(M-121) Population Pharmacokinetics and Exposure-Response Analysis Supports Phase 2 Dose Selection for BMS-986288, a non-fucosylated anti-CTLA4 antibody Prodrug
Huiming Xia: No financial relationships to disclose
Objectives: BMS-986288 is a next generation anti-CTLA-4 monoclonal antibody that integrates the Probody® [1] and non-fucosylation technologies [2] for selective tumor targeting and increased antibody dependent cellular cytotoxicity, respectively. BMS-986288 is being evaluated alone and in combination with nivolumab in advanced solid tumors in a Phase 1/2 study (Study CA043001, NCT03994601). Safety, PK, and preliminary efficacy were explored for BMS-986288 monotherapy at doses of 20, 40, 80, 160, 320, and 480 mg Q4W in part 1A (mono escalation); and at doses of 80, 120 and 160 mg Q4W in combination with nivolumab 480 mg Q4W in Part 1B (combo escalation). BMS-986288 doses of 80 and 120 mg in combination with nivolumab were further evaluated in part 2B expansion cohort in participants with advanced NSCLC with prior immunotherapy treatment. Population PK (PopPK), exposure-response safety and efficacy, PK-PD (serum Interferon‐gamma, IFN-gamma) analyses were conducted by integrating the PK-PD, safety and preliminary efficacy from study CA043001 to evaluate the benefit-risk balance and support Phase II dose selection.
Methods: A two-compartment, PopPK model for each of the three-species was developed to characterize the observed plasma concentration of BMS-986288 for the intact, mono and dual cleaved species with NONMEM v7.2.0. Exposure of active species (mono and dual) were added as predictors for exposure response analyses, with a potency factor of 0.5 for the mono-cleaved species assuming half potency for the mono-cleaved species. PopPK model derived exposure metrics were used to evaluate associations with serum IFN-gamma PD, clinical safety, endpoints, and preliminary efficacy measures of tumor response using an Emax PKPD model, time to event analysis, logistic regression and subgroup analysis.
Results: The PopPK model adequately characterized the observed concentration of the three species of BMS-986288 in the plasma. Body weight (BW) was identified as significant covariate in the population PK model with increased BW associated with increased Vd, and CL. A significant exposure-response relationship was identified for treatment related adverse events (TRAE) Grade 3+, dose delay, dose interruption and treatment discontinuation. Stratifying Gr3+ TRAEs by BW indicated a higher incidence of safety events in the lower BW quartile in the 80 mg combo cohort, which was attributed to higher exposure in lower BW subjects when using the flat dosing strategy and a positive E-R relationship for safety. Exposure was not a significant predictor of the objective tumor response rate in NSCLC. However, there was pharmacodynamic evidence of activity with higher drug concentrations associated with higher time-averaged change from baseline IFN-gamma levels.
Conclusion: The integrated analyses suggested that 80 mg and 120 mg in combination with nivolumab 480 mg Q4W will provide an optimal benefit-risk balance and was the recommended dosing regimen to proceed.
