Early-drug development in the era of immuno-oncology: are we ready to face the challenges?

Area of Science:

• Drug Development
• Immunotherapy
• Clinical Trials

Background:

• Classical drug development is being replaced by accelerated, seamless approaches.
• Current trends involve large expansion cohorts in early trials for rapid regulatory approval.
• Intense competition and focus on combination immunotherapies necessitate re-evaluation of drug assessment strategies.

Purpose of the Study:

• To critically review challenges and limitations in modern immunotherapy development.
• To emphasize the inadequacies of preclinical toxicology models in predicting human toxicity.
• To discuss critical issues in phase I dose determination for immunotherapies.

Main Methods:

• Review of current practices in drug development and clinical trial design.
• Analysis of limitations in preclinical toxicology studies (murine models, cynomolgus monkeys).
• Discussion of dose-escalation methods and dosing strategies (flat vs. body-weight) in phase I trials.

Main Results:

• Preclinical toxicology studies in animal models often fail to predict human toxicity accurately.
• Current phase I trial designs face challenges in optimal dose determination for immunotherapies.
• Existing methods may not adequately balance efficacy and toxicity in early-phase drug evaluation.

Conclusions:

• There is a critical need to address limitations in preclinical models and phase I dose finding for immunotherapies.
• Optimizing dose determination strategies is crucial for maximizing therapeutic benefit while minimizing patient toxicity.
• A revised approach is proposed to enhance the safety and efficacy of novel immunotherapies in clinical development.