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

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

Disclosures

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

In This Article

Factors to Consider

The essential factors for the success of these NCI precision-based medicine trials bring to light fundamental issues inherent in transformative clinical trial design. The data generated from these trials have to be interpreted with certain assumptions: (I) target engagement by the selected agent has been confirmed either preclinically or clinically—even in best of circumstances, errors have been made especially in early development. One glaring example is that of iniparib, which failed to inhibit poly (ADP-ribose) polymerase in vitro, though this was not discovered until it had gone through phase 3 clinical development;[10] (II) the assay used has been validated, confirmed to be reliable for the target, and transferable across sites—guidelines and standard operating procedures must be in place to ensure that biospecimen collection, storage, and processing meet quality standards for further sequencing and that regardless of where the specimen is handled, the same result can be expected. As an example, the lack of these institutional standards delayed initiation of the Cancer Genome Atlas initiative;[11] (III) biopsy material obtained is representative of the entire tumor and metastatic site(s)—while driver mutations likely represent a significant portion of the existing tumor, tumor heterogeneity is a well-known challenge in the design of molecular targeted clinical trials. Even strategies such as serial tumor biopsies cannot completely eliminate this as a factor in the interpretation of data. Future development of circulating tumor cells or circulating DNA may help to further delineate driver mutations from those of bystander mutations. Radiographic record of biopsy sites may improve understanding of tumor heterogeneity; (IV) there is an available therapy for the target of interest—selection of the most reasonable agent for a specific target can sometimes be limited due to factors such as drug availability, ease of administration, or proven ability to combine with established agents in a particular clinical setting. Limitations in therapeutic options can further be complicated in situations of variants of unknown significance where benefit has not yet been confirmed.

The results of both NCI MATCH and MPACT will be informative and provide opportunities for further investigation. Though NCI MATCH's primary endpoint is response rate, it is exploratory in nature. With a mix of histologies, including those of rare tumors, any response could provide interesting leads. How these leads will be explored and confirmed is not currently established. The strength of MPACT is heavily dependent upon accurate selection of the driver mutation in order to focus exploration of a particular pathway. Both trials contain multiple arms with small number of patients designed not as definitive trials but more as exploratory trials in order to guide further exploration of both tumor and pathways.

processing....