Model-Informed Therapeutic Dose Optimization Strategies for Antibody-Drug Conjugates in Oncology: What Can We Learn From US Food and Drug Administration-Approved Antibody-Drug Conjugates?
- ADCs (Antibody-Drug Conjugates) are a promising area in oncology drug development, improving the therapeutic window of potent, nonspecific payloads by conjugating them to antibodies.
- The FDA has approved nine ADCs for solid and hematological tumors, with several more showing promising clinical activity and expected approval in the next one to two years.
- Innovative approaches such as site-specific conjugation and novel payloads are being implemented to develop next-generation ADCs, though their therapeutic window remains relatively narrow compared to other oncology drugs.
- Maximum tolerated dose is often reached before achieving maximum efficacious dose, posing a challenge for dose optimization.
- Various dosing strategies are summarized to broaden the therapeutic window while mitigating safety risks and maintaining efficacy, including:
- BW-based dose capping to prevent overdosing in heavier patients.
- Capping treatment duration to mitigate chronic adverse events (AEs) like peripheral neuropathy (PN).
- Optimizing dose schedules to smaller, more frequent doses to reduce AE risks driven by Cmax.
- Response-guided dosing for personalizing ADC dose based on patient response.
- Randomized dose-finding studies to identify appropriate doses and schedules for late development, enhancing clinical development efficiency.
- Quantitative integration of clinical pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety is crucial for comprehensive risk-benefit evaluation to maximize the therapeutic window of each ADC.
- Continued learning and innovation in dosing strategies are essential, especially for next-generation ADCs.
Antibody–drug conjugates (ADCs) combine the specificity of an antibody with the cytotoxicity of a chemical agent. They represent a rapidly evolving area of oncology drug development and hold significant promise. There are currently nine ADCs on the market, more than half of which gained US Food and Drug Administration approval more recently, since 2019. Despite their enormous promise, the therapeutic window for these ADCs remains relatively narrow, especially when compared with other oncology drugs, such as targeted therapies or checkpoint inhibitors.
In this review, we provide a detailed overview of the five dosing regimen optimization strategies that have been leveraged to broaden the therapeutic window by mitigating the safety risks while maintaining efficacy. These include body weight cap dosing; treatment duration capping; dose schedule (e.g., dosing frequency and dose fractionation); response-guided dosing recommendations; and randomized dose-finding. We then discuss how the lessons learned from these studies can inform ADC development going forward. Informed application of these dosing strategies should allow researchers to maximize the safety and efficacy for next-generation ADCs.
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