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732 Dose Optimization of Inotuzumab Ozogamicin in Adult Patients with Relapsed/Refractory Acute Lymphoblastic LeukemiaClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 612. Acute Lymphoblastic Leukemias: Clinical and Epidemiological: Look into the Crystal B-ALL: Genetic, Phenotypic and Dynamic Outcome Predictors in Lymphoblastic Leukemia
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, ALL, Antibody Therapy, Adult, Diseases, Treatment Considerations, Biological therapies, Lymphoid Malignancies, Adverse Events, Study Population, Human, Measurable Residual Disease
Monday, December 9, 2024: 11:45 AM

Daniel J. DeAngelo, MD, PhD1, Ying Chen2*, Ryan D. Cassaday, MD3, Jennifer Hibma, PharmD4*, Derek Z Yang, Pharm D4*, May Garrett4*, Fan Zhang5*, Svetoslav H Dimitrov, MD6*, Erik Vandendries7 and Hagop M. Kantarjian, MD8

1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
2Pfizer, San Diego, CA
3University of Washington and Fred Hutchinson Cancer Center, Seattle, WA
4Pfizer, San Diego
5Pfizer, Shanghai, China
6Pfizer, New York
7Pfizer Inc, Cambridge, MA
8Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

INTRODUCTION: Inotuzumab ozogamicin (InO) is an antibody drug conjugate composed of a monoclonal CD22-directed antibody linked to a cytotoxic agent, calicheamicin. InO was approved by the FDA in 2017 for the treatment of adults with relapsed/refractory (R/R) CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL). Based on the clinical data from phase 1/2 study B1931010 (DeAngelo et al. Blood Adv 2017;1167-1180) and phase 3 study INO-VATE (study B1931022; Kantarjian et al. NEJM 2016;375:740-53), the recommended dosing regimen is 1.8 mg/m2/cycle (0.8 mg/m2 on Day 1, and 0.5 mg/m2 on Days 8 and 15) for Cycle 1 (3 weeks in duration), but may be extended to 4 weeks if the patient achieves a complete remission (CR)/complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity. For subsequent cycles (4 weeks in duration), the recommended total dose of InO is 1.5 mg/m2/cycle (0.5 mg/m2 on Days 1, 8 and 15) in patients who achieve a CR/CRi.

FDA issued a post-marketing requirement (PMR 3259-2) due to their concern that the proposed dose of 1.8 mg/m2/cycle may not be optimal in balancing the safety and efficacy of InO. Therefore, the Phase 4 dose optimization study B1931030 (NCT03677596; Özcan et al. Blood 2021;138:1208) was conducted to evaluate the relationship between dose and risk-benefit for both the labeled dose and lower dose of InO (1.8 mg/m2/cycle vs 1.2 mg/m2/cycle) in adults with R/R B-cell ALL who were eligible for hematopoietic stem cell transplant (HSCT) and, accordingly at a higher risk for developing veno-occlusive disease (VOD) post-HSCT. The primary objectives of that study were to evaluate the rates of VOD and hematologic remission (CR/CRi) for the two InO dose levels.

The goal of the analyses reported here is to support a particular InO dosing regimen.

METHODS: The exposure-response analyses for efficacy and safety endpoints were previously conducted using data from studies B1931010 and INO-VATE (n=234) (Chen et al. Clin Transl Sci 2021;14,184-193) and separately from study B1931030 (n=98). To quantitatively measure the optimal tradeoff between efficacy and safety, clinical utility index (CUI) was calculated in the current analysis using a 1:1 weighting scheme to estimate the difference between the predicted probability of efficacy (e.g., CR/CRi and MRD-negativity) and safety endpoints (e.g., VOD or neutropenia) which had statistically significant relationships with InO exposure. An optimal dosing regimen was expected to have a greater CUI. The rates of CR/CRi, MRD-negativity and VOD by dose categories were also summarized.

RESULTS: Based on pooled data from studies B1931010 and INO-VATE, the starting dose of 1.8 mg/m2/cycle had a greater CUI compared to the lower doses (e.g., 1.2 mg/m2/cycle) in a R/R ALL patient with median exposure regardless of whether the patient proceeded to post-treatment HSCT. Lower starting doses of InO were associated with a lower risk of VOD, but were also associated with a significantly lower efficacy. According to average dose per cycle in studies B1931010 and INO-VATE, the CR/CRi rates for patients at doses <1.35 mg/m2, between ≥1.35 and <1.65 mg/m2, ≥1.65 mg/m2 were 46% (16/35 patients), 52% (14/27 patients) and 81% (139/172 patients), respectively. Of the patients who achieved CR/CRi, 36%, 52% and 67% of patients achieved MRD-negativity at above dose categories. The VOD rates for patients with HSCT in study INO-VATE at doses <1.35 mg/m2, between ≥1.35 and <1.65 mg/m2, ≥1.65 mg/m2 were 43% (3/7 patients), 28% (12/43 patients) and 15% (4/27 patients), respectively.

The starting dose of 1.8 mg/m2/cycle had a greater CUI compared to the lower dose (1.2 mg/m2/cycle) based on the analysis using data from patients at higher risk of VOD on B1931030. The CR/CRi rates for patients at doses of 1.2 mg/m2/cycle and 1.8 mg/m2/cycle were 72% (46/64 patients) and 68% (26/38 patients), respectively. Of the patients who achieved CR/CRi, 72% and 69% of patients achieved MRD-negativity at above two doses. VOD rates for patients with post-HSCT at doses of 1.2 mg/m²/cycle and 1.8 mg/m²/cycle were 26% (8/31 patients) and 17% (2/12 patients), respectively.

CONCLUSIONS: These analyses indicate that the current FDA approved higher dose of 1.8 mg/m2/cycle provides a favorable balance of safety and efficacy as compared to the lower dose of 1.2 mg/m2/cycle in adult patients with R/R ALL.

Disclosures: DeAngelo: Amgen, Autolus, Blueprint, Gilead, Incyte, Jazz, Novartis, Pfizer, Servier, Takeda: Consultancy; Mt Sinai MPN Consortium: Other: Mt Sinai MPN Consortium; Daiichi-Sankyo, Fibrogen: Other: DSMB; AbbVie, Blueprint, GlycoMimetics, Novartis: Research Funding; Dana-Farber Cancer Institute: Current Employment. Chen: Pfizer: Current Employment. Cassaday: PeproMene Bio: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Honoraria, Research Funding; Jazz: Consultancy; Incyte: Research Funding; Autolus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Seagen: Ended employment in the past 24 months; Servier: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding. Hibma: Pfizer: Current Employment. Yang: Pfizer: Current Employment. Garrett: Pfizer: Current Employment. Zhang: Pfizer: Current Employment. Dimitrov: Pfizer: Current Employment. Vandendries: Pfizer: Current Employment, Current equity holder in private company. Kantarjian: AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria.

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