091: Clinical Pharmacology of Bispecific T-cell Engagers: A Summary Based on FDA Approvals

Statement of Purpose, Innovation or Hypothesis: Bispecific T cell engagers (BiTEs) have recently attracted significant attention and shown promise for treating various cancers due to their unique structures and mechanisms of action (MOA) (Figure 1). As of Feb. 2024, FDA has approved 8 BiTEs (Table 1). As the understanding of BiTEs continues to evolve, it is crucial to assess the current practice and knowledge gap pertaining to clinical pharmacology to inform future development strategies in and beyond oncology.

Description of Methods & Materials: We searched Drugs@FDA website for approved BiTEs. We then investigated the labeling and FDA reviews for their clinical pharmacology characterizations, including: 1) PK and dose regimen; 2) renal/hepatic impairment (RI/HI); 3) immunogenicity (i.e., anti-drug antibody (ADA)); 4) Drug-drug interaction (DDI); and 5) PBPK modeling. The current practice is summarized based on 8 approved BiTEs and the knowledge gap is evaluated to inform future strategies for these characterizations.

Data & Results: For 8 approved BiTEs which all engage CD3 on T cells, 7 are indicated for hematological cancers, and 1 for uveal melanoma (Table 1). Seven have linear PK except epcoritamab, and 2 fusion proteins have much shorter t_1/2 than 6 mAbs. All 8 approved BiTEs involve 1-3 step-up doses to mitigate the safety concerns (e.g., cytokine release syndrome [CRS]) before the full treatment dose, except for one indication of blinatumomab due to low baseline B cell levels. Four BiTEs have lower full treatment dose level or longer dosing interval in later cycles compared to initial cycles. Limited impact was observed for mild/moderate RI and mild HI, while no data for severe RI and moderate/severe HI. Four BiTEs targeting B cells and 1 targeting myeloma cells have < 3% ADA+, while 2 BiTEs targeting myeloma cells and 1 targeting uveal melanoma cells have 9-33% ADA+; dosing route seems not a major determine factor, with ADA incidence ranging from < 1% to 20-30% for both subcutaneous and intravenous administrations. For cytokine mediated DDIs related to MOA of BiTEs, the commonly elevated cytokines are IL-2/6/10, IFN-γ, TNF-α, with highest elevation observed after the first step-up or first full treatment dose. DDI risk is generally monitored till 14 days after the last significant cytokine increase, and during and after CRS. Five BiTEs have PBPK modeling submitted for DDI risk prediction, however, FDA determined that current PBPK modeling is inadequate due to multiple limitations (e.g., unknown exposure-response relationship between IL-6 levels and CYP activities in humans, unable to capture the time course of recovery from cytokine suppression).

Interpretation, Conclusion or Significance: Our research will help understand current practice and knowledge gap to inform the strategy for efficient and consistent clinical pharmacology characterization of these emerging new modalities. Although knowledge about BiTEs has advanced dramatically in recent years, more efforts are warranted to address the knowledge gap (e.g., collect DDI data at clinically relevant cytokine levels, improve model to reflect the delayed CYP suppression). The continued research for BiTEs, including clinical pharmacology characterization will help facilitate the development process and bring more of these promising therapies to patients efficiently.

Disclosures:

Citations/References:

Additional Information/Authors: NA