Oncologists Highlight Major Unanswered Questions Remaining for Approved CAR T Treatment in MCL

A phase 2 study demonstrated encouraging findings for patients with relapsed/refractory mantle cell lymphoma (MCL) who were treated with a chimeric antigen receptor (CAR) T-cell therapy, brexucabtagene autoleucel (formerly KTE-X19; Tecartus). This therapy was approved by the FDA in July 2020 after demonstrating a 93% response rate among a highly refractory group of patients. However, some patients with MCL still progressed on this therapy, and there is little data available on how to manage patients appropriately following progressive disease (PD) on the CAR T-cell product.

In a report published online, investigators reported findings for 6 patients with MCL who were treated in the ZUMA-2 clinical trial (NCT02601313) and progressed following treatment with therapy brexucabtagene autoleucel. The addition of anti-CD19 CAR T-cell therapies to this treatment paradigm has been a major advancement, but more research is necessary to determine the characteristics and appropriate management techniques for this population.

Among 16 patients with relapsed/refractory MCL, 15 received brexucabtagene autoleucel and 1 received an experimental CAR product, and 6 patients in the brexucabtagene autoleucel arm progressed on therapy, all of whom had progressed on prior ibrutinib as well. This group of patients had a median of 6 prior lines of therapy (range, 2-4), and following progression, 2 had transformed to aggressive histology, while 3 did not receive a biopsy and 1 had remained blastoid MCL.

Among these patients, 3 patients also had high Ki-67 of ≥70% following progression, and 4 patients had an extra-nodal site of relapse, which included 2 skin and soft tissues, 1 central nervous system, and 1 testicular with skin involvement.

Among the 9 patients who stayed on the study and continued maintaining their complete response (CR), the median number of prior lines of therapy was 3 (range, 2-5), and all of these patients had also progressed on prior ibrutinib.

At or before the cell infusion, 2 patients had blastoid histology, while 7 had classic morphology MCL. The median Ki-67 percentage was 60% (range, 45%-100%), and in comparison, 2 patients in the arm that progressed had blastoid at/before cell infusion, 4 had classic morphology, and the median Ki-67 percentage was 70% (range, 20%-95%).

In all 15 patients who received brexucabtagene autoleucel, the same dose was given at 2 x 10⁶ T cells/kg body weight. All had similar conditioning under cohort 1 of the study.

Responses to Subsequent Therapy Following CAR T Progression

It was observed that 5 patients of the 6 who progressed were able to achieve a CR after treatment, and 1 patient had a partial response on brexucabtagene autoleucel. The median duration of response was 5 months (range, 1.2-31.2), and 5 patients had died at the last time of follow-up.

The median survival among these patients from the time to starting treatment with brexucabtagene autoleucel to the last follow-up was 17 months. The median survival after progression was 4.1 months, and the 1-year survival rate was 0%. The median number of subsequent lines of therapy was 2 (range, 0-6), and these treatments were selected based on clinical fitness, eligibility for clinical trial enrollment, and patient preferences.

Patient 1 was unable to receive any subsequent therapy and died with PD, while patients 2 and 4 had stable disease and later died with PD. Patient 3 was a non-responder to subsequent treatment. Patient 5 achieved a partial response on investigational therapy and remains alive, under follow-up. Patient 6 had a PR on subsequent therapy but later died with PD.

The subsequent therapies included a range of chemoimmunotherapy treatment with or without local radiation, venetoclax (Venclexta), acalabrutinib (Calquence), copanlisib (Aliqopa), and abemaciclib (Verzenio However, none of these therapies appeared successful in this patient population.

Patient 5, a 68-year-old male with transformed blastoid histology at the start of treatment, and patient 6, a 67-year-old male of the same histology, were the only 2 patients who survived beyond 6 months in the group of those who had progressed following brexucabtagene autoleucel. These 2 patients also had no apparent difference in the cell product, processing, or the characteristics compared with the other 4 patients. However, these patients (5 and 6) were physically fit to receive consecutive lines of therapy and achieved PRs, which were likely the cause for their longer survival following progression on brexucabtagene autoleucel.

Next Steps for Clinical Trials in MCL

The number of patients with MCL who progress on brexucabtagene autoleucel appears small, but longer follow-up on ongoing MCL studies of this CAR T-cell therapy could improve understanding around the pattern of relapses in this population. The report demonstrated that the management of these patients remains challenging and is an area of urgent clinical need, considering patients who progress on brexucabtagene autoleucel tend to have dismal outcomes on subsequent therapy.

Patients with high-risk disease, who are characterized by aggressive histology, high Ki-67 percentage, TP53mutations, and complex karyotype, tend not to respond to the therapies that are currently available, according to these findings.

At this time, it is unclear what mechanisms of resistance exist in MCL, representing an area of clinical need that remains to be investigated. The findings from patients who progressed on brexucabtagene autoleucel in the ZUMA-2 study demonstrated that the loss of CD19 following progression was observed in 1 patient alone, while it was unknown in 1 other patient, and 4 patients retained CD19 after progression.

In conclusion, clinical trials with newer agents should be considered for the treatment of patients with MCL who progress on or fail treatment with brexucabtagene autoleucel. For example, a combination of BTK inhibitors with brexucabtagene autoleucel may also influence the expansion of CAR T cells, help reach negative minimal residual disease, and prolong duration of remission, which is an active area of research.

While brexucabtagene autoleucel has been a promising new therapy in the treatment paradigm for MCL, it has posed many important questions that should be addressed in future studies. With more clinical trials and research, the use of new treatments, such as CAR T-cell therapy, could be improved to provide even more beneficial outcomes to patients with MCL.

_Reference

_{Jain P, Nastoupil L, Westin J, et al. Outcomes and management of patients with mantle cell lymphoma after progression on brexucabtagene autoleucel therapy. [Published Online November 05, 2020]. Br J Haematol. doi: 10.1111/bjh.17197}