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After a lung cancer stops responding to an ALK-blocking tablet, finding a change inside the ALK protein itself is good news: it means the cancer still depends on ALK, and a later-generation tablet is likely to work. Finding none means the opposite.
Each generation of ALK inhibitor selects its own set of secondary mutations in the ALK kinase domain. Across 103 repeat biopsies, crizotinib was followed by a diverse spectrum (L1196M, G1269A and others) in a minority of patients, while second-generation inhibitors (alectinib, brigatinib, ceritinib) were followed by mutations in the majority, with the solvent-front substitution G1202R rising significantly in frequency (Gainor 2016). The readout is predictive rather than descriptive: in the lorlatinib registration study, among patients who had failed one or more second-generation inhibitors, objective response was 69% with an ALK mutation on tissue genotyping against 27% without, and progression-free survival 11.0 against 5.4 months (hazard ratio 0.47); after crizotinib alone, mutation status made no difference (Shaw 2019). Compound mutations can reverse the ordering entirely: C1156Y with L1198F confers resistance to lorlatinib and restores sensitivity to crizotinib (Shaw 2016).
In plain words · ALK is a gene fusion driver in about 4 to 5% of non-small-cell lung cancers that responds to a succession of ALK inhibitor pills. Lorlatinib kept about 60% of patients progression-free at five years, alectinib is approved after surgery, and neladalkib targets compound resistance mutations.
A repeat biopsy or blood test when a treatment stops working is not a formality here. Finding a change in the ALK protein usually means another tablet in the same family will work; finding none usually means it is time for a different kind of treatment.
Written only from the label or guideline text cited on this page. Not medical advice; your own report and the reading your team gives it come first.
Presence of a secondary missense substitution in the ALK kinase domain on tumour tissue or plasma sequencing taken at progression, reported with the specific residue and with the inhibitors already received, since the spectrum differs by generation.
“each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALK G1202R, increases significantly after treatment with second-generation agents”
Gainor et al., Cancer Discovery 2016No approval uses this readout as a threshold. It is defined by Shaw et al., J Clin Oncol 2019: ALK resistance mutations and the efficacy of lorlatinib.
Matched on the name and aliases of the readout in the title, setting and summary of each trial; a match is a mention, not proof the readout was an entry criterion.
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.
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 Resistance routes: how a blocked pathway comes back, Drug resistance (primary and acquired), Receptor tyrosine kinase activation, Comprehensive genomic profiling and the tags biomarker, resistance.
Shares Non-small-cell lung cancer and the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares the tags biomarker, resistance.
Shares Liquid biopsy (ctDNA) and the tag biomarker.
Shares ALK fusion (ALK-positive), Gene fusion, Non-small-cell lung cancer and the tag biomarker.
Shares Gene fusion, Receptor tyrosine kinase activation, Comprehensive genomic profiling, Non-small-cell lung cancer and the tag biomarker.
Shares ALK fusion (ALK-positive), Gene fusion, Non-small-cell lung cancer and the tag biomarker.