Neelapu Hopeful FDA Will Approve Axicabtagene Ciloleucel for NHL

Sattva S. Neelapu, MD

Last month, a biologics license application (BLA) was submitted to the FDA for the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; KTE-C19) as a potential treatment for transplant ineligible patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL)

The BLA was based on findings from the phase II ZUMA-1 study, in which axi-cel demonstrated an objective response rate (ORR) of 82% and a complete response (CR) rate of 54% for patients with NHL.

“We are hoping that this [data] will lead to an FDA approval of this product. This is the first anti-CD19 CAR T-cell therapy trial that has shown significant clinical benefits in patients with chemotherapy refractory aggressive B-cell NHL,” said Sattva S. Neelapu, MD, an author on the ZUMA-1 trial.

OncLive: Can you provide some background on the objectives ZUMA-1?

In an interview with OncLive at the 2017 AACR Annual Meeting, Neelapu, associate professor, The University of Texas MD Anderson Cancer Center, discussed the ZUMA-1 trial and the potential impact of these results on patients with non-Hodgkin lymphoma.Neelapu: ZUMA-1 is the first multicenter trial of anti-CD19 CAR T-cell therapy—specifically axicabtagene ciloleucel, also known as axi-cel or KTE-C19—in patients with refractory aggressive B-cell NHL.

To be eligible for this trial, patients had to have either diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma. They also had to have chemotherapy refractory disease, which is defined as stable disease or progressive disease to the last line of therapy or relapsed within 12 months after prior autotransplant.

How was the trial designed?

The primary objective for the trial was ORR.This single-arm study had 2 cohorts. Cohort 1 included patients with DLBCL. Cohort 2 included patients with primary mediastinal B-cell lymphoma and transformed follicular lymphoma.

What were the significant findings from this study?

Following enrollment, the patients underwent leukapheresis and once the product had been manufactured, they resumed conditioning chemotherapy with cyclophosphamide and fludarabine for 3 days. Two days later, patients received an autologous CD19 CAR T-cell therapy particle, axi-cel, at a dose of 2 million cells/kg of body weight.We enrolled a total of 101 patients at 22 different sites. Of these 101 patients in the primary analysis, we discovered the best ORR was 82% and the CR rate was 54%. The study met its primary endpoint at this analysis with a P value of less than .0001.

What were the toxicities associated with this treatment?

At the median follow-up of 8.7 months, 44% of patients had ongoing responses and 39% had ongoing complete remissions. This compares very favorably to historical data where in a similar refractory population, the ORR with existing therapy is 26% and the CR rate is only 8%. The median survival for these patients with the current therapies is 6 and a half months. This study had a median follow-up of 8.7 months, with the majority of the patients still alive. In fact, at just 6 months, 80% of the patients were still alive.There are 2 toxicities observed with axi-cel. In this particular study, it was determined that 13% of the patients had cytokine release syndrome of grade 3 or higher and 28% of the patients had neurological toxicities of grade 3 or higher. The cytokine release syndrome is usually manifested as a fever, or perhaps hypertension or hypoxia. However, the majority of the side effects were reversible.

Can you discuss why new therapies are needed for these patients?

What are the next steps regarding this research?

There were 2 common agents, tocilizumab and corticosteroids, that were used to treat the toxicities. In this particular study, about one-third of the patients received tocilizumab and about 30% of the patients received corticosteroids, but there was no difference in efficacy of either agent.Once patients with aggressive B-cell NHL fail in the first-line or second-line of therapy and are not eligible for stem-cell transplants, there is no existing standard of care. The current standard of care is usually to use either third-line or fourth-line chemotherapy regimens, but these patients have very low response rates with the median survival only being 6 months. The majority of patients die within a year after the failure of the first 2 lines of therapy, creating a great unmet need for these patients at this point.We are hoping that this will lead to an FDA approval of this product. This is the first anti-CD19 CAR T-cell therapy trial that has shown significant clinical benefits in patients with chemotherapy refractory aggressive B-cell NHL.

Do you know when an FDA approval might be possible?

In terms of the next steps, we are connecting additional studies in the other B-cell malignancies. We have a ZUMA-2 study that is ongoing in mantle cell lymphoma patients. The ZUMA-3 and ZUMA-4 studies are being done in pediatric and adult ALL patients. There is a ZUMA-5 study that is about to begin in patients with follicular lymphoma and marginal zone B-cell lymphoma. The ZUMA-6 study is focused on a combination approach to further improve the efficacy of this product, using axi-cel in combination with an anti-PD-L1 agent.The biological licensing application for this product was filed by the sponsor, Kite Pharma at the beginning of April 2017. Over the next 3 to 6 months, we expect the FDA to review the product and hopefully approve it.

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