Tumor-Specific Activity of Precision Medicines in the NCI-MATCH Trial

Abstract

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.

Figure 1:. Tumor types with significant differences in tumor volume change in NCI-MATCH subprotocols.

Each panel shows a distribution of tumor volume changes (TVC) under the null hypothesis of no difference between tumor types, and observed average TVC for each tumor type (red line). A) Dabrafenib with trametinib in BRAFV600E-mutated tumors. ‘Biliary’ denotes intrahepatic cholangiocarcinoma. B) Capivasertib in AKT E17K-mutated tumors. We classified tumor types as gynecologic, breast, or other. C) AZD4547 in FGFR-mutated tumors. D) Trametinib in BRAF Non-V600E mutated tumors. E) Afatinib in HER2-mutated tumors. F) Binimetinib in NRAS-mutated tumors. ‘Biliary’ denotes cholangiocarcinoma. G) Nivolumab in mismatch-repair deficient tumors. ‘Endometrial’ denotes Endometrial endometrioid adenocarcinoma and Endometrial endometrioid adenocarcinoma variants. H) Copanlisib in PIK3CA-mutated tumors. I) Ado-trastuzumab emtansine in HER2-amplified tumors. J) Taselisib in PIK3CA-mutated tumors. ‘SCC anog Region’ denotes squamous cell carcinoma of the anogenital region. For all trials, subgroups of miscellaneous tumors (denoted “other”), or subgroups of fewer than three patients, were not tested for differences.

Figure 2:. Tumor type-specific hazard ratios and differences in tumor volume change compared to each subprotocol’s average.

A) Scatterplot of each tumor type’s Hazard Ratio (PFS of tumor type versus PFS of all tumors in a subprotocol) and difference in tumor volume change (average TVC of tumor type compared with average TVC of all tumors in a subprotocol). Note, HR of 1 means a tumor type exhibited the same PFS as that of all tumor types; it does not mean no therapeutic effect. B) Summary of tumor types with significantly better TVC and/or PFS compared to all tumors enrolled in a subprotocol.