In the primary overall survival analysis of ZUMA-7, second-line treatment with axicabtagene ciloleucel significantly improved overall survival compared with high-dose therapy plus autologous stem cell transplantation (auto-HCT) in patients with early relapsed or refractory large B-cell lymphoma. Patients treated with the chimeric antigen receptor (CAR) T-cell therapy experienced a 27.4% relative reduction in mortality as compared with patients receiving high-dose therapy and auto-HCT.
“ZUMA-7 confirms axicabtagene ciloleucel as a second-line standard of care for patients with refractory or early relapsed large B-cell lymphoma, based on superior survival,” said Jason Westin, MD, Director of the Lymphoma Clinical Research Program and Section Chief of the Aggressive Lymphoma Research Team in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, Houston. “Saving CAR T-cell therapy for third-line treatment after a lack of durable response to chemotherapy cannot match second-line treatment with axicabtagene ciloleucel.”
“Saving CAR T-cell therapy for third-line treatment after a lack of durable response to chemotherapy cannot match second-line treatment with axicabtagene ciloleucel.”— Jason Westin, MD
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ZUMA-7 is the first randomized controlled trial in nearly 30 years to show an overall survival benefit in the second-line setting for patients with large B-cell lymphoma, he said during a presentation at the 2023 ASCO Annual Meeting.1 The findings were simultaneously published in The New England Journal of Medicine.2
CAR T-cell therapy is a major advance in the treatment of these patients. Chemotherapy followed by high-dose therapy and auto-HCT has been the standard second-line therapy for decades, but patients are often ineligible, and just 10% are cured with this approach, Dr. Westin said.
The anti-CD19 CAR T-cell therapy axicabtagene ciloleucel is approved for patients with large B-cell lymphoma with early relapse (≤ 12 months after first-line therapy) and as treatment for third and later lines. This approval is based on superior event-free survival in the primary analysis of ZUMA-7 (hazard ratio [HR] = 0.398; P < .0001).3
Overall Survival Data
In the current primary overall survival analysis, at a median follow-up of 47.2 months, the median overall survival with axicabtagene ciloleucel was not reached and was 31 months in the control arm (HR = 0.726; P = .0168). The 4-year overall survival rate was 54.6% vs 46.0%, respectively, and the benefit was similar across key prespecified subsets.
In fact, this benefit was observed even though 57% of patients in the control arm, upon disease progression, subsequently received third-line cellular immunotherapy off-protocol. Also of note, survival rates in the control arm were higher than expected based on historical controls, yet overall survival with axicabtagene ciloleucel was still superior, Dr. Westin said.
KEY POINTS
- The primary overall survival analysis of ZUMA-7 showed a 27.4% reduction in deaths with second-line treatment using axicabtagene ciloleucel, in patients with relapsed or refractory large B-cell lymphoma.
- A survival benefit was observed even though 57% of the control arm, who received standard high-dose chemotherapy plus autologous stem cell transplantation, ultimately also received chimeric antigen receptor T-cell therapy off-protocol.
- The findings could result in the use of axicabtagene ciloleucel after first relapse or in patients who relapse up to 12 months after front-line therapy.
“I’ll call your attention to the fact that in patients with aggressive and refractory lymphomas, long-term survival that plateaus, as shown [in the Kaplan-Meier curve of this trial], is generally consistent with curative therapy,” he said during his presentation.
In the current overall survival analysis, axicabtagene ciloleucel also significantly improved progression-free survival. Median progression-free survival, as confirmed by investigators, was 14.7 months with CAR T-cell therapy vs 3.7 months with auto-HCT (HR = 0.506; P < .0001), and the 4-year progression-free survival rate was 41.8% vs 24.4%, respectively.
Dr. Westin and his colleagues believe the findings will effectively shift the treatment paradigm. “The initial question for a treating physician will no longer be, ‘Is my patient eligible for transplant?’ Instead, it will be, ‘How long ago did my patient relapse?’ In the vast majority who relapse within the first year of initial treatment, we believe the preferred treatment is CAR T-cell therapy,” he said.
About ZUMA-7
The 359 patients enrolled in the trial had relapsed or refractory large B-cell lymphoma, had disease progression within 12 months of first-line therapy, and planned to undergo high-dose therapy with auto-HCT. Patients who were randomly assigned to receive CAR T-cell therapy underwent prior conditioning chemotherapy. Patients assigned to receive the standard of care underwent at least two cycles of investigator-selected platinum-based chemoimmunotherapy; responders proceeded to transplantation, whereas nonresponders received an off-protocol treatment. The primary endpoint was event-free survival by blinded central review. Overall survival was a key secondary endpoint.
Baseline characteristics were balanced between the arms. Approximately 30% of patients were aged 65 or older, and approximately 74% had primary refractory disease. Of the 180 patients in the CAR T-cell arm, 170 (94%) received an infusion. Of the 170 patients in the standard-of-care arm, 64 (36%) ultimately received high-dose therapy and auto-HCT. “Nearly three times as many patients received definitive therapy with axicabtagene ciloleucel. The reason for not proceeding to definitive therapy on the standard of care was largely because of progressive disease,” he noted.
Tolerability Consistent With Previous Analysis
There were no changes in the rates of cumulative treatment-related serious or fatal adverse effects since the primary event-free analysis. Given that 57% of control patients received subsequent cellular immunotherapy, tolerability comparisons between cohorts are difficult, Dr. Westin noted. Regardless, cytokine-release syndrome of any grade was reported in 92% of patients given axicabtagene ciloleucel (6% grade 3). The CAR T-cell therapy arm experienced more neurologic events, hypogammaglobulinemia, and infections.
Definitive treatment-related deaths occurred in one patient in the CAR T-cell arm and two patients in the control arm. Deaths “during the protocol-specific reporting period” were noted for eight and two patients, respectively. New or secondary malignancies arose in two patients on CAR T-cell therapy and none on standard therapy.
DISCLOSURE: Dr Westin has served as a consultant or advisor to AbbVie, ADC Therapeutics, AstraZeneca, Bristol Myers Squibb/Celgene/Juno, Genentech/Roche, Iksuda Therapeutics, Janssen Scientific Affairs, Kite/Gilead, Merck, Monte Rosa Therapeutics, MorphoSys/Incyte, Novartis, and Seagen.
REFERENCES
1. Westin JR, Oluwole OO, Kersten MJ, et al: Primary overall survival analysis of the phase 3 randomized ZUMA-7 study of axicabtagene ciloleucel versus standard-of-care therapy in relapsed/refractory large B-cell lymphoma. 2023 ASCO Annual Meeting. Abstract LBA107. Presented June 5, 2023.
2. Westin JR, Oluwole OO, Kersten MJ; ZUMA-7 Investigators: Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med. June 5, 2023 (early release online).
3. Locke FL, Miklos DB, Jacobson CA, et al: Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med 386:640-654, 2022.
