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

MPACT Trial

MPACT was designed to address the question of whether targeting an oncogenic driver would be more efficacious than not targeting the mutation. This pilot trial aims to establish whether advanced cancer patients who have exhausted all standard treatment options with proven benefit and have tumor harboring mutations in one of three main genetic pathways (DNA repair, PI3K, or RAS/RAF/MEK) are more likely to derive clinical benefit if treated with agents targeting that pathway than if treated with agents targeting one of the other pathways not identified to be dysregulated within the tumor. The agents administered in this trial are at recommended phase 2 dosing schedules. Currently the trial involves three pathways and four treatment arms (Figure 2): (I) veliparib (PARP inhibitor) with temozolomide for defects in the DNA repair pathway; (II) AZD-1775 (Wee1 inhibitor) plus carboplatin for defects in DNA repair pathway; (III) everolimus (mTOR inhibitor) for mutations in the PI3K pathway; or (IV) trametinib DMSO (MEK inhibitor) for mutations in the RAS/RAF/MEK pathway. Because of known benefits of BRAF inhibitor in melanoma and PARP inhibitors in BRCA ovarian cancer patients, these selected exclusions were built into the trial. The patients may remain eligible to be screened but will only be eligible to receive any of the study treatments if they have other actionable mutations.

Figure 2.

MPACT pathway (5). MPACT, Molecular Profiling-based Assignment of Cancer Therapy; COSMIC, the Catalogue of Somatic Mutations in Cancer.

Similar to NCI MATCH, patients undergo tumor biopsies at the time of enrollment with the tumor sequenced in a CLIA-certified lab for actionable mutations. Distinct from NCI MATCH, patients for whom an actionable mutation is detected undergo a 2:1 randomization to one of two arms based on results of molecular profiling analysis (Figure 3) where the investigator and patients are blinded to the molecular target. Patients randomized to the treatment arm would receive drug or drug combinations designed to target the identified genetic mutation. Patients randomized to Arm B would receive drug or drug combinations not prospectively identified to target the identified mutation. Patients in whom no actionable mutations are identified in one of the three pathways (DNA repair, PI3K, or RAS/RAF/MEK) would be deemed ineligible for further treatment. Patients who have been treated and subsequently progress on their respective treatment arm will have their molecular profiling analysis unblinded and are permitted to crossover to the treatment arm if originally assigned to the control arm. Similar to NCI MATCH, emphasis is placed on repeat biopsy at time of progression to further understand the resistance mechanisms and whether exposure to targeted agents may have created a selection pressure for the acquisition of new lesions. Given the relative frequencies of mutations in the pathways of interest in this study, approximately 700 patients will be enrolled to acquire 180 evaluable patients with the initial four arms, assuming the population screened is similar between the treatment arm and the control arm. This trial is also designed to have flexibility with regard to the addition of new pathways/treatment arms. The endpoint of the study will compare the response rate [complete response (CR) + partial response (PR)] and/or 4-month progression-free-survival of the treatment arm versus the control arm. MPACT is currently open in the Developmental Therapeutics Clinic, NCI but will be available at other sites through the NCI-sponsored Experimental Therapeutics Clinical Trials Network (ETCTN) in the near future.

Figure 3.

MPACT study design (5). MPACT, Molecular Profiling-based Assignment of Cancer Therapy.

The backbone of both these precision-based medicine trials is heavily dependent upon having an accurate, reliable, and rapid molecular assay for the identification of actionable mutations. For MPACT, genetic sequencing will be performed in the CLIA-certified MoCha at the Frederick National Laboratory for Cancer Research (FNLCR). The genetic variants to be assessed and treatment algorithms have been prospectively defined to allow for assignment of specific treatment arms on study. For MPACT, 20 genes were selected for the initial analysis panel based on several criteria: (I) the biological pathway(s) affected by the targeted therapy were examined (pathways: RAS/RAF/MEK signaling pathway, PI3K/AKT pathway and DNA repair pathways; (II) genes within these pathways were selected based on demonstrating a minimum frequency (5%) of somatic variants as listed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database; (III) genes known to modulate the targets of the study drugs; (IV) a Molecular Tumor Board review of the preclinical and clinical literature for the selection. A variety of specimen and assay quality checks are built into the assay process.

As the selection of treatment arm is rule-based, an informatics system, called GeneMed was designed to streamline the annotation of sequencing data, facilitate the review of variant mutations, and aid the identification of the actionable mutation. The results from the assay are processed based on predefined rules, and a treatment selection is assigned. If patient has two actionable mutations, the decision of which mutation will determine treatment selection is also rule-based.

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