CAR T-Cell Therapies Continue to Raise the Bar in Lymphoma Management

Pashna N. Munshi, MD.

CAR T-cell therapies continue to elicit encouraging responses with manageable toxicity in older patients with lymphomas who may be unable to tolerate more intensive approaches, according to Pashna N. Munshi, MD.

In July 2020, the FDA approved brexucabtagene autoleucel (Tecartus; formerly KTE-X19)for the treatment of adult patients with relapsed/refractory mantle cell lymphoma (MCL) based on data from the ZUMA-2 trial. In 60 patients evaluable for efficacy based on a minimum duration of follow-up for response of 6 months, results showed that a single infusion of the product resulted in an 87% objective response rate (ORR), with a 62% complete remission (CR) rate.1

“Brexucabtagene autoleucel is going to provide patients with MCL with another treatment option. MCL is a very heterogeneous disorder; it can behave indolently in some patients, but in others, it's a very aggressive disease,” said Munshi, associate clinical director of the Stem Cell Transplant and Cellular Immunotherapy Program at MedStar Georgetown University Hospital. “Patients who relapse early often don't do very well and cannot get into remission. Having an option like CAR T-cell therapy gives these patients a chance to receive [a treatment] that is targeted, with manageable toxicities.”

The ZUMA-5 trial with axicabtagene ciloleucel (axi-cel; Yescarta) showed similarly impressive response rates, according to Munshi. Results from an interim analysis revealed that at a median follow-up of 15.3 months, patients with follicular lymphoma and marginal zone lymphoma (MZL) who received treatment with the CAR T-cell product experienced an ORR of 93% and a CR rate of 80%.2

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Leukemia/Lymphoma, Munshi, who is also an assistant professor of medicine at Georgetown University, discussed the CAR T-cell therapies that have emerged in the lymphoma space and highlighted the next steps for research with these products.

OncLive^®: Could you highlight some of the CAR T-cell products that are generating excitement in lymphoma?

Munshi: The most recently approved therapy was brexucabtagene autoleucel, which was evaluated in the ZUMA-2 trial; this was a phase 2, single-arm, open-label, multicenter trial done in patients with relapsed/refractory MCL. This product is similar to the CD19-targeted CAR T-cell product axicabtagene ciloleucel, although some differences exist.[Results showed] an ORR of 93%, with CR rates of 67% in a total of 68 patients. The ORR and the durability of those responses resulted in the approval of the product.

Another important clinical trial that is currently underway is ZUMA-5, which is being done in patients with relapsed/refractory indolent non-Hodgkin lymphoma. This trial had 2 cohorts: patients with follicular lymphoma and those with MZL. The follicular lymphoma cohort is now closed to enrollment and the results were [presented during] the 2020 ASCO Virtual Scientific Program and those results will be presented at the 2020 ASH Annual Meeting.

Ninety-six patients were evaluable for efficacy. [The ORR] was 95% in the follicular lymphoma arm and 81% for the MZL arm. At the time of data cutoff, 68% of patients had ongoing responses, so this is a very exciting therapy. We hope this will be a new indication for the treatment of patients with relapsed/refractory indolent lymphoma, especially follicular lymphoma.

What is the clinical significance of the brexucabtagene autoleucel approval?

One type of treatment approach that patients with MCL are offered is a high-dose chemotherapy with autologous stem cell transplantation. However, many patients may not be eligible for such high-intensity chemotherapy. Patients may be older, frail, and not in good enough shape to receive high-intensity treatment. CAR T-cell therapy may be given to these patients.

[In the ZUMA-2] trial, there was a substantial number of older patients [who achieved] very good responses [with the therapy]. The ORR was 87% at a median follow-up of about 8.6 months; this was later updated because 4 patients in the initial study were deemed as nonresponders by an independent radiology review. This therapy can potentially be given more up front for patients with MCL who have progressed on 2 or more lines of therapy.

Many older patients were also included on the ZUMA-5 trial. Could you expand on this? What does the safety look like with this product?

The median age range of participants was vast; the trial included patients who were as young as 34 years up to those who were 79 years. Many of these patients were older; they were over 60 years and yet, they could tolerate this therapy with really impressive ORRs.

Even though these therapies do have toxicities, such as cytokine release syndrome (CRS) and neurological effects, they are well [managed] by experts. We use therapies, such as the IL-6 inhibitor tocilizumab (Actemra) up front to treat CRS, as well as up-front steroids, in patients who may have some level of neurological involvement. In terms of the ZUMA-5 trial, it is important to note the age range and the fact that at least 73% of these patients were refractory to the last therapy they had received.

What are some of the updates that have been reported with tisagenlecleucel (tisa-cel; Kymriah)?

The [manufacturers of] tisa-cel presented real-world data with their commercial product and compared it with clinical trial results. They saw, if not similar, an almost improved toxicity profile and similar response rates which were reflective of their clinical trial.

Based on the initial JULIET study, 92% of patients were allowed bridging therapy. Only 72% to 75% of patients received bridging therapy on the commercial side. The real-world data showed a median ORR of approximately 60%, with approximately 40% achieving a CR; [this] is similar to the 40% best responses observed on the clinical trial.

The grade 3 or higher toxicities were very low; only 4.3% of patients experienced CRS; that is remarkable. More patients are increasingly being given up-front tocilizumab or steroid use, which is mitigating the toxicity of these therapies and making it safer for patients.

What are the next steps for research with this modality?

A Pandora's box has been opened. We’re not limited to CAR T-cell therapies; many, many targets are now being explored. There are CAR natural killer cell therapies; there are specific targets in leukemia that are being studied. CD33-targeted CAR T-cell trials are being done, and investigators are also exploring a combination of CD33-targeted and CD123-targeted products.

[Additionally], there are bispecific CAR T-cell engagers. Different methods are being used to try to see why relapse happens with CAR T-cell therapy. Maybe 1 antigen is lost and, therefore, you need a second antigen to be targeted, [hence] the CD19/CD22 combinations being examined in acute lymphoblastic leukemia. Many different forms of therapies are under exploration.

The next step is to find a way to [minimize] toxicities and relapse in the CAR T-cell world. The final stage is to look at off-the-shelf or allogeneic CAR T products. With these options, patients may not have to wait for their own cells to be processed as CAR T cells; the product will be readily available. That will really change how quickly these patients receive treatment, and it also potentially shifts the bar for many diseases.

For example, if this [approach] is successful in acute myeloid leukemia, many patients may get this therapy when they were not otherwise eligible for allogeneic stem cell therapy. If this therapy were to put them in remission, they could potentially make it to an allogeneic stem cell transplant or may not even need to undergo a transplant if these therapies prove durable. It's a very exciting future for CAR T cells.

What is your take-home message to your colleagues?

What I'd like to tell all the providers out there who are seeing patients with lymphoma and myeloma, especially with regard to refractory lymphomas, early referral is key. This is an autologous product, so it can take anywhere from 2 weeks to 3 weeks [to manufacture], depending on the type of product. When patients have an active malignancy, they're really waiting with active disease and it's hard to treat them with new therapy in between while they wait to receive CAR T-cells.

There is an aspect of overcoming insurance hurdles with some of these patients, as these are expensive products. Many milestones need to be achieved before patients can [receive] these therapies. Family members need education about the care that patients need once they're sent home. Also, referring providers may need to see these patients more frequently after they're treated with CAR T-cells, depending on their need.

There is some education that goes into this and we are armed as specialized, authorized treatment centers to arm patients and their caregivers with the knowledge about these therapies, the adverse effects of these approaches, and potentially provide them with a therapy that would make a change to the cancer in their body.

References

1. US FDA approves Kite’s Tecartus, the first and only CAR T treatment for relapsed or refractory mantle cell lymphoma. News Release. Kite. July 24, 2020. Accessed August 27, 2020. https://bit.ly/2ZVy6v9.
2. Jacobson CA, Chavez JC, Sehgal AR, et al. Interim analysis of ZUMA-5: a phase II study of axicabtagene ciloleucel (axi-cel) in patients (pts) with relapsed/refractory indolent non-Hodgkin lymphoma (R/R iNHL). J Clin Oncol. 2020;38(suppl 15):8008. doi:10.1200/JCO.2020.38.15_suppl.8008