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Axicabtagene ciloleucel CAR T-cell therapy shows long-term benefit for non-Hodgkin lymphoma
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SALT LAKE CITY — The chimeric antigen receptor T-cell therapy axicabtagene ciloleucel induced significant clinical benefit with manageable adverse events among patients with refractory aggressive non-Hodgkin lymphoma, according to long-term follow-up of the pivotal ZUMA-1 clinical trial presented at the BMT Tandem Meetings.
“There is clearly an unmet need in refractory large B-cell lymphoma,” Frederick Locke, MD, interim chair of the department of blood and marrow transplant and cellular immunotherapy program co-leader, immunology of Moffitt Cancer Center, said during his presentation. “In the SCHOLAR-1 trial — a large patient meta-analysis that evaluated patients who had not responded to their last line of chemotherapy — the overall response rate to the next line of therapy was 26% ... and median OS was 6.3 months.”
In the primary analysis of ZUMA-1, axicabtagene ciloleucel (Yescarta; Kite Pharma, Gilead) — a second-generation chimeric antigen receptor (CAR) T-cell therapy approved for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy — showed an ORR of 82%, including 54% complete responses, with a manageable safety profile.
In the current analysis, Locke and colleagues provided 1-year follow-up data from ZUMA-1 — combining data from seven patients from the phase 1 portion with 101 patients from the phase 2 portion, for a total of 108 patients (median age, 58 years; 68% men) — as well as results of exploratory biomarker analyses to understand resistance mechanisms.
Patients had refractory diffuse large B-cell lymphoma, transformed follicular lymphoma or primary mediastinal large B-cell lymphoma and previously received anti-CD20 therapy and an anthracycline-containing regimen.
Seventy percent of patients had received three or more prior lines of therapy, and 74% were refractory to second- or later-line of therapy.
ORR served as the study’s primary endpoint. Key secondary endpoints included duration of response, OS and adverse events.
Data cutoff for this long-term analysis was Aug. 11, 2017, after a median follow-up of 15.4 months.
In combined updated analysis, ORR was 82%, with 58% of patients achieving complete response.
Forty-two percent of patients had an ongoing response, including 40% of patients with an ongoing complete response. Fifty-seven percent of patients in the phase 1 portion of the trial achieved a complete response.
“Importantly, in the updated analysis, 23 out of 60 patients, or over a third of patients, who had either a partial response or stable disease at the first tumor assessment 1 month after infusion, subsequently achieved a complete response up to 15 months postinfusion without additional therapy,” Locke said.
Median time to conversion from partial response to complete response was 64 days (range, 49-424).
“This suggests that if you have a patient who has had stable disease or partial response to axicabtagene ciloleucel therapy, continuing to follow that patient rather than doing consolidative transplant would be an appropriate action,” Locke said.
High-risk covariates such as stage III or IV disease, high international prognostic index risk score and being refractory to two consecutive lines of therapy did not predict for decreased likelihood of ongoing response beyond 1 year. Receiving tocilizumab (Actemra, Genentech) or corticosteroids for adverse events also did not predict reduced likelihood for ongoing response.
Duration of response was 11.1 months (95% CI, 3.9-not reached) overall and not reached for patients in complete response. However, patients in partial response appeared to have a shorter duration of response, at 1.9 months (95% CI, 1.4-2.1).
“Those patients fared poorly but, keep in mind, many of those patients are bumped up [to the complete response curve] when they eventually attained a complete response,” Locke said.
Also, 43% of phase 1 patients had an ongoing complete response at 24 months.
At the time of median follow-up, researchers reported a 42% PFS rate and 56% OS rate. Landmark 18-month analyses showed a 41% PFS rate and 52% OS rate.
Ninety-seven percent of patients experienced a grade 3 or higher adverse event, many of which were hematologic in nature and associated with chemotherapy.
Twelve percent of patients had grade 3 or higher cytokine release syndrome, and 31% had grade 3 or higher neurologic event.
Four patients experienced a grade 5 adverse event, two of which were attributed to CAR T-cell therapy — hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of cytokine release syndrome. One patient died of pulmonary embolism, and one patient died of intracranial hemorrhage deemed unrelated to therapy.
Most patients experienced hypogammaglobulinemia and B-cell aplasia, and 8% of patients had IV immunoglobin G support at any point during the study.
However, since the primary analysis with 6 additional months of follow-up there have been no new cases of therapy-related cytokine release syndrome, neurologic events or grade 5 adverse events.
Infections — including lung infection, pneumonia or viral upper respiratory infections — were the most common new-onset treatment-related serious adverse event reported after 6 months, occurring in eight patients. These all resolved at the time of the data cut-off.
Researchers observed persisting CAR T cells in 71% of patients who remained in response at 1 year. However, durable responses occurred for patients with and without detectable persisting CAR T cells, “suggesting that at the 1-year time point, ongoing appearance of CAR T cells may not be necessary for continued remission,” Locke said.
Twenty-one patients with progression had a biopsy evaluated by central review. Thirty-three percent of these biopsies were CD19 negative by immunohistochemistry, whereas 67% remained CD19 positive. Sixty-two percent were PD-L1 positive.
“These data suggest there are two possible mechanisms for evasion of CAR T-cell therapy, loss of CD19 antigen at the binding epitope of the CAR T cells, or upregulation of negative regulator molecules within the immune environment,” Locke said.
Overall, these data show that axicabtagene ciloleucel is “highly effective in patients with large B-cell lymphoma who otherwise have no curative options,” Locke said. – by Alexandra Todak
Reference:
Neelapu SS, et al. Abstract 63. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Disclosures: Locke reports research support from and a scientific advisory board role with Kite, a Gilead Company. He also reports a consultant role with Cellular BioMedicine Group. Please see the abstract for all other authors’ relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.