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Responses with CAR T-cell therapy appear durable for non-Hodgkin lymphoma
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ATLANTA — More than half of patients with refractory, aggressive non-Hodgkin lymphoma remained alive at least 1 year after receiving a single infusion of anti-CD19 chimeric antigen receptor T-cell therapy axicabtagene ciloleucel, according to updated results of the ZUMA-1 trial presented at the ASH Annual Meeting and Exposition.
“These results, published online in The New England Journal of Medicine, suggest that axicabtagene ciloleucel [Yescarta, Kite Pharma/Gilead Sciences] is highly effective for patients with diffuse large B-cell lymphoma who otherwise have no curative treatment options,” Sattva S. Neelapu, MD, professor at The University of Texas MD Anderson Cancer Center, said during a press conference.
As HemOnc Today previously reported, primary results from ZUMA-1 showed an overall response rate of 82% — including a 54% complete response rate — after a single infusion of axicabtagene ciloleucel. Forty-four patients remained in response at the time of the earlier analysis, conducted after a median follow-up of 8.7 months.
Based on these data, FDA approved the chimeric antigen receptor (CAR) T-cell therapy in October.
Neelapu presented 1-year follow-up of the trial to confirm the stability of response and to conduct exploratory biomarker analyses to understand the mechanisms of resistance to anti-CD19 CAR T-cell therapy.
The analysis included 108 patients (median age, 58 years) — including seven from the phase 1 trial and 101 from the phase 2 trial — with refractory diffuse large B-cell lymphoma, transformed follicular lymphoma or primary mediastinal large B-cell lymphoma.
Patients had progressed or demonstrated stable disease as their best response to last therapy, or had relapsed within 1 year of undergoing autologous stem cell transplantation. Seventy percent of patients had received three or more prior therapies, 74% were refractory to a second- or later-line of treatment, and 23% had relapsed following stem cell transplantation.
“What this reflects is that three-quarters of these patients could never get to a transplant, highlighting the refractory nature of these patients,” Neelapu said.
Patients underwent a conditioning regimen that included 500 mg/m2 cyclophosphamide plus 30 mg/m2 fludarabine for 3 days, followed by an infusion of axicabtagene ciloleucel at 2 × 106 CAR T cells/kg.
ORR served as the study’s primary endpoint.
After a median follow-up of 15.4 months, ORR was 82% and complete response rate was 58%.
Forty-two percent of patients remained in remission and 40% had an ongoing complete response. Duration of response was 11.1 months (95% CI, 3.9 to not estimable) overall, not reached for complete response, and 1.9 months (95% CI, 1.4-2.1) for partial response.
Median PFS was 5.8 months (95% CI, 3.3 to not estimable), and median OS was not reached (95% CI, 12-not estimable). At median follow-up, 42% of patients were progression free and 56% were alive.
Forty-six percent of patients experienced a grade 3 or worse serious adverse event. Twelve percent of patients experienced grade 3 or worse cytokine release syndrome and 31% experienced a grade 3 or worse neurological event. However, these all had been reported at the primary analysis, and researchers observed no new occurrences of cytokine release syndrome or neurologic events related to CAR T-cell therapy.
Ten patients experienced a serious adverse event 6 months following the primary analysis, including eight patients who experienced infections.
Although four patients died within 2 months of treatment, two of which were related to CAR T-cell therapy, researchers observed no new deaths related to therapy since the last analysis.
Researchers compared baseline and postprogression biopsies from patients to evaluate expression of CD19 and PD-L1. Three of 11 (27%) of patients with CD19-positive status at baseline no longer had CD19 present on their cancer cells at the time of disease progression.
Eight of 10 (80%) of patients evaluable for PD-L1 at the time of progression were positive. Of the eight patients who remained CD19 positive, five (63%) had PD-L1-positive tumor cells. Two of the three patients with CD19-negative cells had PD-L1-posiistve tumor cells.
Researchers have planned a randomized trial among patients with aggressive B-cell non-Hodgkin lymphoma to compare the efficacy of axicabtagene ciloleucel with the standard second-line therapy, which includes autologous stem cell transplantation after relapse.
“Long-term follow-up of ZUMA-1 confirms that these responses can be durable and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission,” Neelapu said in a press release. “With existing therapy, the median survival for people with this disease is only 6 months. Here, we see more than half of patients — 59% — are still alive over a year after treatment.”– by Alexandra Todak
Reference:
Neelapu SS, et al. Abstract 578. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: The study was funded by Kite Pharma, now Gilead Sciences. Neelapu reports research funding from Bristol-Myers Squibb, Celgene, Merck and Poseida, and consultant roles with Cellectis and Kite Pharma. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Andre Goy, MD
This is an update of the ZUMA-1 trial in refractory DLBCL among patients who failed induction therapy or relapsed within 12 months of autologous stem cell transplant. The response rate is high, at greater than 80%, and responses also are very durable.
The update shows that in 8 months, 41% of patients remained disease free. In a population of refractory DLBCL, there are no other treatment options, so having the ability to have 41% of patients responding without progression over 15 months the median follow-up now is something very important; these patients are potentially cured.
The next step is to try to understand mechanisms of resistance, which is obviously a challenge. The researchers started to evaluate data that suggest what makes a patient progress. Among some patients, what really matters is T-cell expansion at baseline, probably more than the persistence of the T cells, although you can detect these in most patients over time.
Researchers observed some loss of CD19 expression, but this was not observed in a large number of patients. The other marker is overexpression of PD-L1, which downregulates the immune control of lymphoma cells. Based on that, there is a rationale to combine the CAR T-cell therapy with atezolizumab (Tecentriq, Genentech), which is being evaluated in the ongoing ZUMA-6 trial. It seems very promising and is the next step in how we can expand on the CAR T-cell results.
Perspective
Back to TopRenier J. Brentjens, MD, PhD
These are phase 1/phase 2 data demonstrating outcomes with CAR T-cell therapy targeting CD19 for 108 patients with refractory non-Hodgkin lymphoma. Significantly, more than half of these patients are still alive more than a year after receiving therapy, which clearly is an outlier as far as phase 1/phase 2 trials go for patient outcomes. The ZUMA-1 trial has data that led to the approval of this CAR T-cell product for patients with DLBCL. In terms of safety, no new deaths were reported related to the therapy since the most recent update earlier this year. The study also provides some of the first clues as to why patients don’t respond to therapy.
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