A Groundbreaking First in CLL/SLL: Liso-Cel Makes its Mark as Only CAR T-Cell Therapy Approved

The FDA approval of lisocabtagene maraleucel (liso-cel; Breyanzi) for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) expands the previously limited arsenal for those with double-refractory disease and shows potential for becoming a favored third-line option in this space,according to Saad J. Kenderian, MB, CHB. He added that future research opportunities will likely explore the therapy in earlier lines.

On March 14, 2024, the FDA granted accelerated approval to liso-cel for the treatment of adult patients with relapsed/refractory CLL or SLL who have been treated with 2 or more prior lines of therapy, including a BCL-2 inhibitor and a BTK inhibitor. The decision was supported by response data from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198). Patients who received the CAR T-cell therapy achieved an objective response rate (ORR) of 45% (95% CI, 32.3%-57.5%), which included a complete response (CR) rate of 20% (95% CI, 11.1%-31.8%). In the overall population, the median duration of response (DOR) was 35.3 months (95% CI, 12.4-not reached [NR]). In those who achieved a CR, the median DOR was NR (95% CI, 15-NR).

“There could be room for improvement with CAR T-cell therapy, and we’re working to figure out how to make [these agents] better in CLL,” said Kenderian, who works as a consultant in the Division of Hematology, Department of Internal Medicine, Department of Immunology, and Department of Molecular Medicine at the Mayo Clinic in Rochester, Minnesota. Kenderian is also an assistant professor of oncology, immunology, and medicine. “Nevertheless, having [an agent that can generate] CR in 1 in 5 patients who are heavily pretreated and don’t have effective options is quite significant.”

In an interview with OncLive®, Kenderian discussed how the FDA approval of liso-cel helps address the limited amount of options in relapsed/refractory CLL, highlighted the efficacy and safety of the agent as reported in the TRANSCEND CLL 004 study, and expanded on ongoing efforts to optimize the use of liso-cel and other CAR T-cell therapies in various CLL subtypes.

OncLive: What is the significance of the FDA approval of liso-cel in previously treated CLL/SLL?

Kenderian: We are seeing that the response rate [with liso-cel] is decent and that approximately 20% of patients go into complete, deep remission. Arguably, [these [patients] are potentially cured of CLL. We know that in [this disease], some of the first patients who were treated with CAR T-cell therapy are in remission more than 10 years later. Also, some of our patients who are treated with liso-cel on the trial are in remission 3 or 4 years later. We are excited about this [approval] and excited to be able to use [this agent] in more patients.

What is unique about liso-cel’s mechanism of action compared with other CAR T-cell therapies available in hematologic malignancies?

Liso-cel is a 41BB CAR T-cell [product that targets] CD19. There are 2 CAR T-cell [therapies currently] used in the clinic. Some of [these therapies] have a 41BB [costimulatory domain] and some use a CD28 costimulatory domain. What we have learned in CLL, so far, is that liso-cel has significant activity in CLL. There was an early, phase 1 clinical trial [done in this disease] that used a CAR T product that has a CD28 costimulatory domain, and that [agent] did not have major efficacy. We’re excited that liso-cel specifically has activity [in CLL] and has been approved [for this population.]

How might the approval of liso-cel address unmet needs in CLL?

Patients with double-refractory CLL, who are refractory to BTK and BCL-2 inhibitors, have limited treatment options. The options [that are available] for these patients induce remission for a short period of time without meaningful disease control. Liso-cel presents a real opportunity [to expand effective] therapies in an area that has unmet need. [If] we continue to see this activity in the clinic, then we’ll be able to move liso-cel into earlier lines in CLL, similar to what we’re doing in lymphoma.

Please expand on some of the key data from TRANSCEND CLL 004 that supported the approval of the therapy. What should be known about the agent’s safety profile based on this study?

The significant findings are that [liso-cel] was well tolerated. The rate of CR was 20% in the subgroup [of patients] who were double refractory, and many [patients achieved] minimal residual disease negativity.

In general, the rates of toxicities following liso-cel [treatment] seem to be lower compared with other products, [especially] cytokine release syndrome [CRS]. Part of this is because liso-cel has a 1:1 ratio of CD4 and CD8 CAR T cells. The [toxicities observed] in TRANSCEND CLL 004 were in line with what we see in other trials, but the rates of CRS and neurotoxicity were on the lower side. This is encouraging for any disease affecting an older population that is heavily pretreated. Most CRS events were grade 1/2, and less than 10% [of patients] had grade 3 /4 CRS in the study. Most neurotoxicity was also grade 1/2, and approximately 18% [of patients experienced] grade 3 events.

What role do you see liso-cel playing in the third-line setting for this disease?

[Liso-cel is] definitely going to be an option for patients who progress following both BTK and BCL-2 inhibitors. Recently, we saw the FDA approval of pirtobrutinib [in CLL, which provides] another option. As far as the [optimal] third-line therapy goes, [that decision will be made] on a case-by-case basis. But certainly, the chances of [achieving] long-term durable remission makes liso-cel a favorable third-line option in CLL.

What research is needed to potentially move liso-cel into earlier lines of therapy for patients with CLL, and why might this be an advantageous strategy?

It makes sense to investigate liso-cel as a second-line therapy in CLL, because we know that CLL is a disease characterized by immune suppression. Patients with CLL have intrinsic T-cell defects, [which] continue to build up with time. The longer patients have the disease, the higher the chances that their T cells will become dysfunctional. If [a patient is treated with] CAR T-cell therapy at an earlier time point, there is a higher chance that [the agent] will be effective.

[This is] similar to what we’re seeing in lymphoma, [where] CAR T-cell [therapies used in] the second line [are associated with] higher response rates than [when used in] the third line. I expect that’s going to be more significant in CLL, because CLL T cells are more dysfunctional. There are early studies planned or currently taking place in the second-line setting in CLL, [that are] comparing CAR T-cell therapy with a second-line therapy in a randomized fashion.

What efforts to investigate liso-cel and other CAR T-cell therapies are planned or ongoing in this disease?

We’re continuously trying to figure out how to make CAR T-cell therapy more effective in CLL. We’re trying to understand why they don’t work as well in CLL and the mechanisms of resistance, [which] seem to be mostly mediated by the tumor microenvironment. We’re also trying to figure out how to engineer CAR T-cell therapies to overcome or be resistant to this inhibition. We’re excited about that area.

Within the CAR T-cell field, we are learning that a rational combination [regimen consisting of] FDA-approved therapies is a potentially translatable strategy to make CAR T-cell therapy better. For example, early data from the combination of ibrutinib [Imbruvica] and CAR T-cell therapy in CLL seems to be promising, with higher response rates and lower rates of toxicity. We’re excited about all the next-generation therapeutics within CLL.

Reference

US FDA approves Bristol Myers Squibb’s Breyanzi as the first and only CAR T cell therapy for adults with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. March 14, 2024. Accessed March 18, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Breyanzi--as-the-First-and-Only-CAR-T-Cell-Therapy-for-Adults-with-Relapsed-or-Refractory-Chronic-Lymphocytic-Leukemia-CLL-or-Small-Lymphocytic-Lymphoma-SLL/default.aspx