Background: As we move away from the traditional chemotherapy era to targeted therapy,
the validity of old assessment paradigms associated with therapeutics are being raised in the context of
immunotherapy. The old paradigm required elaborating on the toxicity assessment, with no expectation
of efficacy in early phase trials. Safety data from Phase 1 and 2 studies with many immunotherapeutics
show limited toxicities and draw attention to the need to demonstrate efficacy in the early
evaluation of new agents.
Methods: Literature searches indicate that molecular oncology mechanistic-based agents are being
linked with molecular disease status and clinical benefit. Biomarkers and other endpoints are being
employed to accomplish this. Perspectives for a meaningful context of integrating biomarkers and
clinical trial design are reviewed.
Results: The design and conduct of clinical trials have not been fully adjusted to the new era of personalized
oncology, and so we are in transition. A part of this transition is the management of expectations
and trial designs that need to be considered relative to preclinical experience in the development
of therapeutics. For example, pathological complete response is now considered a surrogate marker for
favorable prognosis in breast cancer patients who are treated in the neoadjuvant setting. This surrogate
marker is tied to novel agents’ mechanistic characteristics with no preclinical counterpart.
Conclusion: The old paradigm considers patients equal with similar chances to respond to treatments,
but the new paradigm considers patient’s heterogeneity, a major fact that informs the design of clinical
trials. By linking every treatment to a mechanism of action and to the presence of a specific biomarker,
new trials are going to have more subjects who are likely to respond to the treatment.