Sequencing of Treatment in Third-Line R/R LBCL

This is the second part of an interview with Manali Kamdar, MD. For the first part, click here.

Manali Kamdar, MD

At the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, 5-year survival data were presented from patients treated in the large B-cell lymphoma (LBCL) cohort in the TRANSCEND-NHL-001 clinical trial (NCT02631044) evaluating Bristol Myers Squibb’s lisocabtagene maraleucel (liso-cel, marketed as Breyanzi), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved by the FDA for the treatment of third-line relapsed/refractory (r/r) LBCL. Notably, the data demonstrated the curative potential of liso-cel in this setting.

After the conference, CGTLive® spoke with Manali Kamdar, MD, the associate professor of medicine–hematology and clinical director of lymphoma services at the University of Colorado, to discuss the implications of the new data. Kamdar suggested that one of the main questions facing treating physicians going forward is how to sequence liso-cel with other approved treatment options in the third-line setting.

CGTLive: With regard to the new data, are there any areas of interest where more research is still needed for liso-cel?

Manali Kamdar, MD, PhD: I think at this point in time, the question that is quite a big debate at this point [regards] a new class of agents, which is the T-cell engagers, such as Glofitamab (Columvi) and epcoritamab (Epkinly). These are CD20-bispecific T-cell engagers (BiTEs) and based on 2 pivotal studies, they have also been approved in the third-line setting. So I think I will say in patients who have not received CAR T-cell therapy in the second-line setting—which is also where axicabtagene ciloleucel and liso-cel have their approval—then in the third-line setting the big question is really about sequencing: sequencing of CAR T-cell therapy before BiTEs and vice versa.

I will say, just as a function of how they got approved, we have longer-term follow-up data with CAR T-cell therapy, which we don't have with CD20-BiTEs. We have more prospective data that suggests that CD20 BiTEs work in patients who progress after CAR T-cell therapy. We only have retrospective data to suggest that CAR-T therapies would work in case BiTEs would not if we were to reverse the sequence.

For me, the most important thing is the curative potential at the 5-year mark and across the 3 constructs, especially such as liso-cel, with not just a good efficacy, but also a highly manageable safety profile. I would poise a patient to get a more curative-intent treatment before I sequence BiTEs first. Now, of course, as a function of follow up, as we get more 5-year data, it will be unraveled if we get a cure from CD20 BiTEs, as well.

The other issue with CAR-T versus BiTEs is, of course, the fact that CAR-T is a more one-and-done treatment. It is agnostic of tumor antigen expression. For CD20 BiTEs, you need CD20 expression to give it to a patient. In addition to which, liso-cel and the other CD19 CARs have shown that they do penetrate the blood-brain barrier, so they are highly effective in patients who have central nervous system (CNS) disease, which I will say is not proven [for CD20 BiTEs]—patients who enrolled on the CD20 BiTEs [trials] were excluded if they had CNS disease.

So I would say these are the 4 distinct advantages of CAR-T before BiTEs. However, BiTEs are off-the-shelf molecules, there is no manufacturing time required, and therefore there is no bridging. The level of upfront commitment and the need for a caregiver are there, as of today, as the community starts learning how to give this, but over a period of time, I think the requirement for having a primary caregiver may go down with CD20 BiTEs because there is a slightly lower chance of developing cytokine release syndrome and it's very rare to develop neurotoxicity.

I think that is potentially the main question: Based on the 5-year follow-up of the TRANSCEND-NHL-001 study demonstrating a curative potential of liso-cel, how [do we] pitch it against CD20 BiTEs?

This transcript has been edited for clarity.

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REFERENCE
Abramson JS, Palomba ML, Gordon LI, et al. Five-year survival of patients (pts) from Transcend NHL 001 (TRANSCEND) supports curative potential of lisocabtagene maraleucel (liso-cel) in relapsed or refractory (r/r) large B-cell lymphoma (LBCL). Presented at: ASH 2024 Annual Meeting. December 7-10, 2024; San Diego, CA. Abstract 3125