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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., (©2023 American Association for Cancer Research.)

Most advanced cancers are treated with drug combinations. Rational design aims to identify synergistic combinations, but existing synergy metrics apply to preclinical, not clinical data. Here we propose a model of drug additivity for progression-free survival (PFS) to assess whether clinical efficacies of approved drug combinations are additive or synergistic. This model includes patient-to-patient variability in best single-drug response plus the weaker drug per patient. Among US Food and Drug Administration approvals of drug combinations for advanced cancers (1995-2020), 95% exhibited additive or less than additive effects on PFS times. Among positive or negative phase 3 trials published between 2014-2018, every combination that improved PFS was expected to succeed by additivity (100% sensitivity) and most failures were expected to fail (78% specificity). This study shows synergy is neither a necessary nor common property of clinically effective drug combinations. The predictable efficacy of approved combinations suggests that additivity can be a design principle for combination therapies., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)