Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1

Purpose Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-β (TGF-β) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)–pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-β is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs). Methods The PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 ( n = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration ( C avg ), derived using a population PK model. The percentage of patients with trough concentrations associated with PD-L1 or TGF-β inhibition across various dosing regimens was derived. Results The probability of bleeding AEs increased with increasing C avg ; 50% dose reduction was chosen based on the integration of modeling and clinical considerations. The resulting AE management guidance to investigators regarding temporary or permanent treatment discontinuation was further refined with recommendations on restarting at RP2D or at 50% dose, depending on the grade and type of bleeding (tumoral versus nontumoral) and investigator assessment of risk of additional bleeding. Conclusion A pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.