Dose Optimization of Inotuzumab Ozogamicin in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

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.