Frederick L. Locke, MD
In the primary analysis of the phase III ZUMA-7 trial, the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel led to a fourfold increase in event-free survival over the standard of care in the second-line treatment of relapsed or refractory large B-cell lymphoma, according to findings presented by Frederick L. Locke, MD, and colleagues during the Plenary Session of the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 2).
“The results of ZUMA-7 herald a paradigm shift in how we treat large B-cell lymphoma,” said Dr. Locke, Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy, and Program Co-Leader of Immuno-Oncology, at Moffitt Cancer Center, Tampa, Florida, who called the benefit in second-line treatment “remarkable.”
Axicabtagene ciloleucel is currently approved by the U.S. Food and Drug Administration as a third-line therapy for this disease. The global phase III ZUMA-7 trial evaluated its benefit in the second line, as compared to platinum-based chemotherapy and hematopoietic autologous stem cell transplant (ASCT). Median follow-up was 24.9 months.
At a press briefing, Dr. Locke drove home the benefits observed with axicabtagene ciloleucel in ZUMA-7: “ZUMA-7 is the first randomized CAR T-cell trial with 24.9 months’ median follow-up…. [Axicabtagene ciloleucel] showed superiority over the standard of care, with more than a fourfold greater median event-free survival, a 2.5-fold greater 2-year event-free survival, a 33% higher objective response rate, double the complete response rate, and nearly three times the number of patients receiving definitive therapy, vs the standard of care.”
Laurie Sehn, MD
Laurie Sehn, MD, Clinical Professor at the BC Cancer Centre for Lymphoid Cancer and University of British Columbia, Vancouver, also said the results of ZUMA-7 and TRANSFORM, both presented at the press briefing she moderated, were remarkable. “They are so far in favor of CAR T-cell therapy that I think it’s inevitable this approach will become the standard of care” in the second-line setting, she said.
Dr. Sehn added that with axicabtagene ciloleucel in particular, the data are “very mature,” suggesting, after more than 24 months’ median follow-up, “there is a real difference in the curability” between axicabtagene ciloleucel and standard therapy. “For someone who has spent her career giving chemotherapy,” the move into a new era of therapy is “remarkably exciting and transformative,” she commented.
About ZUMA-7
Axicabtagene ciloleucel is an autologous anti-CD19 CAR T-cell therapy approved for relapsed/refractory large B-cell lymphoma after two or more prior systemic therapies. The phase III ZUMA-7 intended to determine if axicabtagene ciloleucel is beneficial as a second-line therapy for these patients. The study enrolled 359 patients who relapsed within 12 months of first-line chemoimmunotherapy and were transplant-eligible. Three quarters had primary refractory disease, and about half had high age-adjusted International Prognostic Index scores.
Patients were randomly assigned to axicabtagene ciloleucel, given as a single infusion of 2 × 106 CAR T cells/kg after conditioning with cyclophosphamide and fludarabine or platinum-based chemotherapy, or to platinum-based chemotherapy followed by ASCT in responders. Patients received their infusions a median of 29 days after randomization, and CAR T-cell levels peaked about 1 week after infusion.
Of 140 patients randomly assigned to axicabtagene ciloleucel, 94% were infused. Of the 179 patients randomly assigned to the control arm, only 64 (36%) reached transplant. Control arm patients not responding to the standard treatment could cross over to receive CAR T-cell therapy off protocol, as 56% did. The primary endpoint was event-free survival by blinded central review.
Importantly, the optional bridging treatment was corticosteroid only, a design feature that Dr. Locke emphasized in the press briefing. He explained that allowing chemotherapy as a bridging regimen meant that the benefits directly attributable to axicabtagene ciloleucel would be unclear. He considered this to be important: “When a patient randomized to [axicabtagene ciloleucel] could not get chemotherapy if needed, this was counted as an event,” he said.
This was unlike the design of the TRANSFORM study, which evaluated lisocabtagene maraleucel in similar patients and did allow chemotherapy for bridging (Abstract 91), he said. “We wanted to give [axicabtagene ciloleucel] without the confounding effects of chemotherapy, which we know can cause a response,” he explained.
Event-Free Survival Quadrupled
At a median follow-up of 24.9 months, the study’s primary endpoint was met: treatment with axicabtagene ciloleucel resulted in a median event-free survival of 8.3 months vs 2.0 months with the standard of care (hazard ratio [HR] = 0.398; P < .0001). The 24-month estimated event-free survival rate was 41% vs 16%, respectively.
Objective response rates were significantly higher than those seen with standard second-line therapy: 83% vs 50% (odds ratio = 5.31; P < .0001), and complete response rates were similarly increased: 65% vs 32%, respectively.
While median overall survival favored axicabtagene ciloleucel, it has not yet met statistical significance. Median overall survival was not reached but was 35.1 months in the control arm (HR = 0.730; P = .027). More than half the control arm crossed over to receive CAR T-cell therapy off protocol.
“For both study arms, the rates and types of adverse events were consistent with expectations based on previous trials and real-world experience,” Dr. Locke reported. “Rates of any adverse event, or serious adverse events, were similar between the arms, though the nature of the toxicities was different. The definitive therapy-related mortality, meaning the investigator attributed the death to [axicabtagene ciloleucel] or ASCT, was 1% and 3%, respectively.”
Dr. Locke concluded by noting, “By giving CAR T-cell therapy as an earlier line of treatment, we are able to reduce the amount of chemotherapy that patients are exposed to and get them quickly to a definitive therapy that can eradicate lymphoma for many years, if not forever, without a stem cell transplant.” The findings indicate that patients not responding to initial treatment or relapsing within 12 months “should have the opportunity to be treated with [axicabtagene ciloleucel],” he said.
Disclosure: Dr. Locke reported financial relationships with Allogene Therapeutics, Amgen, Bluebird Bio, EcoR1, Emerging Therapy Solutions, Gerson Lehrman Group, Iovance Biotherapeutics, Takeda, Novartis, Wugen, GammaDelta Therapeutics, Umoja, Cellular Biomedicine Group, Calibr, Cowen, BMS/Celgene, Legend Biotech, Kite, a Gilead Company, and Janssen. For full disclosures of the study authors, visit ash.confex.com.
