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Rebiopsying 103 patients as each generation of drug failed showed that each drug leaves its own signature of escape mutations, and that whether a mutation is present decides whether the next drug in the sequence will work.
One hundred and three repeat biopsies from patients with ALK-positive lung cancer progressing on various ALK inhibitors were analysed. Each ALK inhibitor was associated with a distinct spectrum of ALK resistance mutations, and the frequency of ALK G1202R increased significantly after treatment with second-generation agents. Second-generation inhibitors are generally effective after crizotinib even without a crizotinib-resistant ALK mutation, reflecting incomplete inhibition of ALK by crizotinib in many cases. In a series of ceritinib-resistant patient-derived cell lines, the presence of ALK resistance mutations was highly predictive of sensitivity to the third-generation inhibitor lorlatinib, whereas lines without ALK mutations were resistant.
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.
Shares Cross-resistance, ALK kinase-domain resistance mutation (G1202R and the rest), ALK fusion (ALK-positive), Lorlatinib.
Shares ALK kinase-domain resistance mutation (G1202R and the rest), ALK fusion (ALK-positive), Lorlatinib, Massachusetts General Hospital Cancer Center.
Shares ALK fusion (ALK-positive), Alectinib, Crizotinib, ALK.
Shares Massachusetts General Hospital Cancer Center, Crizotinib, Gene fusion, ALK.
Shares Biopsy, Resistance routes: how a blocked pathway comes back, Clonal evolution & minimal residual disease, Drug resistance (primary and acquired).
Shares Ceritinib, Alectinib, Lorlatinib, Crizotinib.
Shares ALK fusion (ALK-positive), Crizotinib, Gene fusion, ALK.
Shares Massachusetts General Hospital Cancer Center, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Receptor tyrosine kinase activation.