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

NCI MATCH Trial

The NCI MATCH trial was initiated as a broad-based genomic pre-screening study to assign patients whose tumors harbor specific molecular aberrations to relevant targeted treatments, without regards to tumor histology type. This trial aims to establish whether patients with tumor mutations, amplifications or translocations of interest are likely to derive clinical benefit if treated with agents targeting that specific molecular change in a one stage single-arm design. To provide the greatest opportunity to patients, this trial will cover a large range of mutations with matching options. In order to design such a complex trial, a panel of experts in developmental therapeutics, clinical trial design, genetic sequencing, molecular oncology, informatics, and statistics were consulted to develop an algorithm that would define clinical action based on genetic variants reported in the genes of interest. The structure of the study involves a master protocol to ensure the common elements of the subprotocols remain consistent across the arms. This study is additionally designed with the flexibility to open and close arms under the umbrella of the master protocol, with each arm treated as a separate phase 2 trial.

To ensure for adequate patient enrollment, the trial will be run through the NCI National Clinical Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP). NCORP will help bring this nationwide study to patients treated in the community setting and increase accessibility to patients. The ECOG-ACRIN group will coordinate the trial for the NCTN, with broad representation through having separate principal investigators for each of the sub-protocols, each representing the different groups within the NCTN. The large portfolio of agents needed for the success of this trial required the participation of a multitude of pharmaceutical partners. The Cancer Therapy Evaluation Program (CTEP) of the NCI assisted in the coordination and contracting of these agents. The NCI Center for Biomedical Informatics and Information Technology (CBIIT) along with members of the NCI MATCH team generated the informatics structure for this trial. Multiple committees, including Agents and Genes Working Groups, Sample and Sequencing Network Working Group, and Protocol Logistics Working Group, among others, were established to concurrently develop the multitude of components for this massive endeavor.

NCI MATCH will accrue patients with solid tumors, with disease that has progressed following at least one line of standard systemic therapy, or for whom no standard therapy exists. As this is an exploratory trial, histologies for which there is already an FDA approved indication with that agent, or that have been shown to not respond to a particular agent, will accordingly be excluded from the corresponding agent. The study is designed to assign targeted treatment based on a biopsy obtained after enrollment. Molecular changes will be the selection criterion for entry to a particular arm. The study drugs included in this trial include single agents and combinations that have either received FDA approval or are investigational agents that have achieved at least a recommended phase 2 dose.

The NCI MATCH trial will collect somatic (tumor) genomic data from all patients enrolled through a screening biopsy. As tumors sometimes accumulate additional mutations after various treatments or with continued growth and metastasis, a biopsy closest to the time of initiating treatment will be pursued in order to obtain the most reflective state of the tumor. A biopsy after progression will also be pursued, with special interest in those patients who initially responded to treatment, to assist in understanding the mechanism of resistance. The Molecular Characterization (MoCha) Laboratory of the NCI was charged with development of the assay to identify these actionable mutations. The patient's tumor biopsy will be screened for pre-defined variations in genes within a NCI MATCH CLIA-certified laboratory. The molecular profiling assays will include large-scale parallel tumor sequencing (next generation sequencing) strategies, including a targeted Ampliseq panel as well as other molecular assays such as immunohistochemistry (IHC). The selection of treatment will be rule-based and will be applied by a rigorously validated informatics system to derive a tentative treatment assignment. If a patient is ineligible for the original assigned treatment arm because of a pre-defined clinical ineligibility criterion, and patient's tumor harbors additional abnormalities for which treatments are available on the study, the system algorithm will continue to provide assignments until all available options are exhausted (Figure 1).

Figure 1.

NCI MATCH study design (5). MATCH, Molecular Analysis for Therapy Choice; NCI, National Cancer Institute; SD, stable disease; RECIST, Response Evaluation Criteria in Solid Tumors.

On this trial only malignant tissue will be screened. As such, definitive abnormalities in germline tissues (heritable diseases) cannot be identified with any certainty. Due to the concern that some of the genes tested may be of germline origin, a committee of multidisciplinary experts (genetics, oncology, bioethicists, patient advocates) was formed to address this ethical concern. Currently, findings will be communicated to the treating clinician with the recommendation to consider germline testing if clinical and/or family history is consistent with the presence of such an inheritable germline mutation. In many cases the medical significance of genetic variants are unknown.[6,7] With the changing field of genomics, a steering committee has been tasked with monitoring the changing landscape.

This study affords a unique opportunity to collect information about the prevalence of mutations, translocations and amplifications in genes associated with cancer, and how these tumors respond to targeted therapy in the treatment-refractory tumor setting. DNA variants and changes in RNA expression from tumors collected at the point of progression on treatment is anticipated to illuminate resistance mechanisms that will inform subsequent studies and improve upon patient outcomes. NCI MATCH has opened in August 2015.

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