PII-082 - POPULATION EXPOSURE-RESPONSE ANALYSIS OF INOTUZUMAB OZOGAMICIN EFFICACY AND SAFETY IN ADULT PATIENTS WITH RELAPSED OR REFRACTORY B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA.

D. Yang¹, A. Suzuki², J. Hibma¹, M. Garrett³, K. Pelletier⁴, B. Hee³, E. Vandendries⁵, Y. Chen³; ¹Pfizer Inc., San Diego, CA, USA, ²Pfizer Inc., Tokyo, Japan, ³Pfizer Inc., La Jolla, CA, USA, ⁴Pfizer Inc., Groton, CT, USA, ⁵Pfizer Inc., Cambridge, MA, USA.

Background: Inotuzumab ozogamicin (InO), an anti-CD22 monoclonal antibody conjugated to calicheamicin, is approved for treatment of adults with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) at a starting dose of 1.8 mg/m^2/cycle (0.8 mg/m^2 on Day 1, and 0.5 mg/m^2 on Days 8 and 15) for the first cycle (21 days). Subsequent cycles were 28 days in length with a total dose of 1.8 mg/m^2 or 1.5 mg/m^2, depending on hematological remission. The objective of this analysis was to characterize the relationship between InO exposure and efficacy and safety endpoints using data from a post marketing requirement dose optimization study in adult patients with R/R B-cell ALL who were eligible for hematopoietic stem cell transplant (HSCT) and who were at a higher risk for developing veno-occlusive disease (VOD) post-HSCT (NCT03677596).

Methods: This was an open-label, Phase 4 study to evaluate the relationship between dose and risk-benefit for both the recommended dose and lower dose of InO (1.8 mg/m^2/cycle vs 1.2 mg/m^2/cycle) in adults with R/R B-cell ALL (N=102). The exposure-response analyses were performed using binomial logistic regression in R software. Clinical utility index (CUI) was calculated using a 1:1 weighting scheme to estimate the difference between the predicted probability of key efficacy endpoints (eg., complete remission [CR]/complete remission with incomplete hematologic recovery [CRi]) and the predicted probability of safety endpoints (eg., neutropenia based on lab abnormality data).

Results: InO exposure was significantly correlated with CR/CRi and neutropenia Grade ≥ 3. There were no statistically significant relationships between InO exposure and efficacy endpoint minimal residual disease-negativity, and safety endpoints thrombocytopenia Grade ≥ 3, VOD, and hepatic events defined by cluster terms. No additional covariates were found to be significant predictors of efficacy and safety endpoints. The starting dose of 1.8 mg/m^2/cycle had a greater CUI compared to 1.2 mg/m^2/cycle in a R/R ALL patient with median exposure at respective dose.

Conclusion: These analyses support that a lower dose (1.2 mg/m^2/cycle) does not provide a more favorable balance of safety and efficacy than the currently recommended dose (1.8 mg/m^2/cycle).