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Immunostimulatory monoclonal antibodies (imAbs) targeting immune checkpoint molecules are revolutionizing oncology not only regarding cancer therapeutics and clinical care, but also from a drug development point of view. A handful of first-generation molecules have been approved so far based on their tremendous efficacy, after an expedited development phase that has challenged most paradigms established in the era of conventional cytotoxic therapy and to some extent molecularly targeted agents. A huge wave of second-generation imAbs is just entering into phase 1 trials now, in monotherapy or in combination. In order to maximize their chances of success in early phase trials, and eventually for patients’ benefit, their clinical development has to benefit from lessons learnt from previous imAbs phase 1 trials.We reviewed the early clinical development of anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed death-1 receptor/ligand. Particularities of each agent, including safety, dose–toxicity and dose–efficacy relationships, scheduling, pharmacokinetics (PK), pharmacodynamics (PD), trial design, biomarkers, response assessment and overall drug development strategies, are described and challenged.As opposed to conventional cytotoxic agents, dose of imAbs is not linearly associated with efficacy and toxicity. Therefore, the definition of a minimal immunologically active dose could be proposed. Traditional patient eligibility criteria might also be revisited as the toxicity profile and mechanism of toxicity—immune-related adverse events—are mostly known and their physiopathology somehow less unexpected than with molecularly targeted small molecules. Most challenging are the comprehensive investigation of complex PK and PD characteristics as well as the definition of patient selection biomarkers. Finally, the early focus on efficacy (and not only dose confirmation) in expansion cohorts challenges the traditional phase 1/2/3 drug development process.Several drug development paradigms have been challenged by imAbs. Here, we discuss novel approaches for an efficient and successful drug development of these agents.