CAR T-Cell Therapy Starts to Enter MCL Space

Frederick L. Locke, MD

Relapsed/refractory mantle cell lymphoma (MCL) is an aggressive disease that could benefit from the addition of chimeric antigen receptor (CAR) T-cell therapy. The ongoing ZUMA-2 trial is investigating the use of the anti-CD19 CAR T-cell product axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed/refractory MCL (NCT02601313).

The primary endpoint of this study is to evaluate the safety and efficacy of axi-cel as measured by overall response rate (ORR), with secondary endpoints including duration of response, best objective response, and progression-free survival. Patients enrolled on this trial must have had prior therapy with an anthracycline- or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and either ibrutinib (Imbruvica) or acalabrutinib (Calquence). The trial is estimated to have a primary completion date of July 2018.

Axi-cel has been FDA approved for patients with non-Hodgkin lymphoma (NHL) based on the overall objective response rate from the phase II portion of the ZUMA-1 study. The approval was specifically for patients with large B-cell lymphoma following 2 prior therapies, including diffuse large B-cell lymphoma (DLBCL). In the ZUMA-1 trial, axi-cel demonstrated an ORR of 82% and a CR rate of 54%. After 8.7 months of follow-up, 39% of patients remained in CR. The median duration of response in those with a CR was not reached at the time of the assessment (95% CI, 8.1-not estimable).

OncLive: Can you discuss the rationale behind conducting the ZUMA-2 trial for patients with MCL?

In an interview with OncLive, Frederick L. Locke, MD, a medical oncologist at Moffitt Cancer Center, and an investigator on ZUMA-2 and the co-lead investigator on ZUMA-1, discussed the ongoing ZUMA-2 trial investigating axi-cel for patients with MCL.Locke: The ZUMA-2 trial is a Kite Pharma/Gilead Sciences-sponsored multicenter clinical trial to evaluate the anti-CD19 CAR T-cell therapy called axi-cel as a treatment for patients with MCL.

What are the main challenges that exist for this patient population?

If this trial investigating axi-cel is successful, what impact could this type of therapy have on the MCL landscape?

Is it possible for axi-cel to be brought into the frontline setting for patients with MCL?

MCL is a B-cell cancer that can act indolently or aggressively. When the disease becomes refractory, it can grow very quickly. Newer FDA-approved medications with efficacy for late-stage MCL, such as the oral medication ibrutinib, have proven very effective to control disease for many patients. Unfortunately, for patients whose lymphoma grows while on ibrutinib, or the similar medication acalabrutinib, there are not many good options. This trial is attempting to investigate if that set of patients could go into remission for a prolonged period of time with axi-cel.Once ibrutinib stops working or if patients come off ibrutinib, we know that the disease may progress rapidly. These patients have very little time to be referred and enrolled onto the trial, so they could get CAR T cells manufactured.ery quickly. That is one of the big challenges for patients with MCL refractory to ibrutinib; patients need treatment [right away].We saw the FDA-approved indication for axi-cel in patients with DLBCL who have relapsed after 2 lines of therapy, but MCL is another lymphoma [that expresses CD19]. There are clearly patients who die of progressive MCL and need new therapies. If we can prove that axi-cel is safe and effective to use, the study has the potential to save lives.This is also a question that we have in DLBCL. I would not say that it is impossible, but we have to be deliberate and first answer the question of its safety and efficacy in refractory patients. We can then compare it to other earlier lines of therapy, which is the logical next step.

Is there anything else you would like to add?

Patients with MCL can be in remission for many years with upfront chemotherapy, anti-CD20 monoclonal antibodies. If patients are in CR and are consolidated with an autologous stem cell transplant, they could potentially remain in remission for a decade. To say that CAR T-cell therapy can compete with those preexisting responses in MCL is a big leap so we have a ways to go.It is important that people are aware of existing trials, not only for MCL but also for DLBCL, so they can determine whether their patients are eligible for a referral to a center that has clinical trials, especially in the CAR T-cell space and at first relapse. Referring patients at first relapse is important. Waiting for a second relapse or third relapse creates issues of getting those patients onto trials. There are study eligibility criteria, including while blood cell count and platelet count, which can be quite low for patients with MCL, especially if the patients have a large spleen or bone marrow involvement. Early referral is always better.

Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.