Loading
When a cancer that has become resistant to one drug is also resistant to another it has never seen, because the two share a mechanism. It is the central worry in deciding the order (sequencing) of similar drugs.
Two ADCs carrying topoisomerase-I payloads (T-DXd, sacituzumab govitecan, datopotamab deruxtecan) may fail one after another because resistance is to the payload, not the antibody; ARPIs show near-complete cross-resistance in prostate cancer; second-generation ALK or BTK inhibitors overcome some but not all resistance to the first. Cross-resistance data usually come from retrospective series, which is why 'optimal sequencing' remains unresolved in HR-positive breast, HER2-positive breast, prostate and CLL, and why some trials test switching mechanisms (payload class, target) rather than drugs of the same class. The opposite, collateral sensitivity, is when resistance to one drug creates vulnerability to another.
Showing the technology this term belongs to: Antibody-drug conjugate (ADC).
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
It made repeat biopsy and genotyping at progression the standard in ALK-positive lung cancer, because after a second-generation inhibitor the presence or absence of an ALK mutation is what separates patients who should receive a third-generation inhibitor from those who should not.
It is the cleanest demonstration in oncology that resistance is a property of a particular drug bound to a particular protein rather than a property of the tumour, and that genotyping at every progression can reopen an option that looked closed.
Shares BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors, Mantle cell lymphoma, Non-Hodgkin lymphoma (all types).
Shares BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors, Drug resistance (primary and acquired), Mantle cell lymphoma, Non-Hodgkin lymphoma (all types).
Shares AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L), Drug resistance (primary and acquired), Prostate cancer.
Shares Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F, ALK kinase-domain resistance mutation (G1202R and the rest), Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer, Non-small-cell lung cancer.
Shares Lines of therapy, Drug resistance (primary and acquired).
Shares Lines of therapy, Drug resistance (primary and acquired).
Shares Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F, ALK kinase-domain resistance mutation (G1202R and the rest), AR ligand-binding-domain mutation (L702H, W742C, H875Y, T878A, F877L), BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors.
Shares Drug resistance (primary and acquired), Prostate cancer, Non-small-cell lung cancer.