CAR T-Cell Therapy Makes a Splash in MCL, But Optimal Sequencing Remains an Open Question

The FDA approval of brexucabtagene autoleucel (brexu-cel; Tecartus) established CAR T-cell therapy as a treatment option for patients with relapsed/refractory mantle cell lymphoma (MCL), said Brian Till, MD, who added that with the approval comes unanswered questions regarding whether brexu-cel is best sequenced as a second-line treatment, best practices to manage CAR T-cell therapy–related toxicities, and how additional products and novel targets could further the paradigm.

On July 24, 2020, the FDA approved the CD19-directed CAR T-cell therapy for the treatment of adult patients with relapsed/refractory MCL.¹ The regulatory decision was based on findings from the phase 2 ZUMA-2 trial in which a single infusion of brexu-cel induced an objective response rate (ORR) of 87% with a 62% complete response (CR) rate.²

During the 2020 ASH Annual Meeting and Exposition, updated findings from the study demonstrated an ORR of 92% with a 67% CR rate at a median 17.5 months of follow-up. Moreover, 48% of evaluable patients had ongoing responses at the data cutoff.³

In addition to brexu-cel, lisocabtagene maraleucel (liso-cel; Breyanzi) demonstrated an ORR of 84% with a 59% CR rate in 32 patients with relapsed/refractory MCL, according to findings from the ongoing phase 1 TRANSCEND-NHL-001 trial (NCT02631044).⁴

Notably, a lower incidence of severe cytokine release syndrome (CRS) was observed with liso-cel vs brexu-cel, which suggests that if the CAR T-cell therapy obtains FDA approval, it could be administered as outpatient treatment vs as inpatient treatment like brexu-cel, Till explained.

“CAR T-cell therapies are continuing to emerge; they are not going away,” said Till. The response rates are uniformly high across the board and the data look promising. The toxicity profiles are slightly different between the major CD19-targeted [products], but other [therapies] and targets are in development.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on CAR T-cell therapy, Till, a physician at the Seattle Cancer Care Alliance, an associate professor in the Division of Medical Oncology at the University of Washington School of Medicine, and an associate professor of the Clinical Research Division at the Fred Hutchinson Cancer Research Center, discussed the clinical implications of the FDA approval of brexu-cel, the promise of liso-cel, and remaining questions regarding toxicity, administration, and sequencing with these products.

OncLive®: How does the manufacturing process of brexu-cel differ from other CAR T-cell products?

Till: Brexu-cel is now approved. This is a therapy that is essentially the same construct as axicabtagene ciloleucel [Yescarta], but the manufacturing process is slightly different. Patients with MCL sometimes have circulating leukemic disease, so that [disease] is taken out [via] a selection step with brexu-cel. However, it is my understanding that the manufacturing process of the products are otherwise essentially the same.

What stood out to you from the ZUMA-2 data, which led to the FDA approval of brexu-cel?

[The data from the ZUMA-2 trial] were published in the New England Journal of Medicine in 2020 with subsequent FDA approval for [patients with MCL] who had [at least] 1 prior line of therapy.

[Michael Wang, MD, of The University of Texas MD Anderson Cancer Center] presented data with a little bit longer follow-up [than the interim analysis] at the 2020 ASH Annual Meeting and Exposition showing very high response rates of greater than 90% with about two-thirds of patients getting a CR.

What key questions remain with brexu-cel and will the large B-cell lymphoma experience aid in answering these questions?

The big question [with brexu-cel] is going to be durability and how long these remissions will last. Large cell lymphoma is a curable disease with chemotherapy and, in a subset of patients, with stem cell transplant. By contrast, MCL is typically considered incurable, at least with our standard therapies.

Whether CAR T-cell therapies will overcome [the incurable nature of MCL] is a huge question that we want to know. How long are these remissions going to last? The progression-free survival curve for brexu-cel looks promising, although there may be a few late relapses happening. Whether those [late relapses] are going to plateau over time is yet to be seen.

Are similar questions regarding durability being asked with liso-cel given that the data are not as mature as other products?

For liso-cel, [we’re asking] the same [questions]. A relatively small number of patients [have been treated with liso-cel], and the follow-up is relatively short. The preliminary results of the first 30 or so patients look very promising. The response rate is very high at more than 80% with again, about two-thirds of patients getting CR.

[The activity of liso-cel] is pretty similar to brexu-cel. [Regarding] safety, [liso-cel demonstrated] lower rates of CRS, particularly severe CRS [than brexu-cel]. The toxicity rates look comparable with brexu-cel in MCL vs large cell lymphoma as well as with liso-cel in MCL vs large cell lymphoma.

We are definitely seeing some differences in toxicity between [brexu-cel and liso-cel], and [liso-cel could be given as] outpatient [treatment] vs inpatient administration [with brexu-cel].

Do you anticipate that comfort level with CAR T-cell therapy will play a role in moving them into earlier lines of therapy?

There is probably a mix of people [who would or wouldn’t be comfortable taking patients to CAR T-cell therapy in the second-line setting]. Some of us who [give] CAR T-cell therapy more often have maybe a slightly higher comfort level for some of the toxicities [associated with CAR T-cell therapy]. Others may have more trepidation about [giving CAR T-cell therapy because] they view it as a fairly toxic [treatment] that they save for further down the line.

Some people are more comfortable with BTK inhibitors, so they may prefer to treat patients with at least one BTK inhibitor first and then go to CAR T-cell therapy in the third-line setting. That [approach] is fully reasonable, but especially as we get better at managing toxicity and less toxic CAR T-cell options become available to us, we have a more compelling case to [give CAR T-cell therapy] in the second-line setting. [This is] especially [true] if the remissions [associated with CAR T-cell therapy] turn out to be durable and maybe lead to cure. It is too early to say yet, but as the data mature and more options [become available], we will be better positioned to make those recommendations [for second-line CAR T-cell therapy].

What questions still need to be answered with regard to sequencing CAR T-cell therapy?

The future of CAR T-cell therapy is bright, and we are just learning our way in terms of where [these products] will fit into the armamentarium. Will they replace stem cell transplant? Presumably they will move earlier into the paradigm for [MCL], but how to best sequence [CAR T-cell therapies] is still being evaluated.

References

1. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma. FDA. News release. Published July 24, 2020. Accessed April 16, 2021. https://bit.ly/3tpHYtD.
2. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347
3. Wang M, Munoz J, Goy AH, et al. One-year follow-up of ZUMA-2, the multicenter, registrational study of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma. Blood. 2020;136(suppl 1):20-22. doi:10.1182/blood-2020-136382
4. Palomba ML, Gordon LI, Siddiqi T, et al. Safety and preliminary efficacy in patients with relapsed/refractory mantle cell lymphoma receiving lisocabtagene maraleucel in Transcend NHL 001. Blood. 2020;136(suppl 1):10-11. doi:10.1182/blood-2020-136158