Optimizing Dose Selection for Bispecifics: Lessons Learned

Session Description

Bispecific cell engaging therapies represent a promising advancement in cancer immunotherapy, with several recent approvals by FDA and other regulatory agencies worldwide. These drugs work by bringing certain immune cells into proximity with cancer cells, thereby enhancing the immune system's ability to target and destroy malignancies.

The process of dose optimization is crucial to maximize the therapeutic benefits while minimizing the risk of severe side effects, such as cytokine release syndrome and neurotoxicity. One of the unique aspects of cell engaging therapies is the general need to prime the immune system gradually, which is achieved through starting with one or more low step-up doses, before reaching the full therapeutic dose. Another aspect is that more is not always better from efficacy perspective; it is important to use a target dose that maximizes trimer formation between the drug, target immune cells, and tumor cells.

In this session, we will discuss the challenges, strategies, and the role of various modeling approaches in optimizing doses of bispecific drugs during development to achieve the optimal benefit versus risk balance for patients.

We will discuss the different types of modeling that aid in selecting and optimizing doses, including empirical pharmacokinetic (PK) and pharmacodynamic (PD) modeling, as well as mechanistic models, and quantitative systems pharmacology (QSP) models. We will also discuss experiences and considerations for selecting the starting dose in humans. Clinical pharmacology and modeling applications through the different phases of development will be discussed. We will also examine case studies from recent clinical trials and approvals that illustrate successful dose optimization techniques and highlight common challenges.

Learning Objectives

1. To discuss the unique clinical pharmacology aspects of bispecific immune cell engaging treatments and the impact of these aspects on optimal dose selection
2. To understand the role of various modeling techniques, including PK/PD, mechanistic models, and QSP models, in dose optimization for bispecific immune cell engager therapies.
3. To discuss case studies that demonstrate successful dose optimization techniques in clinical trials.

Session Schedule

Introduction
Ahmed Othman, PhD and Mohamed-Eslam Mohamed, RPh, PhD

Optimizing Dosing Regimen for CD3-Targeting Bispecific Antibodies to Balance Anti-Tumor Activity and Safety
Priyanka Madia, PhD

Starting on the Right Foot: First-in-Human Dose Selection of Bispecifics
Jason Williams, PhD

Leveraging a Breadth of Model-Based Analyses in the Selection and Justification of Dosing Regimen of Bispecific Antibodies
Tommy Li, PhD

Panel Discussion