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Update Sustains Liso-Cel as Strong Contender in CAR T-Cell Space

Angelica Welch
Published: Thursday, Jun 14, 2018

Jeremy S. Abramson, MD, MMSc
Jeremy S. Abramson, MD, MMSc
The CD19-directed chimeric antigen receptor (CAR) T-cell therapy lisocabtagene maraleucel (JCAR017; liso-cel) is showing promising response rates in patients with high-risk diffuse large B-cell lymphoma (DLBCL).

Updated findings from the TRANSCEND trial presented at the 2018 ASCO Annual Meeting showed a complete response (CR) rate of 46% (95% CI, 30%-63%) at 6 months, as well as an ongoing objective response rate of 49% (95% CI, 32%-66%). This phase I, multicenter trial also showed durable responses across poor-risk DLBCL subgroups, including those who are chemorefractory.

The median overall survival (OS) had not been reached among patients who achieved a CR at the pivotal dose. The 12-month OS rate in these patients was 89% (95% CI, 72%-96%). Among patients who achieved a partial response, the median OS was 10.3 months (95% CI, 6.8-not evaluable) and the 1-year OS rate was 33% (95% CI, 9%-60%).

In an interview with OncLive during ASCO, lead investigator Jeremy S. Abramson, MD, MMSc, clinical director, Center for Lymphoma, Massachusetts General Hospital, discussed the latest data for liso-cel and its potential to become the third FDA-approved CD19-targeted CAR T-cell therapy.

OncLive: What is the background of the TRANSCEND trial?

Abramson: The TRANSCEND trial is a pivotal trial looking at the anti-CD19 CAR T-cell product JCAR017, now known as lisocabtagene maraleucel, in relapsed/refractory aggressive B-cell lymphomas. Liso-cel targets CD19 using a 4-1BB costimulatory domain, and signals CD3 zeta. We separated the CD4 and CD8 cells, then they were separately transduced and expanded, and then administered back to patients in a 1:1 ratio. What that results in is a fixed precise dose of CD4 and CD8 CAR-positive T cells administered to every patient. We began with a dose-finding component of the study, where we looked at 3 dose levels. [We evaluated] a single-dose level of 50 million cells administered at a single dose, a double-dose level of the same dose of 50 million cells administered 2 weeks apart, and then a dose level of 100 million cells as a single dose.

Based on the findings in that component of the study, we expanded into 2 dose-expansion cohorts, which was both dose level 1 and dose level 2, each administered in a single dose. Based on the results of that, we have expanded into a pivotal cohort of the trial.

What are the updated findings with this study?

At the 2018 ASCO Annual Meeting, I updated the results from the dose-finding and dose-escalation cohorts—the first 2 phases of the study. We have 102 patients who have been treated with liso-cel. All patients have now reached the 6-month time point or beyond, so we are really dealing with maturing data at this point. We are finding really exciting results. All patients have had at least 2 prior lines of therapy. The median prior line is 3, and some patients received up to 8. These are high-risk patients—70% of them have chemorefractory disease, 20% have double-hit lymphoma, about half of patients have never achieved a CR to prior therapies, and 40% have had a prior stem cell transplant, most of which were autologous. This compared favorably to any other conventional therapy that one would give these patients. 

The most important question is durability of remission in large cell lymphoma. When you look 6 months later, we are seeing a high proportion of durable remissions. In fact, 40% are in ongoing response 6 months later.

We then evaluated our core DLBCL population, which is a population that we are now accruing in the pivotal component of the study. Those patients have relapsed/refractory DLBCL, transformed follicular lymphoma, or double-hit or triple-hit lymphoma. It is a narrower set of patients in that cohort. In that subset of patients, the median number of prior therapies is 3 and 70% are chemorefractory. In that population of patients, treated at our second dose level, about half of patients are in ongoing remission 6 months later. We are seeing a very encouraging signal of durable responses in high-risk DLBCL. 

Of course, the other big question when it comes to a CAR T-cell product is toxicity. As we know, the adverse events of special interest are cytokine release syndrome (CRS) and neurologic toxicity. We are seeing low and manageable rates of both of these toxicities. CRS has only been seen in 37% of patients on the study, and only a single patient had severe CRS. Neurologic toxicity has been similarly low at 23%, with 13% of patients having severe CRS. Virtually all of these toxicities have been reversible, and there have been no deaths related to either CRS or neurologic toxicity. We have seen relatively low overall use of rescue medications—anti-cytokine therapy with tocilizumab (Actemra) was seen in 17% of subjects, predominantly for grade 2 CRS. Corticosteroids, primarily with dexamethasone, were used in 21% of patients. 


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