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Updated Follow-up of ZUMA-1 Confirms Benefit of CAR T-Cell Therapy in Aggressive B-Cell Lymphoma


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POSITIVE DATA about chimeric antigen receptor (CAR) T-cell therapy in lymphoma continue to accrue. Long-term follow-up of the pivotal ZUMA-1 trial shows that patients with refractory diffuse large B-cell lymphoma (DLBCL) continue to have durable responses to the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (Yescarta) after more than 1 year.1 

Of 108 patients enrolled in the trial, 42% continue to have ongoing remission after just one CAR T-cell infusion, and 40% of patients have no evidence of cancer at a median follow-up of 15.4 months. More than half of the patients enrolled in the trial are alive at 15.4 months, whereas median survival is about 6 months with existing therapy. 

Axicabtagene ciloleucel is the first CAR T-cell product to be approved by the U.S. Food and Drug Administration. 

Sattva S. Neelapu, MD

Sattva S. Neelapu, MD

“Long-term follow-up of ZUMA-1 confirms these responses can be durable, and the ongoing responses at 24 months suggest late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission,” said lead study author Sattva S. Neelapu, MD, Professor at The University of Texas MD Anderson Cancer Center. 

“We saw no late-onset cytokine-release syndrome or neurologic toxicity due to treatment. Durable responses were observed with and without detectable CAR T cells. We were able to identify two potential mechanisms of resistance—CD19 loss and programmed cell death ligand 1 (PD-L1) expression—suggesting avenues to pursue to prevent resistance,” Dr. Neelapu added. 

The study was published online in The New England Journal of Medicine to coincide with Dr. Neelapu’s presentation at the ASH meeting.2 

Study Details 

ZUMA-1 IS BEING conducted at 22 sites and is the largest study to date with a CD19-directed CAR T-cell therapy. The breakdown of patients included in the trial follows: 7 from phase I with refractory B-cell lymphoma; of the 101 patients enrolled in phase II, 77 had refractory DLBCL and 24 had refractory primary mediastinal B-cell lymphoma or transformed follicular lymphoma. Patients were treated with low-dose conditioning chemotherapy using fludarabine/cyclophosphamide for 3 days, followed by a single infusion of their own re-engineered T cells (axicabtagene ciloleucel). 

“To be successful, a personalized cell therapy must be delivered in a safe and timely manner. In this study, we confirmed the feasibility and reliability of centralized manufacturing and coordination of the leukapheresis procedures and shipping from multiple centers across the country,” Dr. Neelapu stated. Ninety-nine percent of patients had successful manufacturing of their T cells, with a short 17-day turnaround, and 91% were dosed. “The short turnaround time was critical for these patients with aggressive disease,” he added. 

Moreover, the study showed that axicabtagene ciloleucel could be safely administered at centers that perform transplantation, even if they had no prior experience with CAR T-cell therapy. 

At baseline, the median age was 58 years, 83% had stage III/IV disease, and 70% had had three or more prior therapies (74% were refractory to two or more therapies). More than three-quarters of patients did not quality for transplant, and 23% relapsed after transplant. 

Key Findings 

AT 15.4 MONTHS, the objective response rate was 82% (the same as at 8.7 months in the primary analysis). The complete response rate was 58%, compared with 54% at the earlier time point. At the time of follow-up, 42% remained in response and 40% remained in complete response. 

The median duration of response for all patients is 11.1 months. The median duration of complete response has not yet been reached. Moreover, 3 of the 7 patients enrolled in phase I continue to have a complete response at 24 months. “Some patients have converted from partial response to complete response without any additional therapy. We see consistent responses across all subgroups,” Dr. Neelapu revealed. 

Analysis of tumor tissue before and after treatment in relapsing patients showed a loss of the CD19 protein in one-third of patients, and more than two-thirds of tumors expressed the PD-L1 protein. Follow-up studies are now underway to identify possible approaches to overcoming these mechanisms of resistance. 

Safety Analysis 

SINCE THE PRIMARY analysis of the trial at 8.7 months of follow-up, with an additional 6+ months of follow-up, no new treatment-related cytokine-release syndrome or neurologic events nor grade 5 adverse events have been reported. Most patients experienced hypogammaglobulinemia and B-cell aplasia. About 8% received intravenous immunoglobulin support at some point during the trial. 

Serious adverse events occurring after 6 months were mainly infections (in 8 of 10 patients), all of which resolved by data cutoff. 

Renier J. Brentjens, MD, PhD

Renier J. Brentjens, MD, PhD

Stephen J. Schuster, MD

Stephen J. Schuster, MD

Additional Commentary 

“AT FIRST, CAR T-cell therapy seemed like something out of science fiction, but today we know that CAR T-cell therapies can induce long-term remissions in B-cell malignancies. It is encouraging that the data continue to be so strong and suggest that CAR T-cell therapies for B-cell malignancies are here to stay,” said press conference moderator Renier J. Brentjens, MD, PhD, Director of Cellular Therapeutics at Memorial Sloan Kettering Cancer Center, New York. “There is still a lot we need to learn about toxicities—for example, how to manage cytokine-release syndrome, a common, potentially dangerous reaction to this type of infusion.” 

“B-cell cancers are biologically different diseases and include diseases of precursor B cells like acute lymphocytic leukemia and more mature B cells, as in non-Hodgkin lymphomas. They differ in their anatomic location and in their ability to express inhibitory ligands. We see extraordinary responses in pediatric acute lymphoblastic leukemia because the cancer cells are in the bone marrow and blood and the T cells don’t have to search for cells in tissues. In large B-cell lymphoma, about 40% of patients can have durable responses, and in follicular lymphoma, 71% had a complete response lasting 1 year. Failure is due to different factors than in large B-cell lymphoma,” said Stephen J. Schuster, MD, Director of the Lymphoma Program at Penn Medicine in Philadelphia. ■

DISCLOSURE: Funding for this study was provided by Kite Pharma, Inc, now Gilead Sciences. Dr. Neelapu received research funding from Bristol-Myers Squibb, Poseida, Merck, Kite Pharma, and Cellectis. He also serves as a consultant or member of the Scientific Advisory Board for Merck, Kite Pharma, Novartis, Pfizer, and Celgene. Dr. Schuster has received research support from and is a consultant for Novartis. 

REFERENCES 

1. Neelapu SS, Locke FL, Bartlett NL, et al: Long-term follow-up ZUMA-1: A pivotal trial of axicabtagene ciloleucel in patients with refractory aggressive non-Hodgkin lymphoma. 2017 ASH Annual Meeting. Abstract 578. Presented December 11, 2017. 

2. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. December 10, 2017 (early release online). 


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