Behind the FDA Approval of Liso-cel for Relapsed/Refractory CLL/SLL

Tanya Siddiqi, MD

On March 14, 2024, the FDA approved lisocabtagene maraleucel (liso-cel; Breyanzi) as a treatment option for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that had not responded to other treatments.¹ Findings from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) support liso-cel’s approval.^2,3

At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, the study showed that at a median follow-up of 21.0 months (95% CI, 17.5-26.6), the independent review committee (IRC)-assessed complete response (CR)/CR with incomplete hematologic recovery (CRi) rate was 18% (95% CI, 11%-28%) among all 87 patients treated with liso-cel at the recommended phase 2 dose of 100 x 10⁶ CAR-positive T cells (dose level 2 [DL2]).¹

The IRC-assessed objective response rate (ORR) was 47% (95% CI, 36%-58%), the rate of undetectable minimal residual disease (uMRD) in the blood was 64% (95% CI, 53%-74%), and the uMRD rate in marrow was 59% (95% CI, 48%-69%). Best overall response consisted of CR/CRi (18%), partial response (PR)/non confirmed PR (29%), stable disease (39%), and progressive disease (7%). Six patients (7%) were not evaluable.

Then, updated findings were presented during the 2024 Transplantation & Cellular Therapy Meetings, showing that at a median follow-up of 23.5 months, the chimeric antigen receptor (CAR) T-cell therapy given at dose level 2 led to an IRC-assessed CR/CRi rate of 20% (95% CI, 10%-34%) among patients in the prespecified subset who had progressed on a prior Bruton tyrosine kinase (BTK) inhibitor and who had failed previously failed venetoclax (Venclexta; n = 50).²

This group had an IRC-assessed ORR of 44% (95% CI, 30%-59%), 64% (95% CI, 49%-77%) of the patients achieved uMRD in the blood, and the uMRD rate in the marrow was 60% (95% CI, 45%-74%). Additionally, the median time to first response was 1.1 months (95% CI, 0.8-17.4), and time to first CR/CRi was 2.1 months (95% CI, 0.8-18.0).

The median duration of response at a median follow-up of 22.4 months (95% CI, 20.9-23.6) was 35.3 months (95% CI, 12.4-not reached [NR]) among those given liso-cel. Then, at a median follow-up of 24.2 months (95% CI, 23.6-25.2), the overall median progression-free survival (PFS) was 11.9 months (95% CI, 5.7-26.2). Among those who responded, the median PFS was 38.1 months (95% CI, 13.4-NR) compared with 3.7 months (95% CI, 2.4-6.1) among nonresponders.

Further, the total median overall survival (OS) at a median follow-up of 24.3 months (95% CI, 23.6-25.1) was 30.3 months (95% CI, 15.0-NR) with a median OS in responders of not reached vs 10.7 months (95% CI, 7.3-30.3) for nonresponders.

In an interview with Targeted Oncology^TM, Tanya Siddiqi, MD, hematologist, associate professor, medical director in the Division of Lymphoma at City of Hope Orange County in Duarte, California, further discussed the rationale behind the TRANSCEND CLL 004 study.

Targeted Oncology: What was the background behind the TRANSCEND CLL 004 study?

Siddiqi: CLL is considered to be an incurable chronic low-grade B-cell lymphoma. Our treatments have come a long way over the last few years in that we are not doing chemotherapy anymore. We have novel targeted therapies, immunotherapies, etc, but we still do not have a cure. We are now starting to see this population of patients who seem to be relapsing even after some of our best novel therapies. There is a need for better treatments for [patients] who have failed BTK inhibitors and venetoclax. Some of that is where CAR T cells might step in, at least to begin with.

The TRANSCEND CLL trial was especially designed for patients with CLL with relapsed/refractory disease after BTK inhibitors, then 2 or 3 total prior lines of therapy at a minimum. We wanted to see if CAR T cells can help give them durable remissions in that scenario.

What are the methods and design of the study?

Relapsed/refractory [patients with] CLL who had failed or had prior BTK inhibitor therapy and then 2 or 3 other prior lines of therapy in total, those patients would be eligible for this study if they were progressing again. We enrolled 117 patients. Bridging therapy was allowed while the CAR T cells were being manufactured for these 117 patients. Then, they all got their lymphodepletion to fludarabine and cyclophosphamide chemotherapy for 3 days, followed by a couple [of] days [of] rest, and then everybody got their liso-cel CAR T cells. We monitored them closely for the next couple of weeks, and then subsequently.

We enrolled 117 patients, and about 87 of these patients were evaluable for efficacy on dose level 2, because we had already previously shown that dose level 2 is the best dose level to move forward with. The primary analysis and trends on CLL is what we presented at ASCO, and that primary analysis was talking about the dose level 2 patients of which 49 out of those 87 efficacy-evaluable patients were in our so-called double refractory group where they had failed both prior BTK [inhibitor] therapy as well as venetoclax. That was our previously identified primary efficacy analysis subset of patients, those 49 patients. We did hypothesis testing on those patients. We were looking at things like complete remission rate as a primary end point, and there were secondary end points of overall response rate and undetectable minimal residual disease.

What are some important efficacy and safety data from the study?

Out of these 87 efficacy evaluable patients, 49 were on our primary efficacy analysis subset of double refractory, but the medium prior lines of therapy were 5. These 49 had failed probably BTK [inhibitor] and venetoclax therapy as well. Among that subset, the primary end point of complete remission rate was met at 18%. It was highly statistically significant, and it was well above our null hypothesis of less than or equal to 5%. The next criterion to be formally tested statistically was overall response rate, and that was about 43%. But it was not statistically significant, so we could not hierarchically test the next question on the study, which was uMRD rates, but our uMRD rates came back very high. Our null hypothesis was less than or equal to 5%, but the uMRD rate on this trial was as high as 63% in the blood and 59% in the marrow. There was good concordance between the blood and the marrow results.

All these remissions and deep MRD rates occurred as early as day 30 after CAR T cells. There were rapid, deep, and seemingly durable remissions. We followed these patients for a median of a couple of years now, although I certainly have patients now 4 or 5 years out who have not relapsed. Our progression-free survival rate overall has been about 35 months or so, but if [we] look at the complete remission patients, there were like 8 or 9 patients who achieved a complete remission [and] 18%, those patients have not relapsed yet. The median progression-free survival has not been reached for those patients. The deeper the MRD [means] undetectable MRD patients seem to also have a longer durability of remission. For this difficult-to-treat multiple refractory patient population, this 1 shot of CAR T cells seems to lead to hopefully years of remission for these patients without maintenance, without pills, without continuous infusions, which is sort of priceless for them. They enjoy their quality of life and treatment, so I think it has a lot of clinical benefits.

What other research is ongoing in this space?

For patients who failed both BTK [inhibitors] and venetoclax, which we consider to be our best to treatment options for [patients with] CLL, there are trials ongoing with other novel therapies like BTK degraders, which are pills, bispecific antibodies which are injections, and other CAR T-cell targets. It is not under full swing yet, but that would be the next sort of CAR T-cell program to consider, whereas liso-cel is CD19-directed. It is hopeful for these patients [and] there is a lot of research going on.

What unmet needs still exist and how can research help address these challenges?

The biggest message to send, especially to referring patients and referring physicians alike, is to send patients or have them come for clinical trials, because without clinical trials, we cannot get new drugs [that are] approved by the FDA and onto the market for the rest of the population to use. Send patients early for CAR T cells. Do not wait until they fail 5 lines of therapy. Their remission may not be long in that situation, but if you send them as soon as they fail BTK [inhibitors] and venetoclax, we have a trial now that is opening which they could be eligible for. Hopefully, CAR T cells will be FDA-approved in the near future, but until then we have to treat them on trial. Same for patients who need BTK degraders and bispecific antibodies. We have trials for all of that. Send patients early for these things so that they can get the most benefit out of it.

[Overall], send us patients for trials early. Patients themselves should look up and come for trial participation early. Do not miss the opportunity because these are all great drugs. There is no placebo and things like that. Everybody is [going to] get [a good] drug.

REFERENCES:

1. . U.S. 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 15, 2024. https://tinyurl.com/yf8ztnr5

2. Siddiqi T, Maloney DG, Kenderian S, et al. Lisocabtagene maraleucel (liso-cel) in R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): Primary analysis of TRANSCEND CLL 004. J Clin Oncol. 2023;41(suppl 16):7501. doi:10.1200/JCO.2023.41.16_suppl.7501

3. Shah NN, Siddiqi T, Maloney DG, et al. Lisocabtagene maraleucel in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: 24-month median follow-up of TRANSCEND CLL 04. Presented at: 2024 Transplantation & Cellular Therapy Meetings: February 21-24, 2024;Antonio, TX. Abstract 483.