Cellular Immunotherapies: Late Phase and Commercially Available Therapies

The Impact of Inotuzumab Ozogamicin (InO) Treatment on Brexucabtagene Autoleucel (Brexu-cel) Outcomes in Adults with Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia (B-ALL)

Introduction: Brexu-cel is the first approved CD19-directed chimeric antigen receptor (CAR) T-cell therapy for adult patients (pts) with relapsed/refractory (r/r) B-ALL. InO, an anti-CD22 antibody drug conjugate, is also approved for the same indication. With the accessibility to several targeted therapies in r/r B-ALL, the optimal sequence remains uncertain. The effect of prior treatment with InO on brexu-cel outcomes remains underreported, especially as a bridging therapy, as well as the effect of previous response to InO on post brexu-cel outcomes.

Methods: This is a retrospective multicenter analysis from 25 U.S. institutions of adults (≥18 years) with r/r B-ALL treated with commercial brexu-cel from 2021 to 2023 post FDA approval. Methodologies for assessing minimal residual disease (MRD) (minimal threshold of 10 -4) included flow cytometry, NGS, or qPCR depending on institutional practice. Progression-free survival (PFS) and overall survival (OS) were calculated from day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. All living patients were censored at the time of last follow-up prior to data lock, which occurred on June 30, 2023.

Results: Among 152 infused, 83 (54.6%) had pre-CAR InO therapy (InO-exposed), with a median of 3 administered doses (range: 1-22). Within the InO-exposed cohort, 23 (28%) pts received InO as a CAR T-cell bridging therapy (ie, between apheresis and lymphodepletion) with or without pre-apheresis and 60 (72%) pts received InO only during pre-apheresis. Baseline characteristics for InO exposed and InO-naïve pts are shown in Table 1. InO-exposed pts had higher median prior lines of therapies (4 vs. 3; p= 0.05), more frequently had active disease (≥5% marrow blasts) at the time of apheresis (67% vs. 44%, p= 0.02), and had lower incidence of Ph+ disease (19% vs. 45%, p=0.003), compared to InO-naïve pts, respectively.

The incidences of cytokine release syndrome (CRS) (85% vs. 85%, p= 0.26) and ICANS (58% vs. 57%, p= 0.36) post infusion were similar, and post-infusion death in remission occurred in 17% and 12% among InO-exposed and InO-naïve pts, respectively. Morphological complete remission (CR) and MRD- rates following brexu-cel infusion were 89% and 77% for InO-exposed pts, and 92% and 70% for InO-naive pts, respectively. Post CAR therapy, more InO-naïve pts underwent consolidation/maintenance therapy (transplant, chemotherapy, or TKIs) compared to InO-exposed pts (41% vs. 19%, p= 0.004).

The median follow-up after brexu-cel was 8.4 (range) months. Median OS (not reached (NR) vs. 12 months; p= 0.033) and median PFS (NR vs. 7 months; p= 0.029) were superior in InO-naïve pts compared to InO-exposed pts, respectively. However, after adjusting for pre-apheresis disease burden and post-CAR maintenance therapy, there were no longer significant differences in OS (HR= 1.25;95%CI: 0.62-2.53; p= 0.53) or PFS (HR= 1.24;95%CI:0.71-2.16, p=0.45) based on pre-CAR InO exposure. When InO-exposed pts were stratified based on prior InO-response (CR vs. no response), InO-responsive pts had superior estimated 12-month OS (64%) and PFS (38%) relative to InO-refractory pts (OS: 33%; PFS: 34%), but inferior to InO-naïve pts (OS: 75%; PFS 56%), with p-values of 0.0001 and 0.021 for OS and PFS, respectively (Figure 1). The timing of pre-CAR InO therapy did not impact brexu-cel survival outcomes, with comparable estimated 12-month OS (43% vs. 58%, p= 0.35) and PFS (46% vs. 38%, p= 0.57) for InO-exposed pts during bridging therapy and patients who received InO as a therapy prior to apheresis.

Conclusion: After adjusting for pre-CAR disease burden and post-CAR consolidation/maintenance, we found that prior InO exposure does not significantly associate with PFS or OS following brexu-cel. However, relative to InO-responsive patients, patients who were InO-refractory appear to have worse post-CAR survival outcomes. Finally, timing of InO administration (ie as a prior line of therapy or as CAR bridging) did not influence outcomes brexu-cel outcomes.

Aldoss:KiTE: Consultancy; Sobi: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria; Takeda: Consultancy. Advani:Seattle Genetics: Research Funding; Nkarta: Honoraria; OBI: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Kite: Honoraria, Other: consulting, Research Funding; Macrogenics: Research Funding; Servier: Research Funding; Kura: Honoraria; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Taiho: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria; Incyte: Research Funding; Amgen: Honoraria, Other: advisory board, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lin:Biomarin: Current equity holder in publicly-traded company; Rigel Pharmaceuticals: Consultancy. Schwartz:Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy. Dholaria:Lumanity: Consultancy; AstraZeneca: Research Funding; Molecular Templates: Research Funding; Atara: Research Funding; NCI: Research Funding; Allovir: Research Funding; Poseida: Research Funding; Pluri Biotech: Consultancy; Boxer Capital: Consultancy; Ellipsis pharma: Consultancy; Orca Bio: Research Funding; MEI: Research Funding; Adicet: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; Arivan: Consultancy; ADC therapeutics: Consultancy, Honoraria; Gilead: Research Funding; Wugen: Research Funding; Pfizer: Research Funding; BEAM therapeutics: Consultancy; gamida cel: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Poseida: Research Funding. Battiwalla:Fate Therapeutics: Research Funding; Novartis: Research Funding. Shaughnessy:Sanofi: Speakers Bureau; BMS: Speakers Bureau. Logan:Amgen, Autolus Therapeutics, Kadmon, Kite, Pharmacyclics, Talaris: Research Funding; AbbVie, Amgen, Actinium, BMS, Pfizer, Sanofi, Takeda: Consultancy. Hoeg:Orca Bio: Research Funding. Tsai:Jazz Pharmaceutical: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Solh:Bristol-Myers Squibb: Speakers Bureau. Lee:Kadmon: Honoraria; Fresenius Kabi: Consultancy; BMS: Honoraria; Kite Pharma: Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Incyte Corp: Consultancy, Research Funding. Kota:Incyte: Research Funding; Kite: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Koura:BMS: Consultancy, Research Funding. Leonard:Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Pfizer: Consultancy; Takeda: Consultancy; Kite/Gilead: Consultancy. Oliai:Jazz Pharmaceuticals: Research Funding; Arog: Research Funding; Pfizer: Research Funding; Seagen: Research Funding; Novartis: Research Funding; Orca Bio: Research Funding. Bachanova:Citius: Research Funding; BMS: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; ADC: Membership on an entity's Board of Directors or advisory committees; Allogene: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Other: DSMB; Incyte: Research Funding; Gamida Cell: Research Funding. Stock:Kite: Consultancy; Kura: Research Funding; Servier: Other: Data Safety Monitoring Board/Advisory Board; Newave: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy; Amgen: Honoraria. Pullarkat:Amgen: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Cassaday:Merck: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Vanda Pharmaceuticals: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Servier: Research Funding; PeproMene Bio: Membership on an entity's Board of Directors or advisory committees; Seagen: Other: Spouse was employed by and owned stock in Seagen within the last 24 months.. Shah:Pharmacyclics/Janssen, Spectrum/Acrotech, BeiGene, Gilead Sciences: Honoraria; Incyte, Jazz Pharmaceuticals, Kite/Gilead, SERVIER: Research Funding; Moffitt Cancer Center: Current Employment; DSMC, Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Celgene, Novartis, Pfizer, Janssen, Seattle Genetics, AstraZeneca, Stemline Therapeutics, Kite/Gilead: Other: Travel, Accommodations, Expenses; Takeda, AstraZeneca, Adaptive Biotechnologies, BMS/Celgene, Novartis, Pfizer, Amgen, Precision Biosciences, Kite/Gilead, Jazz Pharmaceuticals, Century Therapeutics, Deciphera, Autolus Therapeutics, Lilly, Pepromene: Consultancy. Faramand:Kite: Research Funding; Gilead: Research Funding. Muffly:orca bio: Research Funding; amgen: Consultancy; adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; bms: Research Funding; kite: Consultancy, Honoraria, Research Funding; autolus: Consultancy; astellas: Consultancy, Research Funding; jasper: Research Funding; pfizer: Consultancy.

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2023
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