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In patients whose cancer had already outgrown a second ALK drug, the third-generation drug worked in seven out of ten of those whose tumour carried a resistance mutation and in fewer than three out of ten of those whose tumour did not.
Baseline plasma and tumour tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer in the registrational phase 2 study of lorlatinib. Plasma DNA was analysed for ALK mutations with a commercial assay and tumour tissue DNA with an ALK mutation-focused next-generation sequencing assay. About a quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, lorlatinib efficacy was comparable with and without ALK mutations. In patients who had failed one or more second-generation inhibitors, objective response was higher with ALK mutations, 62% against 32% by plasma and 69% against 27% by tissue, and progression-free survival was similar by plasma genotyping (7.3 against 5.5 months, hazard ratio 0.81) but significantly longer by tissue genotyping (11.0 against 5.4 months, hazard ratio 0.47).
It turned the laboratory prediction into a clinical rule: after a second-generation ALK inhibitor, genotype the tumour, and treat the absence of an ALK mutation as evidence that the cancer has stopped depending on ALK.
Shares Alice T. Shaw, ALK kinase-domain resistance mutation (G1202R and the rest), ALK fusion (ALK-positive), Lorlatinib.
Shares Alice T. Shaw, ROS1, Massachusetts General Hospital Cancer Center, Crizotinib.
Shares ALK kinase-domain resistance mutation (G1202R and the rest), ALK fusion (ALK-positive), Lorlatinib, Massachusetts General Hospital Cancer Center.
Shares ROS1, Guardant360 CDx, ALK, Receptor tyrosine kinase activation.
Shares Alice T. Shaw, ROS1, Lorlatinib, Crizotinib.
Shares Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Receptor tyrosine kinase activation, Circulating tumour DNA (ctDNA).
Shares ROS1, ALK, Receptor tyrosine kinase activation, Circulating tumour DNA (ctDNA).
Shares Guardant360 CDx, Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Receptor tyrosine kinase activation.