Liso-cel Expands CAR T-Cell Options in Lymphoma

Amitkumar Mehta, MD

Fewer than half of patients with relapsed/refractory large B-cell lymphoma respond to standard therapies following failure on second-line therapy.¹ In clinical studies, CD19-directed chimeric antigen receptor (CAR) T-cell therapies have yielded durable responses with tolerable safety profiles, making such agents an attractive option for patients in the third line and beyond. The approval of lisocabtagene maraleucel (liso-cel; Breyanzi) for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from indolent lymphoma, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.²

Investigators evaluated liso-cel in the TRANSCEND-NHL-001 trial (NCT02631044). The therapy was administered 2 to 7 days following completion of lymphodepleting chemotherapy, which consisted of f ludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 daily concurrently for 3 days. Results showed that the overall response rate (ORR) in 192 evaluable patients was 73% (95% CI, 67%-80%), with 54% (95% CI, 47%-61%) of patients experiencing a complete response and 19% (95% CI, 14%-26%) having a partial response. The median duration of response was 16.7 months (95% CI, 5.3-not reached).³

In an interview with OncLive^®, Amitkumar Mehta, MD, assistant professor in the Division of Hematology and Oncology at the University of Alabama at Birmingham (UAB), director of the UAB Lymphoma Working Group, and codirector of the Bone Marrow Transplant-Immune Effector Cell Therapies Program at the O’Neal Comprehensive Cancer Center, discussed the safety profile of liso-cel and how it is advancing the relapsed/refractory large B-cell lymphoma treatment paradigm.

OncLive^®: What was noteworthy about the efficacy data in the TRANSCEND-NHL-001 trial?

Mehta: TRANSCEND-NHL-001 was [a study of an] autologous CAR T-cell therapy in patients with relapsed/refractory aggressive B-cell lymphomas, including some patients with of the aggressive follicular 3B lymphoma. It has a very broad range of indications in aggressive B-cell lymphomas.

The efficacy was very impressive. This was a phase 1 study that was expanded to enroll more patients. This was a larger study, with a total enrollment of 344 patients, and ultimately, approximately 256 patients were evaluable. The ORR was 73%, and complete response rate was approximately 53%. This is very impressive for [patients with] relapsed/refractory aggressive B-cell lymphoma in this particular indication.

Please describe the mechanism of action of lisocabtagene maraleucel.

[Liso-cel] is an autologous CAR T-cell therapy [that begins with] plasmapheresis of a patient’s T cells [to] prepare them to fight CD19-containing B cells. Once the cells are collected, they are expanded and transfected with a vector [containing the anti-CD19 CAR transgene] on the surface of the T cells. The costimulatory domain for this patient population was 4-1BB, and the inherent T-cell activating domain was CD3ζ. It was a unique construct [that] we could personalize for patients with CD19-positive B-cell lymphomas.

What should clinicians know about lisocabtagene maraleucel in terms of safety? 

There are 2 other CAR T-cell therapies approved in this setting—axi-cel [axicabtagene ciloleucel; Yescarta] approved in 2017 and tisa-cel [tisagenlecleucel; Kymriah] approved in 2018—so we have something for comparison. With CAR T-cell therapies, cytokine release syndrome and immune effector cell therapy–associated neurotoxicity [ICAN] are very specialized adverse effects. For lisocabtagene maraleucel, very impressively, the [incidence of] cytokine release [syndrome] was much lower compared with the other 2 products. [Specifically,] the all-grade incidence rate was 42% and 2% for grade 3 or higher. Rates for all-grade ICAN were 30% and 10% for grade 3 or higher.

Other commonly observed adverse effects included cytopenia, neutropenia, anemia, and thrombocytopenia. [Liso-cel] was overall well tolerated in these patients. Knowing how to identify the cytokine release syndrome and ICAN was a learning curve over the past few years, but we now have a team who can identify these adverse effects quickly so that they can be mitigated.

How does this approval affect the treatment standards for relapsed/refractory large B-cell lymphoma?

If you look at patients with relapsed/refractory large B-cell lymphoma, they have inferior outcomes overall [to subsequent lines of therapy]. With conventional therapy, ORRs are inferior, and we learned this from SCHOLAR-1 data. SCHOLAR-1 was a retrospective analysis [in which investigators] benchmarked approximately a 20% overall response rate, with single-digit complete response rate, and an overall survival of just 6 months.⁴

If you compare these data with any of the [newer] CAR T-cell therapies, we have definitely moved the science forward. With lisocabtagene maraleucel, the most important [observation] was that it was well-tolerated and the toxicity rates were far lower [compared with other CAR T-cell products], and it had significantly higher, or at least comparable, response rates. Overall, this is a very important treatment and approval.

Another part I want to highlight is that approximately half of the patients remained in remission at 1 year, so this therapy could be potentially curative in this patient population [for which] there was no cure available.

What does the future hold for lisocabtagene maraleucel? 

One of the most important next steps is outpatient administration in this patient population. Most CAR T-cell therapies are done inpatient, and with the ongoing pandemic, it’s a challenge for these patients to [be admitted for treatment, but] they will sometimes get very ill because of the adverse effects. If a patient [experiences manageable] adverse effects, the therapy could be potentially be rolled out on an outpatient basis. This will expand the access to other patients.

References

1. González-Barca E, Boumendil A, Blaise D, et al. Outcome in patients with diffuse large B-cell lymphoma who relapse after autologous stem cell transplantation and receive active therapy. a retrospective analysis of the Lymphoma Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2020;55(2):393-399. doi:10.1038/s41409-019-0650-x
2. FDA approves lisocabtagene maraleucel for relapsed or refractory large B-cell lymphoma. FDA. Updated February 5, 2021. Accessed April 26, 2021. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-lisocabtagene-maraleucel-relapsed-or-refractory-large-b-cell-lymphoma 
3. Breyanzi. Prescribing information. Juno Therapeutics Inc; 2021. Accessed April 26, 2021. https://www.fda.gov/media/145711/download