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

Abstract

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 (Cavg), 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 Cavg; 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.

Keywords: Clinical pharmacokinetics; Exposure–response relationship; Immune checkpoint inhibitor; Phase 1, 2, 3 trials; Solid tumors.

Conflict of interest statement

Y. Vugmeyster and K. Venkatakrishnan report employment and own stocks at EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. A.-M. Grisic, A.H. Loos, R. Hallwachs, and A. Khandelwal report employment, royalties, and own stocks at Merck. J.J. Wilkins declares no potential conflicts of interest. M. Osada reports employment with Merck Biopharma Co., Ltd., Tokyo, Japan, an affiliate of Merck KGaA.

© 2022. The Author(s).

Figures

Fig. 1

Univariable exposure-safety analysis for bleed_TEAE (A), bleed_GI (B), and bleed_TEAE3 (C). Blue line and shaded area represent model-predicted AE probability (median and 95% CI); pink circles represent observed AE incidence by quartiles of exposure and are placed at 12.5th, 37.5th, 62.5th, and 87.5th percentiles of the exposure distribution (i.e., median for each exposure quartile); the error bars represent 95% CIs; pink dotted lines represent boundaries of exposure quartiles; purple dots individual patient data. Cavg,SD, average bintrafusp alfa concentration over the dosing interval, bleed_TEAE treatment-related bleeding events of any grade, bleed_TEAE3 treatment-related bleeding events of grade ≥ 3, bleed_GI gastrointestinal bleeding events of any grade; CI confidence interval

Fig. 2

Final exposure-safety models for bleed_TEAE (A) and bleed_GI (B). Numbers are odds ratios; horizontal bars represent 95% CIs provided by reduced models. Cavg,SD average bintrafusp alfa concentration over the dosing interval, bleed_TEAE treatment-related bleeding events of any grade, bleed_GI gastrointestinal bleeding events of any grade, BTC biliary tract cancer. ***p < 0.001; **p < 0.01; *p < 0.05

Fig. 3

Guidance for management of bleeding adverse events in monotherapy and combination studies of bintrafusp alfa. Toxicity grading is assigned based on National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Rapid drop in Hg is defined as decrease > 3 g/dL in 3 weeks or 2.0 g/dL in 2 weeks. Alternative explanations for nontumoral bleeding include concomitant use of antithrombotic agents, traumatic event. Thorough assessment of bleeding includes tests such as lower and upper GI endoscopy, enhancement CT. The guidance presented applies regardless of causality with the study intervention. General grade 2 ADR guideline: if a grade 2 ADR resolves to grade ≤ 1 by the last day of the current cycle, treatment may continue; if a grade 2 ADR does not resolve to grade ≤ 1 by the last day of the current cycle but is manageable and/or not clinically relevant, the medical monitor should be consulted to assess if it is clinically reasonable to administer the following infusion (at RP2D). ADR adverse drug reaction, CT computed tomography, Gr grade, Hg hemoglobin, pt participant, Gr ≤ 1 resolved or Gr 1