Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Long-term results from ZUMA-1, a multicenter, single-arm, Phase 1/2 study of axi-cel in patients with refractory LBCL, demonstrated sustained overall survival (OS), with a median of 25.8 months and a 5-year estimate of 43% (Neelapu SS, et al. Blood. 2023). Initial assessments of disease-specific survival (DSS) in ZUMA-1 suggested axi-cel may be curative for a subset of patients. However, endpoints defining curative potential in patients with LBCL are not yet clearly established. Here, we report exploratory analyses from the Phase 2 portion of ZUMA-1 using proposed endpoints to measure cure along with survival analyses with up to 6 years of follow-up.
Methods: Eligible adults in the pivotal Phase 2 Cohorts (1 and 2) of ZUMA-1 had refractory LBCL (diffuse LBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma). Patients were leukapheresed at enrollment, then received lymphodepletion and axi-cel infusion (2×10 6 CAR T cells/kg; Neelapu et al. N Engl J Med. 2017). Exploratory analyses to assess curative potential included lymphoma-related event-free survival (LREFS), duration of complete response (DOCR), and DSS. LREFS was defined as the time from axi-cel infusion until disease progression, initiation of new lymphoma therapy, autologous stem cell transplantation, or death due to progression, whichever was earliest. DSS was defined as time from axi-cel infusion to death due to progression or axi-cel-related adverse events (AEs). Outcomes were analyzed via Kaplan-Meier (KM) estimates and competing risk analyses. Landmark analyses were used to explore prognostic potential of disease status at Week 4 and Months 3, 6, 12 and 24.
Results: At a median follow-up of 63.1 months in the 5-year analysis (data cutoff on August 11, 2021), median LREFS was 5.8 months (95% CI, 3.4-13.9) and the 60-month LREFS rate by KM estimate was 33.5%. Among patients who achieved a complete response (CR) as best response (n=59), median DOCR was not reached (95% CI, 12.9 months-not estimable). Median LREFS among those with a CR was not reached (95% CI, 18.4 months-not estimable) and the 60-month LREFS rate was 56.8%. Among those with a CR at Months 12 and 24, 60-month estimated rates of LREFS and ongoing CR were >80% (Table 1). All 3 lymphoma-related events that occurred after Month 24 in those with a CR were disease progression. Among those with a partial response at Week 4 (n=33) and Month 3 (n=10), estimates of 60-month LREFS were 27.3% and 45.0%, respectively.
The data cutoff date for the 6-year survival analysis was August 11, 2022. Median OS was 25.8 months (95% CI, 12.8-63.7). In a competing risk assessment of OS, the cumulative incidence of death at 72 months was 61.6%. Between Months 24 and 72, there appeared to be an increase of 6% in the cumulative incidences of death due to progression (40.6% and 46.6%, respectively) and other reasons (5.0% and 11%, respectively), while deaths due to axi-cel-related AEs remained 4.0% at each timepoint. Among patients with a best response of a CR, the cumulative incidence rates of death at Month 24 and Month 72 were 20.3% and 27.2% for progression, 3.4% (both timepoints) for axi-cel-related AEs, and 0% and 10.4% for other reasons, respectively. Those who had a CR at Months 12 and 24 had a 72-month cumulative incidence of death of 18.4% and 14.2%, respectively (Table 2). Additionally, those who had a CR at 12 and 24 months had 72-month KM-estimated DSS of 94.4% and 100%, respectively. Among those with a partial response at Week 4 and Month 3, 72-month cumulative incidences of death were 72.7% and 50.0%, respectively.
Conclusion: In this post hoc analysis of ZUMA-1 with up to 6 years of follow-up, axi-cel had long-term LREFS in a substantial proportion of patients, with a 5-year rate of 34% (57% among patients who achieved a CR). Additionally, a CR at 12 and 24 months may be predictive of extended OS. Among patients who achieved a CR, deaths due to axi-cel-related AEs mainly occurred before Month 24. These results demonstrate the curative potential of axi-cel in a subset of patients with R/R LBCL.
Disclosures
Neelapu:Fosun Kite: Consultancy, Other: Advisory board member; Morphosys: Consultancy, Other: Advisory board member; Immunoadoptive Cell Therapy Private Limited: Consultancy, Other: Scientific Advisory Board; Chimagen: Consultancy, Other: Advisory board member; Bluebird Bio: Consultancy, Other: Advisory board member; Takeda: Consultancy, Other: Advisory board member; Orna Therapeutics: Consultancy, Other: Advisory board member; Bristol Myers Squibb: Consultancy, Other: Advisory Board Member, Research Funding; Incyte: Consultancy, Other: Advisory board member; Merck: Consultancy, Other: Advisory Board Member; Janssen: Consultancy, Other: Advisory board member; Astellas Pharma: Consultancy, Other: Advisory board member; Sellas Life Sciences: Consultancy, Other: Advisory board member; Allogene: Consultancy, Other: Advisory board member, Research Funding; Adicet Bio: Consultancy, Other: Advisory board member, Research Funding; Sana Biotechnology: Consultancy, Other: Advisory board member, Research Funding; Caribou: Consultancy, Other: Advisory board member; Athenex: Consultancy, Other: Advisory board member; Kite, A Gilead Company: Consultancy, Other: Advisory Board Member, Research Funding; Synthekine: Consultancy, Other: Advisory board member; Carsgen: Consultancy; Precision Biosciences: Research Funding; Longbow Immunotherapy: Current holder of stock options in a privately-held company; N/A: Patents & Royalties: Related to cell therapy and the safety switch described (intellectual property). Jacobson:Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Abbvie: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; Abintus Bio: Consultancy; Caribou Bio: Consultancy; Instil Bio: Consultancy; ImmPACT Bio: Consultancy; Daiichi-Sankyo: Consultancy; Ipsen: Consultancy; Morphosys: Consultancy; Synthekine: Consultancy; Pfizer: Research Funding; Miltenyi Biotec: Consultancy; Kite, a Gilead company: Consultancy, Research Funding. Ghobadi:Atara: Consultancy; Genentech, Inc.: Research Funding; Wugen Inc: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding; CRISPR Therapeutics: Consultancy; BMS: Consultancy; Amgen: Consultancy, Research Funding. Miklos:MorphoSys: Consultancy, Honoraria; Mustang Bio: Consultancy, Honoraria; Navan Technologies: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Novartis: Consultancy, Honoraria; Umoja: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Bioline Rx: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: rights to royalties from Fred Hutch for patents licensed to Juno, Research Funding; Miltenyi: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; 2Seventy Bio: Research Funding; Adicet: Research Funding; NA: Patents & Royalties: cGVHD patent holder for Ibrutinib as cGVHD therapy but no compensation; Fate Therapeutics: Research Funding; Allogene: Research Funding; Gilead Sciences: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; A2 Biotherapeutics: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria; Legend Biotech: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Honoraria, Other: Travel support. Spooner:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. Miao:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. Xue:Kite, a Gilead Company: Other: Travel Support; Gilead Sciences: Current Employment, Current holder of stock options in a privately-held company; Biogen: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Zheng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current holder of stock options in a privately-held company. Locke:Cellular Medicine Group: Consultancy; Calibr: Consultancy; ASH: Other: Travel Support; Iovance: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Other: Travel Support; Emerging Therapy Solutions: Consultancy, Other; Bluebird Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional; Leukemia and Lymphoma Society: Other; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Other; GammaDelta Therapeutics: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Cancer Institute: Other; Imedex: Other; Cowen: Consultancy; Caribou: Consultancy; EcoR1: Consultancy; Clinical Care Options Oncology: Other; Legend Biotech: Consultancy, Membership on an entity's Board of Directors or advisory committees; CERo Therapeutics: Other: (Institutional); Daiichi Sankyo: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioPharma Communications CARE Education: Other: Institutional; Wugen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Umoja: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional ; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Bristol Myers Squibb/ Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; Gerson Lehrman Group (GLG): Consultancy; Kite, a Gilead Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional , Research Funding; A2 Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support.
