First Data for CAR T-cell Therapy in Follicular Lymphoma: ZUMA-5

Alexander M. Castellino, PhD

December 11, 2020

For the first time, a chimeric antigen receptor (CAR) therapy has yielded a high response rate among patients with relapsed/refractory indolent non-Hodgkin lymphoma (iNHL), including patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL).

The new results come from the ZUMA-5 trial with axicabtagene ciloleucel (axi-cel; Yescarta), in which responses were seen in more than 90% of trial participants.

The results could lead to new indication for the product, which has already been approved for the treatment of large B-cell lymphoma for patients who experience disease progression with at least two prior lines of therapy. The approval was based on data from the ZUMA-1 trial.

The new data were reported at the American Society of Hematology (ASH) 2020 Annual Meeting by Caron Jacobson, MD, the Dana-Farber Cancer Institute, Boston, Massachusetts.

She said the data showed response rates of more than 90% among patients with iNFL, including patients with FL and MZL.

Data from ZUMA-5 in iNHL were more favorable than those seen in ZUMA-1 for patients with aggressive lymphomas.

"We were very impressed with the magnitude of the responses, and also the durability," Jacobsen said in an institute statement. "This treatment has meaningfully impacted high-risk patients with these diseases. I was also struck early on by how favorable the safety profile was compared to what we've been seeing in the fast-growing lymphomas."

Approached for comment, Gary Schiller, MD, professor of medicine and director of the Hematological Malignancy/Stem Cell Transplant Program at the David Geffen School of Medicine, University of California, Los Angeles, agreed.

"I found the results surprising, because the adverse event profile is more favorable than that seen for the other aggressive lymphomas. Even response rates are better than the ones seen in aggressive disease, such as ALL [acute lymphoblastic leukemia] and DLBCL [diffuse large B-cell lymphoma]," Schiller told Medscape Medical News.

In clinical practice, Schiller has used CAR T-cells for patients with diffuse large B-cell lymphoma, an indication specified on the current product labeling. He noted that prior authorization is required for patients with commercial insurance, but he said his patients have never been denied access. For these patients, he typically uses axi-cel after the second relapse.

Schiller pointed out that CAR T-cell therapy is evolving and that the toxicity profile of the therapy needs improvement, but he noted that "in this study, there was a low rate of grade 3/4 cytokine release syndrome — a more daunting side effect of CAR T-cell therapy."

"If approved for this indication [iNHL], I would consider using it," Schiller said.

Although other options are available for patients with iNHL, such as Bruton tyrosine kinase inhibitors, conventional chemoimmunotherapy, and PI3K [phosphatidyl inositol-3 kinase] inhibitors, Schiller noted that two thirds of patients have already received more than three prior lines of therapy and no other treatment options may be available.

"The study has convincingly demonstrated the unprecedent responses of CAR T-cells on heavily pretreated patients with FL, specifically for those who have failed multiple regimens," Henry Fung, MD, chair of the Department of Bone Marrow Transplant and Cellular Therapies, Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News. He predicted that axi-cell "will become a very important option for these patients."

Fung noted that despite the efficacy of CAR T-cell therapy, very few patients with advanced refractory disease are likely to experience a long-lasting response. "Now, we need studies to define the best time for this groundbreaking treatment and who will benefit the most. The ultimate goal should be achieving a durable remission and possibly cure," Fung told Medscape Medical News.

Ongoing clinical trials are exploring earlier use of CAR T-cells, Jacobsen commented. For example, CAR T-cell therapy is being tested in the second-line setting against salvage chemotherapy or autologous stem cell transplants for patients with high-risk disease.

Some results have been reported. For example, results of ZUMA-12 that were presented at the ASH meeting show that for patients with high-risk large B-cell lymphomas who did not experience a complete response to two cycles of an anti-CD20 monoclonal antibody and an anthracycline-containing regimen did experience a response to CAR T-cell therapy. This study will provide insights into the efficacy of CAR T-cells in the pseudo first-line setting, Jacobsen commented.

ZUMA-5 Study Details

ZUMA-5 was a multicenter, single-arm, phase 2 study that involved patients with relapsed or refractory iNHL who had received at least two prior lines of therapy.

Data were reported for 124 patients with FL and 22 patients with MZL. All patients had received CAR T-cells that had been made individually for each patient. About half the patients had bulky disease; 64% had received at least three prior lines of therapy; and 23% had received prior autologous stem cell transplants.

The median follow-up for efficacy was 17.5 months. The efficacy data for 104 patients (FL: 84 patients; MZL: 20 patients) showed an overall response rate of 92% (FL: 94%; MZL: 85%) and a complete response (CR) rate of 76% (FL: 80%; MZL: 60%). High response rates were seen across all groups of patients regardless of tumor burden, number, and type of prior therapies.

The 12-month duration of response was 71.7% for all patients and 77% for patients with FL. It was not evaluable for those with MZL.

One-year progression-free survival was 73.7%, and 1-year overall survival was 92.9%.

Safety data were reported for all 146 patients who received CAR T-cells. Most of the grade ≥3 side effects were cytopenias (70%) and infections (16%). Three patients died; one death, from CRS, was attributed to axi-cel.

CRS was seen in 82% of patients (grade ≥3 CRS: 7%). The median time to onset was 4 days, and the median duration was 6 days. At data cutoff, no patient had ongoing CRS.

Grade ≥3 neurologic events were reported in 15% of patients with FL and in 41% of patients with MZL.

Response rates were slightly higher and rates of adverse events were slightly lower among patients with FL than among those with MZL, Jacobson noted.

The ZUMA-5 trial was sponsored by Kite/Gilead, manufacturer of axi-cel. Jacobson has disclosed no relevant financial relationships. Schiller reported honoraria/research funding/consultancy/stock ownership from AbbVie, Actinium, Actuate, Agios Pharmaceuticals, Amgen, AROG, Astellas, Bristol-Myers Squibb, Celgene, Constellation Pharmaceuticals, Daiichi Sankyo, Deciphera, Delta-Fly, Forma, FujiFilm, Gamida, Genentech, Geron, Gilead, Glycomimetics, Incyte, Jazz Pharmaceuticals, J&J, Juno, Karyopharm, Kite/Gilead, Mateon Therapeutics, MedImmune, Onconova, Pfizer, RegImmune, Samus, Sangamo Therapeutics, Sanofi, Stemline, Takeda, Tolero, and Trovagene. Fung reported being on the speakers' bureaus of Jansen Oncology and Celgene/BMS.

American Society of Hematology (ASH) 2020 Annual Meeting: Abstract 700. Presented December 7, 2020.

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