free compared with 17% [of patients] in the SOC arm.¹ The median EFS was in favor of axi-cel, with a very statistically significant HR of 0.42 [95% CI, 0.33-0.55]. The final nail in the coffin for SOC was that there was an OS advantage [with an] HR of 0.73 that does not cross 1 [95% CI, 0.54-0.98] and at the 4-year point, 55% of the patients were alive who got axi-cel and only 46% with SOC.

There is toxicity; when I talk to patients about CAR T-cell toxicity, I [discuss how] my goal is to prevent grade 3 or higher neurologic events, and I work my way backwards. We’re no longer scared of cytokine release syndrome [CRS]. We can do a very good job of keeping CRS at grade 1 or grade 2. But what often gets caught is high-grade neurotoxicity, which is a length-of-stay extender [that may land] people in the acute rehabilitation facility. We also know that AEs of special interest include hypogammaglobinemia, and then those early and prolonged cytopenias that can be seen with CAR T cells.

Looking at some interesting data by primary refractory vs…early relapsed within…probably 3 to 12 months, when you break it out both by EFS and OS, [although] you still see statistical significance in both arms, it does lose its statistical significance if you look at OS when you’re breaking out the 2 subgroups. Separate, [they are] not statistically significant, but together overall, there is an OS [advantage].

Is complete response (CR) a signal for long-term survival?

I like [seeing] 2 CRs, on day 29 [and at] 3 months. If I can [insurers] to pay for 3 PET scans, and I can get day 29, day 100, and then 6 months at day 180, that’s the trifecta where I think durability lives, in regard to those plateaus on the CAR T-cell curve. CR 3 times usually equals long-term disease-free survival.

How did the TRANSFORM study differ from ZUMA-7?

TRANSFORM was an intent-to-CAR study. The age range was up to 75 years, [with] similar population of those patients who were relapsed or refractory within 12 months from their anthracycline-based therapy. Bridging was allowed—whereas it wasn’t allowed in the ZUMA-7 trial—prior to getting liso-cel. However, you had to have PET positive disease in order to proceed to liso-cel. If you were on the SOC arm and you did not have a partial response or CR, you were then signaled as an event. Within 14 days, your CAR Ts were manufactured because everybody…underwent leukapheresis. The primary end point was similarly EFS.

From that standpoint, in TRANSFORM at 3 years…the median [EFS] was 29.5 months in the liso-cel arm vs 2.4 months in the control arm.² Looking at liso-cel, with the smaller number of patients [than in ZUMA-7], any-grade CRS was 49%. High-grade CRS was only 1%. If you look at neurologic events, there was 4% of grade 3 or higher neurologic events, and similar cytopenias as well as hypogammaglobulinemia [as axi-cel].

What we shouldn’t do is [compare] ZUMA-7 and TRANSFORM side by side in regard to EFS and OS. [However], one of the things that I think you can draw from this is that [in the SOC arms], the EFS is scarily similar between ZUMA-7 and TRANSFORM at 2.3 and 2.4 months. When I say the biggest barrier to getting to [stem cell] transplant is the disease, that is true here, because…the vast majority of patients did not get to other consolidative [stem cell] transplant.

What is important when monitoring for toxicities after CAR T-cell therapy?

When we think about cytopenias, I think we’ve gotten very good at knowing how to manage these, both from ZUMA-1 [NCT02348216] and TRANSCEND-NHL-001 [NCT02631044] in the third-line setting, but also in ZUMA-7 and TRANSFORM. When we are introducing a growth factor, I typically start that after day 14, if absolute neutrophil count is less than 500 cells/µL. [There is] a population that [has cytopenias at] days 20 to 30. Secondary malignancies can be seen, mainly leukemias here.³ There is a thought of a signal with T cell malignancies. If we see T-cell malignancies, you have to ask, are these transgene positive vs transgene negative? [We are] also thinking about whether these are T-cell lymphoproliferative disorders or truly T cell cancers, as we’ve seen a rise of these gastrointestinal tropic infiltrations over time. I think that this certainly is an area to keep your eye on, especially as autologous CAR T cells move into the autoimmune space.

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DISCLOSURES: Lunning previously reported receiving honoraria and/or has served in a consultancy or advisory role for AbbVie, Acrotech, ADC Therapeutics, Astellas, AstraZeneca, Bristol Myers Squibb, Caribou, CRISPR, Daiichi Sankyo, EUSA, Fate Therapeutics, Genentech, Genmab, Instil Bio, Ipsen, Janssen, Kite, Loxo, Miltenyi, MorphoSys, Novartis, Nurix, Pharmacyclics, Regeneron, Sanofi, Seagen, Takeda, and TG Therapeutics; and has received research funding from Bristol Myers Squibb, Curis, FATE Therapeutics, and Sana Therapeutics.

REFERENCES

1. Westin JR, Oluwole OO, Kersten MJ, et al; ZUMA-7 Investigators; Kite Members. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. 2023;389(2):148-157. doi:10.1056/NEJMoa2301665

2. Kamdar M, Solomon SR, Arnason J, et al. Lisocabtagene maraleucel versus standard of care for second-line relapsed/refractory large B-cell lymphoma: 3-year follow-up from the randomized, phase III TRANSFORM study. J Clin Oncol. 2025;43(24):2671-2678. doi:10.1200/JCO-25-00399

3. Elsallab M, Ellithi M, Lunning MA, et al. Second primary malignancies after commercial CAR T-cell therapy: analysis of the FDA Adverse Events Reporting System. Blood. 2024;143(20):2099-2105. doi:10.1182/blood.2024024166