Association of Metabolic Tumor Volume (MTV) and Clinical Outcomes in Second-Line (2L) Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Following Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care (SOC) Therapy in ZUMA-7

Background: ZUMA-7 (NCT03391466), the pivotal Phase 3 study of axi-cel versus SOC in 2L LBCL, showed axi-cel superiority to SOC across common prognostic subgroups, including tumor burden (TB), as calculated by the sum of product diameters (SPD), and lactate dehydrogenase (LDH; Locke et al. ASCO 2022. Abstract 7565). However, SPD is based on ≤6 target lesions only and does not account for non-measured lesions or metabolic activity. TB can also be measured by MTV using fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scans, and though not a standardized clinical assessment, MTV has previously been shown to correlate with clinical outcomes of chimeric antigen receptor T-cell therapy in third-line (3L) relapsed/refractory LBCL (Hong et al. Front Oncol. 2021 and Dean et al. Blood Adv. 2020). Here, we present clinical outcomes for patients (pts) in ZUMA-7 by MTV.

Methods: MTV was obtained from the attenuation corrected whole-body FDG PET scans at screening. Whole tumor volumes of interest (VOI) were placed on tumors using a predefined, semiautomated approach, which included outlining regions of abnormal FDG uptake >normal liver uptake (visual Deauville score >3). Subsequent radiologist-defined adjustments of VOI placement included addition of regions of tumor that were not initially captured and exclusions of normal tissue. MTV was calculated as the number of voxels, or volumetric pixels, with standardized uptake value (SUV) measurements between 41%-100% of tumor SUV_max and reported as MTV_total (mL) per pt. Associations between MTV and baseline characteristics and clinical outcomes were assessed using descriptive statistics (P<.05 was considered significant).

Results: A total of 341 pts were evaluated for MTV (axi-cel: 176 and SOC: 165). Median MTV was 228.1 mL (range, 2.3-16,669.3) in axi-cel pts, 231.9 mL (range, 0.04-2811.2) in SOC pts, and 230.2 mL (range, 0.04-16,669.3) overall. Median MTV was higher in pts who were <65 years of age (n=236) versus ≥65 (n=105; 255.2 mL [range, 0.04-16,669.3] vs 176.7 mL [range, 6.8-4101.8]). Median MTV was higher in pts with elevated (n=185; >median) versus normal (n=156; ≤median) LDH (371.2 mL [range, 2.3-16,669.3] vs 123.9 mL [range, 0-3712.8]). MTV was positively associated with SPD (n=308; Spearman correlation, 0.523 [95% CI, 0.436-0.599]) and LDH (n=341; Spearman correlation, 0.452 [95% CI, 0.362-0.532]).

Axi-cel event-free survival (EFS) was superior to SOC for both low (≤median) and high (>median) MTV (hazard ratio [HR], 0.423 [95% CI, 0.288-0.620] and HR, 0.417 [95% CI, 0.293-0.592], respectively). Axi-cel EFS trended shorter in pts with high MTV (HR, 1.441 [95% CI, 0.978-2.124]) and EFS was shorter in SOC pts with high MTV (HR, 1.486 [95% CI, 1.055-2.093]; Figure). Similarly, axi-cel progression-free survival (PFS) was superior to SOC for both low and high MTV (HR, 0.504 [95% CI, 0.328-0.776] and HR, 0.523 [95% CI, 0.357-0.765], respectively). PFS was shorter in both axi-cel and SOC pts with high MTV (HR, 1.644 [95% CI, 1.090-2.480] and HR, 1.635 [95% CI, 1.098-2.433], respectively). In axi-cel pts, median MTV was higher for pts who experienced Grade ≥3 neurologic events (n=36) versus pts who experienced Grade 1-2 or no neurologic events (n=134; 320.9 mL [range, 24.3-13,527.0] vs 193.9 [range, 2.3-16,669.3]). Median MTV was higher for axi-cel pts who experienced Grade ≥3 cytokine release syndrome (CRS; n=11) compared with pts who experienced Grade 1-2 or no CRS (n=159; 582.9 mL [range, 114.6-2508.6] vs 203.3 [range, 2.3-16,669.3]).

Conclusions: To our knowledge, this analysis is the first to examine MTV in a large, randomized, prospective R/R LBCL study. Similar to associations of efficacy with SPD and LDH previously observed in 2L LBCL (Locke FL et al. ASCO 2022. Abstract 7565), high MTV was associated with superior outcomes in pts treated with axi-cel versus SOC. While tumor burden per SPD did not seem to impact axi-cel outcomes in ZUMA-7 (Locke FL et al. ASCO 2022. Abstract 7565), high MTV was associated with poorer outcomes with axi-cel versus low MTV, and rates of Grade ≥3 neurologic events and CRS were associated with higher MTV. This suggests that MTV is a more accurate and sensitive measure of TB versus SPD. Nevertheless, axi-cel was superior to SOC irrespective of MTV subgroup, including among pts in the high MTV subgroup.

Locke:BMS: Research Funding; CAREducation: Other: Education or editorial activity; BioPharm Communications: Other: Education or editorial activity; ASH: Other: Education or editorial activity; Society for Immunotherapy of Cancer: Other: Education or editorial activity; Takeda: Consultancy; Sana: Consultancy; Daiichi Sankyo: Consultancy; CERo Therapeutics: Research Funding; Clinical Care Options Oncology: Other: Education or editorial activity; Aptitude Health: Other: Education or editorial activity; Imedex: Other: Education or editorial activity; ), National Cancer Institute: Research Funding; Leukemia and Lymphoma Society: Research Funding; A2: Consultancy; Celgene: Consultancy; Other: Patents & Royalties: patents, royalties, other intellectual property from several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy.; Wugen: Consultancy; Umoja: Consultancy; Novartis: Consultancy, Research Funding; Legend Biotech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Iovance: Consultancy; GammaDelta Therapeutics: Consultancy; Emerging Therapy Solutions Gerson Lehrman Group: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; Calibr: Consultancy; Cellular Biomedicine Group: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Bluebird Bio: Consultancy, Research Funding; Allogene: Consultancy, Research Funding; Amgen: Consultancy. Oluwole:Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; TG Therapeutics: Consultancy; Curio Science: Consultancy; ADC Therapeutics: Consultancy; Kite, a Gilead Company: Research Funding. Kuruvilla:Medison Ventures: Consultancy; Antengene: Consultancy; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Astra Zeneca: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Other: DSMB; Seattle Genetics: Consultancy, Honoraria; Inctye: Honoraria; Pfizer: Honoraria; Lymphoma Canada: Membership on an entity's Board of Directors or advisory committees. Thieblemont:Roche: Consultancy, Honoraria, Other: Travel Support; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support; Takeda: Consultancy, Honoraria, Other: Travel Support. Morschhauser:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Genentech: Consultancy; Miltenyi: Membership on an entity's Board of Directors or advisory committees; Allogene therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salles:Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSys AG, Amgen, Bayer, Epizyme, Regeneron, Kite, a Gilead Company: Honoraria; Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys AG, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, Bristol-Myers Squibb, BeiGene, Incyte, Miltenyi Biotec, Ipsen, Kite, a Gilead Company, Loxo, Rapt: Consultancy; AbbVie, BeiGene, Bristol Myers Squibb, Celgene, Debiopharm, Epizyme, Genentech/Roche, Genmab, Incyte, Kite, a Gilead Company, Miltenyi, MorphoSys, Takeda, and VelosBio: Membership on an entity's Board of Directors or advisory committees. Rowe:Precision Molecular, Inc.: Consultancy, Current Employment, Current equity holder in private company, Patents & Royalties; PlenaryAI: Consultancy, Current equity holder in private company, Ended employment in the past 24 months, Patents & Royalties; Lantheus Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau. Vardhanabhuti:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Research Funding. Filosto:Tusk Therapeutics: Patents & Royalties; Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. To:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Cheng:Kite, a Gilead Company: Ended employment in the past 24 months, Other: Travel support; Gilead Sciences: Current equity holder in publicly-traded company. Schupp:Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support; Gilead Sciences: Current equity holder in publicly-traded company. Korn:Imaging Endpoints: Current Employment, Patents & Royalties; Teladoc: Current equity holder in publicly-traded company; Teleview: Current equity holder in publicly-traded company; Globavir: Current equity holder in private company; Verve: Current equity holder in private company; Renibus: Current equity holder in private company; DynamiCure: Consultancy; Fore Bio: Consultancy; SonALAsense: Consultancy; Dracen: Consultancy; Day One: Consultancy; FibroGen: Consultancy. Kersten:Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support ; Miltenyi Biotech: Consultancy, Honoraria, Other: Travel support ; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support , Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding.