# ALK kinase-domain resistance mutation (G1202R and the rest)

Source: https://onco.cc/biomarkers/alk-resistance-mutation/  
OnCo record `alk-resistance-mutation` (Biomarker). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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).

## Fields

- Kind: Biomarker
- Last checked: 2026-09-25
- Also known as: ALK resistance mutation; G1202R; ALK G1202R; L1196M; ALK secondary mutation; solvent front mutation
- Tags: biomarker; resistance

## Sources

- Gainor et al., Cancer Discov 2016: 103 repeat biopsies and the resistance mutations of first- and second-generation ALK inhibitors: https://doi.org/10.1158/2159-8290.CD-16-0596
- Shaw et al., J Clin Oncol 2019: ALK resistance mutations and the efficacy of lorlatinib in 198 patients: https://doi.org/10.1200/JCO.18.02236
- Shaw et al., N Engl J Med 2016: resensitisation to crizotinib by the lorlatinib resistance mutation ALK L1198F: https://doi.org/10.1056/NEJMoa1508887

## Connected records

- biomarkers: [ALK fusion (ALK-positive)](https://onco.cc/biomarkers/alk-fusion/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [ALK](https://onco.cc/targets/alk/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/), [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- terms: [Biopsy](https://onco.cc/terms/biopsy/), [Cross-resistance](https://onco.cc/terms/cross-resistance/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Gene fusion](https://onco.cc/terms/gene-fusion/)
- key papers: [ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019/), [Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer](https://onco.cc/key-papers/paper-gainor-alk-resistance-mutations-cancer-discov-2016/), [Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F](https://onco.cc/key-papers/paper-shaw-alk-l1198f-resensitisation-nejm-2016/)

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