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Tumor-specific activity of precision medicines in the NCI-MATCH trial
Ivvone Zhou1, Deborah Plana2,3, Adam C Palmer1
1Department of Pharmacology, Computational Medicine Program, UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, USA.
Background:
NCI-MATCH is a precision medicine basket trial designed to test the effectiveness of treating cancers based on specific genetic changes in patients' tumors, regardless of cancer type. Multiple subprotocols have each tested different targeted therapies matched to specific genetic aberrations. Most subprotocols exhibited low rates of tumor shrinkage as evaluated across all tumor types enrolled. We hypothesized that these results may arise because these precision cancer therapies have tumor type-specific efficacy, as is common among other cancer therapies.
Methods:
To test the hypothesis that certain tumor types are more sensitive to specific therapies than other tumor types, we applied permutation testing to tumor volume change and progression-free survival data from ten published NCI-MATCH subprotocols (together n=435 patients). False discovery rate was controlled by the Benjamini-Hochberg procedure.
Results:
Six of ten subprotocols exhibited statistically significant evidence of tumor-specific drug sensitivity, four of which were previously considered negative based on response rate across all tumors. This signal-finding analysis highlights potential uses of FGFR tyrosine kinase inhibition in urothelial carcinomas with actionable FGFR aberrations, MEK inhibition in lung cancers with BRAF non-V600E mutations, and MEK inhibition in cholangiocarcinomas with NRAS mutations.
Conclusions:
These findings support the value of basket trials because even when precision medicines do not have tumor-agnostic activity, basket trials can identify tumor-specific activity for future study.
Insights
Precision cancer therapies show tumor-specific efficacy. Basket trials identified specific drug sensitivities in certain cancers, supporting their value for targeted treatment discovery.
Area of Science:
- Oncology
- Genomics
- Clinical Trials
Background:
- The National Cancer Institute (NCI)-MATCH trial investigated precision medicine by matching targeted therapies to genetic alterations in tumors, irrespective of cancer type.
- Most NCI-MATCH subprotocols showed limited tumor shrinkage across all enrolled cancer types.
- A hypothesis was formed that precision therapies might possess tumor type-specific efficacy, similar to conventional treatments.
Approach:
- Permutation testing was used to analyze tumor volume change and progression-free survival data from ten NCI-MATCH subprotocols (435 patients).
- Statistical significance was assessed using the Benjamini-Hochberg procedure to control the false discovery rate.
Key Points:
- Six of ten subprotocols demonstrated statistically significant tumor-specific drug sensitivity.
- Four subprotocols previously deemed ineffective showed potential tumor-specific activity upon re-analysis.
- Identified potential applications include FGFR tyrosine kinase inhibitors for urothelial carcinomas with FGFR aberrations, MEK inhibitors for lung cancers with BRAF non-V600E mutations, and MEK inhibitors for cholangiocarcinomas with NRAS mutations.
Conclusions:
- The study validates the utility of basket trials in precision oncology.
- Basket trials can uncover tumor-specific drug activity even when therapies lack tumor-agnostic effects.
- These findings facilitate the identification of targeted therapies for specific cancer types for future clinical investigation.
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