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The Molecular Analysis for Therapy Choice (NCI-MATCH) Trial: Lessons for Genomic Trial Design
Keith T Flaherty1, Robert Gray2, Alice Chen3
1Massachusetts General Hospital, Boston, MA, USA.
Background:
The proportion of tumors of various histologies that may respond to drugs targeted to molecular alterations is unknown. NCI-MATCH, a collaboration between ECOG-ACRIN Cancer Research Group and the National Cancer Institute, was initiated to find efficacy signals by matching patients with refractory malignancies to treatment targeted to potential tumor molecular drivers regardless of cancer histology.
Methods:
Trial development required assumptions about molecular target prevalence, accrual rates, treatment eligibility, and enrollment rates as well as consideration of logistical requirements. Central tumor profiling was performed with an investigational next-generation DNA-targeted sequencing assay of alterations in 143 genes, and protein expression of protein expression of phosphatase and tensin homolog, mutL homolog 1, mutS homolog 2, and RB transcriptional corepressor 1. Treatments were allocated with a validated computational platform (MATCHBOX). A preplanned interim analysis evaluated assumptions and feasibility in this novel trial.
Results:
At interim analysis, accrual was robust, tumor biopsies were safe (<1% severe events), and profiling success was 87.3%. Actionable molecular alteration frequency met expectations, but assignment and enrollment lagged due to histology exclusions and mismatch of resources to demand. To address this lag, we revised estimates of mutation frequencies, increased screening sample size, added treatments, and improved assay throughput and efficiency (93.9% completion and 14-day turnaround).
Conclusions:
The experiences in the design and implementation of the NCI-MATCH trial suggest that profiling from fresh tumor biopsies and assigning treatment can be performed efficiently in a large national network trial. The success of such trials necessitates a broad screening approach and many treatment options easily accessible to patients.
Insights
The National Cancer Institute Matching Agents To ক্যান্সertumor (NCI-MATCH) trial demonstrates that matching patients with refractory malignancies to targeted therapies based on molecular alterations is feasible. Despite initial enrollment challenges, the trial successfully refined its processes for efficient tumor profiling and treatment assignment in a national network.
Area of Science:
- Precision oncology
- Molecular tumor profiling
- Clinical trial design
Background:
- The efficacy of histology-independent, molecularly targeted therapies in refractory malignancies remains largely unknown.
- The National Cancer Institute (NCI)-MATCH trial was designed to identify efficacy signals by matching patients with refractory cancers to treatments targeting specific molecular drivers.
Purpose of the Study:
- To evaluate the feasibility and assumptions of a large-scale, molecularly-driven cancer clinical trial.
- To assess the efficiency of central tumor profiling and targeted treatment assignment in a national network.
Main Methods:
- Utilized next-generation DNA sequencing for profiling alterations in 143 genes and key protein expression.
- Employed the MATCHBOX computational platform for treatment allocation based on molecular profiles.
- Conducted a preplanned interim analysis to assess trial feasibility, accrual, and profiling success.
Main Results:
- Achieved robust accrual with safe tumor biopsies (<1% severe events) and high profiling success (87.3%).
- Observed actionable molecular alteration frequencies aligned with expectations, but enrollment lagged due to logistical issues.
- Successfully addressed enrollment lags by revising mutation frequency estimates, expanding screening, adding treatments, and improving assay efficiency (93.9% completion, 14-day turnaround).
Conclusions:
- Profiling fresh tumor biopsies and assigning targeted treatments can be efficiently executed within a large national clinical trial network.
- Successful implementation of such precision oncology trials requires a broad screening strategy and readily available diverse treatment options.
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