An Overview of the NCI Precision Medicine Trials—NCI MATCH and MPACT

Khanh Do; Geraldine O'Sullivan Coyne; Alice P. Chen


Chin Clin Oncol. 2015;4(3):2304-3865. 

In This Article

Exceptional Responder

Despite best efforts, the majority of single agent anti-neoplastic drugs that enter phase 1 and 2 clinical trials ultimately fail to demonstrate sufficient efficacy to support further development. In rare exceptions, however, one or two patients achieve a significant response to the therapy or derive unexpected long-term benefit on these trials. These small subsets of responders from these otherwise "failed" trials/treatments may hold the key to insight in tumor biology and the identification of the molecular markers that predict for response to treatment. In support of this approach, several case reports have highlighted these "Exceptional Responders". As an example, a urothelial cancer patient with a TSC1 and NF2 mutation achieved a durable CR to everolimus in a phase 2 trial that had failed to meet its phase 2 endpoint.[8] Alterations in these genes were known to be associated with mTORC dependence in preclinical studies. The authors sequenced 13 additional patients with bladder cancer who had received everolimus, and found that 4 of 5 patients with TSC1 mutations had tumor shrinkage, whereas those without the mutation did not. A second patient with urothelial cancer, identified to have a novel mTOR mutation by whole exome sequencing, also had a CR to the combination of everolimus and pazopanib.[9] These reports, as well as others in the literature, suggest that a search for elusive molecular targets in responders as a means to enrich studies for those patients most likely to benefit from any particular treatment holds promise for a more successful drug trial. The ability to identify molecular markers that are able to predict a clinical response in any particular subsets of patients will provide the tools necessary to conduct further studies consistent with the principles of precision medicine and allow for more rapid development of novel strategies.

The Exceptional Responders initiative aims to establish a repository of information on tumor biology based on data collected from these unique responders. The success of this endeavor depends upon having accurate and reliable demographics, clinical history, and response data for patients who have been treated, adequate tissue for analysis, robust analytical techniques/platforms, and appropriate bioinformatics/biostatistical tools. The Exceptional Responders project will collect tissues from patients who fit the definition of Exceptional Responders (Table 1) and use whole exome sequencing, and/or targeted NGS assay deep sequencing for full genomic analysis of patient tumors. If sufficient material is available, further exploration with additional analyses [e.g., whole genome sequencing, messenger RNA (mRNA)-sequencing, micro RNA (miRNA) sequencing, promoter methylation analysis, single nucleotide polymorphism (SNP) analysis, etc] will be performed. All data will be de-identified and placed in a controlled-access database to serve as a repository of information to allow investigators to mine data and design and build clinical trials around this information, based on molecular features predictive of benefit to a particular drug or drug class.