Treating MCL 1 Year After the First CAR T-Cell Therapy Approval

Michael Wang, MD

The emergence of chimeric antigen receptor (CAR) T-cell therapies in the mantle cell lymphoma paradigm are a revolutionary addition that has improved efficacy outcomes in patients, according to multiple clinical trials.

Brexucabtagene autoleucel (formerly KTE-X19; Tecartus) was the first FDA-approved CAR T-cell product for relapsed/refractory MCL, which was granted based on results from the phase 2 ZUMA-2 clinical trial. In the study, brexucabtagene autoleucel achieved durable remission in most of the patients treated and the toxicities experienced by patients were consistent with the know toxicities observed with other CAR T cells therapies.¹

Overall, 74 patients were enrolled in the study, and 71 were administered brexucabtagene autoleucel at 2 × 10⁶ CAR T cells per kilogram of body weight. Objective responses were achieved in 85% of patients with a CR rate of 59%. The treatment also had an estimated progression-free survival of 61%.

Other CAR T products are being studied as a treatment for relapsed/refractory MCL and are showing promise, including lisocabtagene maraleucel (lisocel; Breyanzi). The drug is already approved for the treatment of relapsed/refractory aggressive large B-cell lymphoma as of February 2021.^2,3

In an interview with Targeted Oncology™, Michael Wang, MD, professor in the Department of Lymphoma & Myeloma at the University of Texas MD Anderson Cancer Center, discussed the evolution of treatment in the MCL space specifically with the emergence of CAR T cells.

TARGETED ONCOLOGY™: Can you explain what it’s been like to treat MCL since last year’s approval of the first CAR T-cell therapy for this disease?

Wang: During the SOHO Annual Meeting, my assignment was to talk about the CAR T-cell therapies in mantle cell carcinoma. I remember very clearly when the FDA approved brexucabtagene autoleucel on July 24, 2020. After that, we have been using this therapy to save patient’s lives ever since. There is a very intense usage of this product and it benefits our patients. We have treated over 30 patients since then and in the hospitals, there has increasing numbers every week and every month. For SOHO, we summarized our real-world data with brexucabtagene autoleucel in an abstract. This is from an ongoing project with multiple institutions such as the Mayo Clinic and Moffitt Cancer Center. So, the use of brexucabtagene autoleucel is high, and we will have much more real-world experience with this. This is an exciting time for our patients because this therapy could put patients with advanced mantle cell lymphoma into long-term remissions.

So far, have real-world outcomes with CAR T-cell therapy in relapsed/refractory MCL been similar to clinical trial outcomes?

Without any solid data, among the patients that have been treated at MD Anderson Cancer Center, we feel the efficacy is relatively the same. And of course, the study was conducted several years ago, even some 5 years ago and then we did not have so much therapy, knowledge or skills, or drug agents to combat cytokine release syndrome, neurotoxicity, and B-cell aplasia infections. Now, 5 years later, we have more agents, knowledge and comprehension on how to manage the toxicities. I feel that toxicity is much easier these days because we are better equipped. However, you can never let your guard down because CAR T-cell therapy is still relatively new, and the complications can still be life-threatening at times. While we enjoy our knowledge and skills to manage the disease, we continue to pay attention to patients’ symptoms and get them better. We not only want to protect them from toxicities but also get them into remission using CAR T cells.

This year, we also saw some excitement with liso-cel. Can you discuss the FDA approval of liso-cel and how it’s impacted treatment sense?

The liso-cel clinical trial were in large-cell lymphoma and mantle cell lymphoma. The large cell lymphoma trial has been reported to be very efficacious, and the deciding factor for toxicity is tolerable. During the last ASH meeting, M. Lia Palomba, MD, from Memorial Sloan Kettering Cancer Center, myself, and other colleagues reported the efficacy of liso-cel in relapsed mantle cell lymphoma from 32 patients. The overall response rate was 84% with a complete response rate of over 66%. We cannot compare trials across trial, but the efficacy of the brexucabtagene autoleucel can put us into the right context. The overall response rate of was 93% and the CR rate was 67%. So, you can see the CR rates between the 2 products in the 2 separate trials are relatively close. I really think the data on liso-cel relapse in relapsed/refractory mantle cell lymphoma shows good efficacy, and quite has been well-tolerated in relapsed/refractory mantle cell lymphoma. After the 32 patients, the trial is still ongoing and we are really looking forward to next presentation of data.

What advice can you give provide on the use of CAR T cells in MCL for community physicians who may still be using historic standards of care?

The clinical trials are conducted in the academic centers, and then the data is accumulated then FDA approved. Then those in the academic field will continue to use presentations to inform the community doctors on FDA-approved therapies. So, there's a lag time in getting information to the community, however, the lag time is improving.

Ever since the approval a little more than a year ago, I have started receiving referrals from the community oncologist for their patients and to be considered on CAR T-cell therapy. And so really, I think yes there are still oncologists using the older therapies, but I think the knowledge gap is closing very rapidly and everybody has heard about the CAR T cells. The MCL patient population is also very educated. So, I really think that with CAR T-cell therapies the efficacy and safety information will continue to spread and the usage of it will continue to rise. I think the future is bright.

With the agent that are coming down the pipeline, what clinical questions or challenges with treating MCL do you hope will be addressed?

In MCL, there are so many options, and with those options, how do know which therapy to use first. Also, how do you use the therapy later? We also need to know how do you design the whole strategy in a sequence? This all requires experience, knowledge, and skills and as well as good communication between the physicians and the patient. So those are the challenges in the future. But I think those are challenges that can be easily met.

_References:

_{1. 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; 382:1331-1342. doi: 10.1056/NEJMoa1914347}

_{2. Abramson JS, Palomba ML, Gordon LI, et al. Pivotal safety and efficacy results from Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso-cel) in relapsed/refractory (R/R) large B cell lymphomas. Blood. 2019;134(suppl 1):241. doi:10.1182/blood-2019-127508}

_{3. FDA approves new treatment for adults with relapsed or refractory large-b-cell lymphoma. News release. February 5, 2021. Accessed September 22, 2021. https://bit.ly/3zyWFNh}