Dr Westin on Brexucabtagene Autoleucel as a “Transformative” CAR-T Therapy for R/R MCL

Jason Westin, MD, FACP, Director of Lymphoma Clinical Research and Section Chief for Aggressive Lymphomas, MD Anderson Cancer Center, Houston, Texas, discusses the ZUMA-2 trial on the efficacy of brexucabtagene autoleucel (KTE-X19), an anti-CD19 CAR-T cell therapy, for patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) after several prior lines of therapy.

Transcript

Hi, my name's Dr Jason Westin. I'm the director of lymphoma clinical research and section chief for aggressive lymphomas at MD Anderson in Houston, Texas.

The study in question for today's discussion came from the unmet need in a subtype of non-Hodgkin lymphoma called MCL. MCL is a disease that has characteristics of both slow-growing lymphomas and aggressive lymphomas. Slow-growing in that it frequently relapses and comes back despite good responses to initial therapy and aggressive lymphoma in that when it does relapse, it can do so in a fulminate manner and be life-threatening.

This clinical trial, the so-called ZUMA-2 trial which led to the FDA approval of brexucabtagene, a CAR T-cell product, was designed to tackle this unmet need and provide a highly effective novel therapy for patients with R/R MCL.

The ZUMA-2 trial was designed to target patients with R/R MCL who had exposure to several lines of prior therapy, including a prior CD20 antibody, prior BTK inhibitor, and prior chemotherapy. This was an adverse group of patients with heavily pretreated disease usually go along with lower responses to future therapy.

This trial enrolled patients who had adequate organ function and adequate blood counts. They underwent a procedure called apheresis, which is collection of their immune cells, specifically their T-cells, which could then be modified genetically by the trial team to now express a chimeric antigen receptor, or a CAR, on the surface of the T-cells.

This CAR receptor on the surface of the T-cells could now target the CD19 on the outside of the lymphoma cells and basically turn their native T-cells into heat-seeking missiles going after the cancer, now being able to see the wolf in sheep's clothing.

On the ZUMA-2 trial, we found an extremely high response rate. Nearly 90% of patients responded in this R/R population with an acceptable safety profile.

What was notable to me on this particular clinical trial was that the high response rates were achieved greater than what we had seen with prior therapies in this space and the toxicities were generally similar to what we had seen on prior CAR T-cell studies with the main toxicities of note being so-called cytokine release syndrome and neurologic toxicity or ICANS. Both of those are known and well-managed by CAR T-cell physicians at specialty centers.

The real-world applications of the ZUMA-2 trial include that the FDA has reviewed these data and deemed this appropriate and significant enough for an approval of this product, which is now known as brexucabtagene.

Brexucabtagene is a transformative therapy for patients with R/R MCL and is changing the standard of care across all areas where CAR T-cells are approved, currently in the US but likely to expand to the EU and to other areas where CAR T-cells are rightly utilized.

It's too early yet to know the future for this product in terms of its ability to provide cures or long-term disease controls, but it looks incredible thus far, with patients who have achieved a good response, a complete response, having a durable response in the majority of patients.

We know that MCL, unfortunately, does have a history in the past of responding well to therapies and then relapsing at a later date, but we're hopeful with the power of the CAR T-cell based therapy that we may be able to provide for, at least a good portion of our patients, a long-term disease control and, if we can be so bold as to hope that these may be curative therapies in some patients.

Obviously, we need more follow up to confirm that, but that's our hope for this clinical trial.

The ZUMA-2 trial was led by my colleague, Dr Michael Wong here at MD Anderson. He and the other co-investigators on this clinical trial are absolutely planning additional research to follow on to this.

In the large cell lymphoma space, and the follicular lymphoma space, and in the MCL space there is an avalanche of new clinical research ongoing using cellular therapies, both autologous CAR T-cells, allogeneic CAR T-cells, NK cells, you name it. There is an explosion of research because it seems that these therapies have the potential to overcome disease resistance in ways that chemotherapy or even other targeted therapies have not.

Specifically following on to the ZUMA-2 trial, there are additional studies in mantle cell patients looking at the idea of combining CAR T-cell with other therapies relevant, such as BTK inhibitors or BCL-2 inhibitors, other immune therapies to try and further improve the response rates and decrease the toxicity. Using these CAR T-cell products in earlier lines of therapy to avoid the aggressive disease we can see in the R/R population.

The last thing that I would note about this clinical research is shows the power of clinical trials. Many times our patients come to see us and they're hesitant to enroll in a clinical trial. They don't want to be treated as a guinea pig, or they don't want to be experimented upon. They had a friend or a family member who had a bad experience on a clinical trial.

Literally all new drugs come from clinical trials. It is the engine of discovery. For many of our patients, it is the best option for treatment of their disease.

For patients who are considering clinical trials or their physician's recommending them, they're thinking about going for a second opinion at a site that has clinical trials. I would strongly, strongly encourage you to do that because these types of therapies don't just show up without having been studied in clinical research.

Perhaps you could both help yourself by getting tomorrow's treatment today, as well as to be a pioneer in the field leading to others behind you getting breakthrough therapies.