Suboptimal Trial Results Push Stakeholders to Revisit Rationale and Trial Design

Robert L. Ferris, MD, PhD

Director Hillman Cancer Center

University of Pittsburgh Medical Center

Pittsburgh, PA

An observation over time as a clinical investigator in the field of oncology is the experience of testing 1 or more agents in trials that have shown efficacy in multiple cancer types but surprisingly negative results in following trials in other cancers. An example is PD-1 inhibition alone or with anti–CTLA-4 showing a positive result in some cancers but having negative trials in other subsets of patients or diseases, some of which are quite similar etiologically, such as smoking-induced aerodigestive cancers. Or adding immune-oncology therapy and other agents to chemotherapy or radiation therapy, which has shown benefit in select diseases but has demonstrated some surprisingly negative results lately in others.

All cancers are different, and heterogeneity of cancers in various populations may lead to negative results based on biology. Additional reasons, and perhaps more cynical interpretations, may suggest study design flaws or even just bad luck. Enrollment by less-experienced sites or investigators may be responsible as well, warranting the proliferation of contract research organizations (or CROs), which are very expensive trial-conduct groups that raise the specter of poorly run trials and data management to justify their intermediary role in oncology research and clinical trial implementation.

What should be done when a trial results in a negative finding? The field, cooperative group, clinical trial committee, pharmaceutical sponsor, and perhaps even the FDA are at a loss as to whether to scrap the agent or regimen, move on to a different cancer hoping for a better clinical response, perform a follow-up companion trial with a similar agent, or simply move on from that disease.

In the end, none of these results are satisfactory for patients, the sponsor, or the oncologist investigators who spent many hours designing and conducting the trial with high hopes for exciting and practice-changing results in contributions to patient care. Thus, we should more clearly define when agents seem to fail in 1 cancer type vs another—when this surprising result conflicts with positive outcomes in other cancers—to determine whether an active agent was prematurely discarded in a disease, whether a trial was not designed or conducted ideally, or whether biology was speaking. The implications for sunk costs and patient outcomes from new agents may be substantial.