What have we learned from exceptional tumour responses?: Review and perspectives

Understanding the basis of exceptional responses may increase our knowledge of disease biology and the mechanism of action of targeted agents, and identify subpopulations of patients who derive important benefit from drugs that would otherwise not be developed due to lack of sufficient activity in the general population. We will discuss in this review the value of a systematic phenotype-to-genotype approach in these outlier responders to identify actionable therapeutic targets that can help to personalize the delivery of cancer treatment.

Genomic mapping of outlier responders by next-generation sequencing is deciphering cancer biology at the individual level and providing insight in the somatic DNA alterations resulting in exceptional sensitivity to targeted agents in mono or combinational therapy.

In the era of targeted drugs, outlier or exceptional responders are frequently witnessed within early phase clinical trials. The genomic analysis of anecdotal 'exceptional responders' in trials that may otherwise not achieve prespecified efficacy endpoints may lead to the identification of predictive biomarkers for targeted therapies and revitalize or reposition the use of targeted agents in enriched populations. The era of unselected early clinical trials has passed with the advent of genomic-driven medicine and novel adaptive and biomarker-enrichment trials will accelerate drug approval, and overcome the challenges of testing targeted drugs against aberrations with low prevalence.