Expert Discusses ZUMA-2 Trial Investigating CAR T-Cell Therapy in MCL

Frederick L. Locke, MD

Frederick L. Locke, MD

While relapsed/refractory mantle cell lymphoma (MCL) is considered an aggressive disease, new findings show patients may benefit from adding chimeric antigen receptor (CAR) T-cell therapy to their treatment regimen. ZUMA-2, a currently ongoing trial, aims to understand the potential benefits with axicabtagene ciloleucel (axi-cel; Yescarta), an anti-CD19 CAR T-cell product, for patients with relapsed/refractory MCL (NCT02601313).

The ZUMA-2 trial set a primary endpoint of safety and efficacy of axi-cel, measured by overall response rate (ORR). Secondary endpoints were selected as duration of response, best objective response, and progression-free survival. It was required that patients in the trial had prior therapy with an anthracycline- or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and either ibrutinib (Imbruvica) or acalabrutinib (Calquence). Researchers estimate a primary completion date for this study in July 2018.

The FDA has approved axi-cel for patients with non-Hodgkin lymphoma (NHL) based on findings from the ZUMA-1 trial. The approval was specified for patients with large B-cell lymphoma that had received 2 prior lines of therapy, also including diffuse large B-cell lymphoma (DLBCL). An ORR of 82% was reached with Axi-cel, as well as a CR rate of 54%. With an 8.7 month follow-up, 39% of the patients in the ZUMA-1 trial remained in CR. Median duration of response was not reached, though, at the time of assessment (95% CI, 8.1-not estimable).

In an interview with Targeted Oncology, Frederick L. Locke, MD, a medical oncologist at Moffitt Cancer Center, investigator on ZUMA-2, and co-lead investigator on ZUMA-1, discussed the ongoing ZUMA-2 trial investigating axi-cel for patients with MCL. He also highlights the impact this trial and its results will have on the treatment landscape of this disease.

TARGETED ONCOLOGY:Can you discuss the rationale behind conducting the ZUMA-2 trial 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. 

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.

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

Locke: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].

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

Locke: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.

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

Locke: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.

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.

TARGETED ONCOLOGY:Is there anything else you would like to add?

Locke: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.

Reference:

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.