Liso-Cel Maintains Longer-Term Responses in Pretreated Relapsed/Refractory CLL/SLL

Durable responses seen with lisocabtagene maraleucel (Breyanzi; liso-cel) after longer-term follow-up of the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) signal the agent’s viability as a much-needed later-line option for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have exhausted all available regimens, according to Tatyana Feldman, MD.

Updated results from a 24-month median follow-up analysis of the TRANSCEND CLL 004 trial were presented at the 2023 ASH Annual Meeting, and showed a complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 20% (95% CI, 10%-34%) in patients who were treated with liso-cel at the target dose of 100 x 106 T cells (n = 50) and had experienced progression on BTK inhibition and venetoclax (Venclexta) failure.¹ The overall response rate (ORR) with the agent was 44% (95% CI, 30%-59%) per independent review committee assessment. Moreover, patients achieved sustained, undetectable minimal residual disease (MRD) rates of 64% in blood (95% CI, 49%-77%).

Previously reported data from the primary analysis of this trial supported the FDA’s decision to grant priority review to a supplemental biologics license application seeking to expand the indication of liso-cel to patients with CLL/SLL and prior exposure to a BTK and BCL-2 inhibitor.²

“The fact that we have such a long duration of CRs, which are basically not reached, as well as a very [encouraging] duration of partial response [PR] with [liso-cel is encouraging,]” said Feldman, who is a hematologist and director of the T Cell Lymphoma Program at John Theurer Cancer Center, in Hackensack, New Jersey.“[Liso-cel] is a very important next-line therapy, which should be adopted by the community, particularly for the patients who progress after BTK inhibitors and BCL-2 inhibitors.”

In an interview with OncLive®, Feldman discussed the rationale for evaluating the efficacy of liso-cel in CLL/SLL following progression on BTK and BCL-2 inhibitors; reported updated efficacy findings for this agent from the TRANSCEND 004 study; and highlighted the potential impact of liso-cel if approved as an option in the CLL treatment arsenal.

OncLive: Why is it important to evaluate the long-term efficacy and safety of liso-cel after progression on a BTK and BCL-2 inhibitor in CLL/SLL?

Feldman: We have excellent treatment options for CLL, which include BTK inhibitors and BCL-2 inhibitors, which have changed outcomes for patients with CLL. Suddenly, [many of] my patients are surviving, and no one is running out of options. However, we’re [now] accumulating patients who started to relapse after long-term, or [even shorter-term,] treatment with a BTK inhibitor or BCL-2 inhibitor. Even though we have a lot of options, one of the important ones [for use post-progression is liso-cel, which was assessed in the] TRANSCEND 004 study.

Please detail the design of TRANSCEND 004. What was being evaluated in the most recent analysis of the trial?

Long-term follow-up [data from] TRANSCEND 004 was presented at the 2023 ASH Annual Meeting, and [findings from] the primary analysis [were presented] at [the 2023 ASCO meeting. In the most recent analysis], the median follow-up was [23.5] months. TRANSCEND 004 evaluated liso-cel, which is a CD19-targeted CAR T-cell [therapy], in patients with relapsed CLL/SLL.

This [analysis featured] a cohort of patients who must have [progressed on] a BTK inhibitor and venetoclax, so they were double-refractory patients. This is particularly a difficult population to treat, as their median overall survival [OS] is quite short. Patients received the study drug at 2 dose levels. The second dose level was considered the [recommended dose for] all patients. There were also 2 cohorts, 1 [comprising] all patients and another cohort just for patients [previously exposed to] venetoclax and BTK [inhibition]. The overall efficacy cohort had 88 patients, 50 [of whom were] double refractory.

What results were reported during the 2023 ASH Annual Meeting?

The results are quite impressive. We saw an ORR of approximately 40% and a CR rate of 20%, which was the primary end point. Importantly, [the rate of patients with] undetectable MRD in blood was [64% at dose level 2]. As this analysis showed, that translates into meaningful DOR that was NR, and partial responses [were seen in 25 patients] for the total cohort and 12 [patients in] the double-refractory cohort. [For] OS, there is a significant signal [of benefit], although we need more data to [confirm this.] OS was NR in patients who [responded] and [10.7] months for non-responders.

From a toxicity standpoint, there were no novel safety signals. [Any-grade] cytokine release syndrome and [neurologic events occurred at] incidences of 85% and 45%, respectively. However, most of [these events were] grade 1 or 2 and easily manageable. This may be the next approved intervention in the armamentarium for patients with CLL.

What unanswered questions remain regarding the role and future impact of liso-cel for patients who have progressed on all prior therapeutic options?

Question number 1 is whether some of those patients are cured. There is the potential for some of these patients to be cured and never require any therapy [again]. For most of these patients, it means resetting the clock. It means that the patients who have no [other] options at this point will have another couple of years of worry-free life [as] novel drug development is ongoing, and a couple of years later, we’ll have something new. That’s what we’re really seeing in the CLL space. We have patients who live normal, productive lives with a good quality of life, just moving from one agent to another agent. We may not be curing the disease, but we’re clearly making major headway.

What other lymphoma research presented during the meeting was of particular interest to you?

My interest is in T-cell lymphomas, so I’m pleased to see that the field is developing novel therapies. Two important abstracts were presented [at the meeting]: one is a phase 1 trial exploring valemetostat tosilate [Ezharmia] and the [other is the] phase 2 VALENTINE-PTCL01 trial [(NCT04703192) of] the same agent. Valemetostat is an EZH1/EZH2 selective inhibitor. EZH2 mutations are well-known in B-cell lymphomas. In T-cell lymphomas there may not necessarily be increased mutations [in EZH2], but [there] definitely [is] increased signaling, which leads to an antiapoptotic epigenetic landscape in the cell. An EZH1/2 inhibitor reverses [the tumor environment] back to an antiproliferative and anticancer [landscape.]

There were [2] T-cell cohorts [in the trial]. These included [patients with] relapsed/refractory peripheral T-cell lymphoma and [those with] adult T-cell leukemia [(ATL), respectively, the latter of] which is a particularly difficult leukemia to treat with a poor prognosis. [We saw] patients with ATL having overall responses of [approximately] 50% and PRs of approximately 30%. [For patients with] multiple relapses, that’s unheard of. We see a differential [in patients] with the T-follicular helper [(TFH) phenotype] of PTCL, [as these patients are] doing a little bit better [than other subtypes]. Another important [result from] this trial was that the duration of remission is long, which is quite significant in this field.

References

1. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel (liso-cel) in R/R CLL/SLL: 24-month median follow-up of TRANSCEND CLL 004. Blood. 2023;142(suppl 1):330. doi:10.1182/blood-2023-179529
2. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Breyanzi (lisocabtagene maraleucel) for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. November 9, 2023. Accessed February 16, 2024. https://news.bms.com/news/details/2023/U.S.-Food-and-Drug-Administration-Accepts-for-Priority-Review-Bristol-Myers-Squibbs-Application-for-Breyanzi-lisocabtagene-maraleucelfor-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx