# ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer

Source: https://onco.cc/key-papers/paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019/  
OnCo record `paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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).

## Fields

- Kind: Key paper
- Last checked: 2026-09-25
- Journal: Journal of Clinical Oncology
- Year: 2019
- DOI: 10.1200/JCO.18.02236
- Authors: Shaw AT, Solomon BJ, Besse B, et al.
- Findings: About a quarter of previously treated patients carried a detectable ALK resistance mutation.; After a second-generation inhibitor, response was 69% with an ALK mutation on tissue against 27% without.; Progression-free survival 11.0 against 5.4 months by tissue genotyping, hazard ratio 0.47.; After crizotinib alone, mutation status made no difference.
- What it means: 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.
- Caveats: A single-arm registrational study, so the comparison is between subgroups rather than between treatments.; Tissue and plasma disagreed, and the tissue result separated the groups more sharply.; Not all patients had both sample types.

## Sources

- 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
- PubMed: https://pubmed.ncbi.nlm.nih.gov/30892989/

## Connected records

- biomarkers: [ALK fusion (ALK-positive)](https://onco.cc/biomarkers/alk-fusion/), [ALK kinase-domain resistance mutation (G1202R and the rest)](https://onco.cc/biomarkers/alk-resistance-mutation/)
- 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/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Crizotinib](https://onco.cc/drugs/crizotinib/), [Guardant360 CDx](https://onco.cc/drugs/guardant360-cdx/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/)
- institutions: [Massachusetts General Hospital Cancer Center](https://onco.cc/institutions/mgh/)
- pathways: [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: [Circulating tumour DNA (ctDNA)](https://onco.cc/terms/ctdna/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Gene fusion](https://onco.cc/terms/gene-fusion/)
- people: [Alice T. Shaw](https://onco.cc/people/alice-shaw/)
- journals: [Journal of Clinical Oncology](https://onco.cc/journals/jco/)

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