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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.
Purpose:
National Cancer Institute Molecular Analysis for Therapy Choice (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.
Experimental Design:
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 10 published NCI-MATCH subprotocols (together n = 435 patients). FDR 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 and MEK inhibition in lung cancers with BRAF non-V600E mutations. In addition, it identifies low-grade serious ovarian carcinoma with BRAF v600E mutation as especially sensitive to BRAF and MEK co-inhibition (dabrafenib plus trametinib), a treatment that received accelerated FDA approval for advanced solid tumors with BRAF v600E mutation.
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 therapy trials like NCI-MATCH can reveal tumor-specific drug activity. Analyzing National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) data identified specific cancer types sensitive to targeted therapies, even if not effective across all tumors.
Area of Science:
- Oncology
- Genetics
- Clinical Trials
Background:
- The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial investigated precision medicine by matching targeted therapies to genetic alterations in tumors, irrespective of cancer type.
- Initial analyses of most NCI-MATCH subprotocols showed limited tumor shrinkage rates across all enrolled cancer types.
- A hypothesis was formed that the efficacy of these precision cancer therapies might be specific to certain tumor types, similar to conventional cancer treatments.
Purpose of the Study:
- To test the hypothesis that specific tumor types exhibit differential sensitivity to particular targeted therapies.
- To re-evaluate data from NCI-MATCH subprotocols to identify tumor-specific drug efficacy signals.
Main Methods:
- Permutation testing was applied to tumor volume change and progression-free survival data from 10 NCI-MATCH subprotocols, encompassing 435 patients.
- Statistical significance was assessed, controlling the False Discovery Rate (FDR) using the Benjamini-Hochberg procedure.
Main Results:
- Six out of ten subprotocols demonstrated statistically significant evidence of tumor-specific drug sensitivity.
- Four subprotocols, previously deemed ineffective based on overall response rates, showed significant tumor-specific activity upon re-analysis.
- Key findings include potential efficacy of FGFR tyrosine kinase inhibitors in urothelial carcinomas with FGFR aberrations and MEK inhibitors in lung cancers with BRAF non-V600E mutations.
- Low-grade serious ovarian carcinoma with BRAF V600E mutation showed high sensitivity to combined BRAF and MEK inhibition (dabrafenib plus trametinib).
Conclusions:
- The study validates the utility of basket trials in precision oncology.
- Even in the absence of tumor-agnostic effects, basket trials can uncover valuable tumor-specific therapeutic activities for further investigation.
- These findings support the targeted approach in cancer treatment, highlighting the importance of considering tumor-specific responses.
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