Cancer is traditionally diagnosed and treated on the basis of its organ of origin (e.g., lung or
colon cancer). However, organ-of-origin diagnostics does not reveal the underlying oncogenic drivers. Fortunately, molecular diagnostics have advanced at a breathtaking pace, and it is increasingly apparent that
cancer is a disease of the genome. Hence, we now have multiple genomic
biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted
therapies (
larotrectinib/
entrectinib, for NTRK fusions;
selpercatinib, RET fusions;
dabrafenib plus
trametinib, BRAFV600E mutations;
pembrolizumab/
dostarlimab,
microsatellite instability; and
pembrolizumab for high
tumor mutational burden;
pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid
neoplasms). There are emerging targets as well, including but not limited to ALK, BRCA and/or homologous repair deficiency, ERBB2 (HER2), IDH1/2, KIT, KRASG12C, NRG1, and VHL. Many tissue-agnostic approvals center on rare/ultra-rare
biomarkers (often < 1 % of
cancers), necessitating screening hundreds of
tumors to find a single one harboring the cognate molecular alteration. Approval has generally been based on small single-arm studies (<30-100 patients) with high response rates (>30 % to > 75 %) of remarkable durability. Because of
biomarker rarity, single-gene testing is not practical; next generation sequencing of hundreds of genes must be performed to obtain timely answers. Resistance to
biomarker-driven
therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for
customized drug combinations matched to the complex molecular alteration portfolio in each
tumor. Future investigation should expand tissue-agnostic
therapeutics to encompass both hematologic and solid
malignancies and include
biomarkers beyond those that are
DNA-based.