Conference Coverage

CARs race for supremacy against aggressive non-Hodgkin lymphoma

 

Key clinical point: CAR-T cell therapies are showing good activity against relapsed/refractory non-Hodgkin lymphomas.

Major finding: In ZUMA-1, the objective response rate was 82%. In JULIET, it was 59%

Data source: Two multicenter trials of CAR-T cells in patients with relapsed/refractory DLBCL, PMBCL, and TFL.

Disclosures: The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.


 

AT EHA 2017

– Two chimeric antigen receptor T cell (CAR-T) constructs are showing promising activity against treatment-refractory, aggressive forms of non-Hodgkin lymphoma in multicenter clinical trials.

In the ZUMA-1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 CAR-T product, was associated with an 82% objective response rate (ORR), including 54% complete responses, in patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), or transformed follicular lymphoma (TFL), reported Yi Lin, MD, PhD, from the Mayo Clinic in Rochester Minnesota.

Yi Lin, MD, from the Mayo Clinic in Rochester Minnesota Nancy Baron/Frontline Medical News

Dr. Yi Lin

The 54% complete response rate “is almost seven-times higher than in historical controls,” she said in a briefing reported at the annual congress of the European Hematology Association here.

In an interim analysis from the JULIET study, a different anti-CD19 CAR-T construct labeled CTL019 was associated with a 59% ORR, consisting of 43% complete responses and 16% partial responses (PR) in patients with relapsed or refractory DLBCL, reported Gilles Salles, MD, PhD, from the University of Lyon, France.

The analysis “confirms the high response rates and durable responses observed in the previous single-center trial,” Dr. Salles said.

Although the CAR-T cell constructs in the study have different costimulatory molecules, each is created in a centralized facility, which allows for consistent manufacturing of cells sufficient for harvesting, transfecting, expanding, and reinfusing into heavily pretreated patients.

The construct used in ZUMA-1, also called KTE-C19 (Kite Pharma), has CD28 and CD3-zeta signaling domains. CTL019 (Novarits, U. Pennsylvania, and Oxford Biomedica) has CD3-zeta and 4-1BB costimulatory domains.

ZUMA-1

Dr. Lin reported phase II results from ZUMA-1, investigating axi-cel at a target dose of 2 x 106 cells per kilogram in 72 patients with refractory DLBCL (cohort 1), and 20 patients with refractory PMBCL or TFL (cohort 2).

The median patient age was 58 years. Patients had stage III or IV disease, 47% had International Prognostic Index (IPI) scores of 3-4, 77% had disease that was refractory to second-line therapies or beyond, and 21% had disease that relapsed within 12 months of an autologous bone marrow transplant

The axi-cel construct was successfully manufactured in 99% of patients, with an average turnaround time from apheresis to the clinical site of 17 days.

As noted before, the trial met its primary endpoint with an 82% ORR, consisting of 54% complete responses and 28% partial responses.

The median duration of response was 8.2 months, and for patients with complete responses the median duration has not been reached.

Median overall survival has also not been reached.

The treatment was generally safe, with only 13% of patients experiencing grade 3 or greater cytokine release syndrome (CRS), and 28% having grade 3 or greater neurologic events. The events were generally reversible, and the rates of each declined over time. The use of tociluzumab or steroids to control adverse events did not have a negative effect on responses, Dr. Lin said.

JULIET

In the ongoing JULIET study, patients with relapsed/refractory DLBCL after at least two prior lines of therapy and who are not candidates for stem cell transplants are enrolled.

Gilles Salles, MD, from the University of Lyon, France. Nancy Baron/Frontline Medical News

Dr. Gilles Salles

Dr. Salles presented results of an interim analysis of available efficacy data on 51 patients with at least 3 months of follow-up. In this population, the best overall response rate was 59%. Three-month ORR was 45%, consisting of 37% complete responses and 8% partial responses. Relapse-free survival at 6 months was 79%, and all patients who had responses at 3 months continued to have responses at the time of data cutoff.

In a safety analysis including 85 patients, the CRS was seen in 57% of all patients, including grade 3 in 17% and grade 4 in 9%.

Other common adverse events occurring within 8 weeks of CTL019 infusion were infections in 26% of patients, cytopenias lasting longer than 28 days in 26%, neurologic events in 21%, febrile neutropenia in 14%, and tumor lysis syndrome in 1%.

There were no cases of cerebral edema, and no deaths attributable to the CAR-T cell construct, Dr. Salles said.

Peter Borchmann, MD, from the University of Cologne, Germany, who attended the briefing but was not involved with either study, commented that investigators in ZUMA-1 need to monitor patients carefully, because previous clinical trials using other CAR-T cells with CD28 costimuatory domains have been associated with several cases of fatal cerebral edema.

“I think you can use CD28 in lymphoma, and it’s highly active as we have seen, but my personal impression is that you have to be aware that this might happen,” he said in an interview.

The ZUMA-1 study is funded by Kite Pharma. Dr. Lin disclosed research funding from Janssen. The JULIET study is supported by Novartis. Dr. Salles disclosed serving on an advisory board for the company. Dr. Borchmann had no disclosures.

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