Liso-Cel Efficacy Not Impacted by Prior CD19 Exposure in LBCL

Prior exposure to an anti-CD19 therapy does not impact responses to lisocabtagene maraleceul (Breyanzi; liso-cel), opening up a new therapy option for patients with relapsed/refractory large B-cell lymphoma (LBCL), according to a subgroup analysis presented at the 2021 Transplantation & Cellular Therapy Meeting.

The analysis stemmed from the TRANSCEND-NHL-001 (NCT02631044), which evaluated the safety and pharmacokinetics of liso-cel in patients with LBCL. However, unlike many similar studies , it did not exempt people with prior anti-CD19 exposure.

Twelve patients were included in the analysis, and the subset reflected the primary cohort well. In total, 11 out of 12 of the patients experienced an objective response to liso-cel, with 6 complete responses. Additionally, 5 patients experienced a duration of response lasting 9 months or longer, with 1 out 3 patients were continuing to respond at the time of data cutoff.

In an interview with Targeted Oncology, Scott R. Solomon, MD, a medical oncologist with the Blood and Marrow Transplant Program, Leukemia and Cellular Immunotherapy Program at the Northside Hospital Cancer Institute, discussed the efficacy of liso-cel in LBCL patients with prior anti-CD19 exposure and future research.

TARGETED ONCOLOGY: Could you discuss the rationale for conducting this analysis?

SOLOMON: It’s well known now that CD19-directed CAR T-cell therapy provides unprecedented efficacy for patients with relapsed refractory large B cell lymphoma. The third line setting this is now the standard of care, and multiple commercial products are now available. But one important question that is still not quite answered is whether this CAR T-cell product which targets CD19 would maintain its efficacy in patients with prior exposure to anti-CD19 therapies, whether they be monoclonal antibodies, or bi-specific antibodies, or antibody drug immunoconjugates. All of these are now being used commonly in clinical studies of patients with LBCL, and more patients that have been exposed to these anti-CD19 therapies are now going to CAR T-cell therapy. It's an important question to answer. Do you maintain efficacy of CAR T in patients with prior exposure to anti-CD19 therapy?

We used the data set from the TRANSCEND study, which was a large digital study looking at the CAR T construct liso-cel, which is now commercially approved. What's interesting about this study is that the study permitted patients with prior exposure to anti-CD19 agents. So many of the other CAR T studies excluded these patients. But because of the study design that allows us to do a post-hoc analysis of this subset of patients that had been exposed to anti-CD19 treatments prior to liso-cel administration.

TARGETED ONCOLOGY: Regarding this study, what sort of methods were implemented? And could you provide insight into this sub population of patients who had prior CD19-directed therapies?

SOLOMON:What we did was we identified 12 patients, so not a large subset, but all the patients on the transplant study that had been exposed to prior anti-CD19 therapies. The first thing we did was we looked at their baseline characteristics and tried to compare it to the main TRANSCEND dataset. Realizing that we have a small population, we can't make statistical arguments about the comparison, but within our ability to look at the baseline characteristics, these patients look comparatively similar to the total present population, meaning that they were similar in age and had similar prior lines of therapy. They also were similar in the amount of patients that were chemo-refractory going into liso-cel therapy. They appeared to be a good representation of the total population that was treated on the TRANSCEND study.

These patients did receive different types of therapy, which is indicated in the poster. Meaning some of them received anti-CD19, monoclonal antibodies, some of them bi-specific antibodies, and some of them antibody drug conjugates. It's impossible to sort of slice down to any finer level than that. But all of those patients did receive this therapy prior to liso-cel administration. And all of these patients were required to show that their tumor cells still expressed the CD19 antigen prior to liso-cel administration.

Then we looked at the outcomes. And of the 12 patients that were studied in this analysis, 11 patients responded, 5 of them achieving a complete remission. That's a 50% CR rate. And those response rates also compare very similarly to the total transplant population. And of these responses,5 of them were quite durable, meaning they were greater than or equal to 9 months. These responses were ongoing at the time of our data cutoff. So again, within reason, the prior exposure to anti CD19 therapy does not appear to affect efficacy of this party.

TARGETED ONCOLOGY: Were there any notable safety differences in regard to liso-cel in this population?

SOLOMON:No, there wasn't. We expected there could have been some differences in efficacy, we really wouldn't have expected there to be any increase in adverse events. But it is an important question to ask. In this patient population, the adverse events were pretty similar to that of the total population in the TRANSCEND study. And the most important adverse events we're looking at are cytokine release syndrome and neurological events. And in that situation, there were no grade 3/4/5 events of either type in this patient population, all of them were grade 1/2 events. And so, the safety appears to be similar between these patients and those in the TRANSCEND population.

TARGETED ONCOLOGY: What would you say are the clinical implications of these findings?Do you think that CD19 patients with prior CD19-directed therapies should be included in all of the CAR T cell therapy trials?

SOLOMON: This data set at least gives us some confidence that prior exposure to anti-CD19 does not clearly affect efficacy. This is a small data set; it needs to be studied in a larger patient population. But I don't think there's any apriority reason to exclude these patients from future studies, as long as you show that the CD19 target is still expressed in those patients.

The one other thing that we did show in the study is we did also look at the kinetics of the cellular expansion. So, the CAR T cells, how rapidly they expanded? And how long did they these CAR Ts persist in vivo? And between these 12 patients and the rest of the group on the TRANSCEND study that weren't exposed at anti-CD19 therapy, and there really was no difference in the expansion kinetics or persistence of these cells. It reinforced what we're seeing in the efficacy data.