Real-world evidence provides clinical insights into tissue-agnostic therapeutic approvals
George W. Sledge, Takayuki Yoshino, Joanne Xiu, Anthony Helmstetter, Jennifer R. Ribeiro, Sergey Klimov, Brady Gilg, Jianguo Gao, Jeff Elton, Matthew J. Oberley, Milan Radovich, Jim Abraham, David Spetzler
Abstract
The US Food and Drug Administration approves tissue-agnostic therapies to target tumor biomarkers regardless of tumor type. In light of the growing number of such approvals in recent years, a better understanding of their relative clinical benefit across cancer types is required. To address this need, we analyzed tissue-agnostic indications (TMB-High, MSI-High/MMRd, BRAFV600E mutations, and NTRK and RET fusions) in a database of 295,316 molecularly-profiled tumor samples with associated clinical outcomes data. Here, we show that 21.5% of tumors harbored at least one of the tissue-agnostic indications investigated, including 5.4% lacking a cancer-specific indication. Our analysis reveals poor uptake of targeted therapies for rare NTRK fusions, significant differences in pembrolizumab-associated outcomes across tumor types for TMB-High and MSI-High/MMRd, as well as clinical benefits in tumor types and drugs of the same class not investigated in the pivotal clinical trials. These results demonstrate that treatment effects are not necessarily tissue-agnostic, and suggest possible expansion of therapeutic avenues for a given tissue-agnostic indication. Tissue agnostic treatments can be used to target known cancer mutations, independent of cancer type. Here, the authors identified tissue-agnostic biomarkers in 21.5% of patients in a cohort of 295,316 tumor samples, and observed variable clinical benefit of tissue-agnostic treatments across cancer types.