# ALK

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

## TL;DR

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.

## Summary

ALK rearrangements occur in ~4-5% of NSCLC, typically in younger never-smokers. Lorlatinib achieved 5-year PFS of ~60% in CROWN, the longest of any targeted therapy in metastatic NSCLC. Alectinib is approved in the adjuvant setting (ALINA). Fourth-generation inhibitors (neladalkib) address compound resistance mutations.

## Fields

- Kind: Target
- Last checked: 2026-09-04
- Tags: driver; kinase
- Symbol: ALK
- Class: kinase
- Biology: ALK is a receptor tyrosine kinase; the EML4-ALK fusion is most common. It is also altered in anaplastic large-cell lymphoma and neuroblastoma.
- Where found: NSCLC (~5%); Anaplastic large-cell lymphoma; Neuroblastoma; Pancreatic ductal adenocarcinoma: gene fusion (eml4-alk, strn-alk) 0.2%; Colorectal cancer: gene fusion 0.1%; Non-small-cell lung cancer: rearrangement, usually eml4-alk 3-6%

## Notes

- Pancreatic ductal adenocarcinoma: ALK fusions in 5 of 3,170 tumours, 0.16%, all KRAS wild-type and all in patients under 50, among whom the rate is 1.3%; 3 of 4 treated with an ALK inhibitor benefited (Singhi 2017). It is the reason a young patient with a KRAS wild-type tumour should have fusion testing.
- Colorectal cancer: ALK fusions in about 0.1% of tumours (cBioPortal). ALK point mutations read far higher on panels but are overwhelmingly passengers in hypermutated tumours; only a fusion is actionable.
- Lung cancer: rearranged in 3 to 6% of adenocarcinomas, 5.6% in never smokers, with EML4 the partner in the large majority (cBioPortal; Soda 2007). Panel-based rates run below the fluorescence in situ hybridisation rate of 8% found by the Lung Cancer Mutation Consortium because a DNA panel sees a rearrangement only where it baits the breakpoint intron (Kris 2014). ALK point mutations found at diagnosis are almost all passengers; only a fusion is actionable. At progression the same gene is read again for a different purpose: each inhibitor generation selects its own resistance spectrum, G1202R dominates after a second-generation inhibitor, and the presence of an ALK mutation is what predicts benefit from lorlatinib (69% against 27% response) (Gainor 2016, Shaw 2019).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase
- Wikipedia: https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase

## 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: [ALK-negative anaplastic large cell lymphoma](https://onco.cc/cancers/alk-negative-anaplastic-large-cell-lymphoma/), [ALK-positive anaplastic large cell lymphoma](https://onco.cc/cancers/alk-positive-anaplastic-large-cell-lymphoma/), [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms](https://onco.cc/cancers/histiocytoses/), [High-risk neuroblastoma](https://onco.cc/cancers/neuroblastoma-high-risk/), [Inflammatory myofibroblastic tumour (IMT)](https://onco.cc/cancers/inflammatory-myofibroblastic-tumour/), [KRAS wild-type pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-wild-type-pdac/), [Lung cancer (all types)](https://onco.cc/cancers/lung-cancer/), [Neuroblastoma (paediatric)](https://onco.cc/cancers/neuroblastoma/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Paediatric high-grade glioma (excluding diffuse midline glioma)](https://onco.cc/cancers/paediatric-high-grade-glioma/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)](https://onco.cc/cancers/peripheral-t-cell-lymphoma/), [Resectable stage I to III non-small-cell lung cancer](https://onco.cc/cancers/resectable-nsclc/), [Uterine sarcoma](https://onco.cc/cancers/uterine-sarcoma/)
- drugs: [Alectinib](https://onco.cc/drugs/alectinib/), [Brigatinib](https://onco.cc/drugs/brigatinib/), [Ceritinib](https://onco.cc/drugs/ceritinib/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Ensartinib](https://onco.cc/drugs/ensartinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Guardant360 CDx](https://onco.cc/drugs/guardant360-cdx/), [Iruplinalkib](https://onco.cc/drugs/iruplinalkib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Neladalkib](https://onco.cc/drugs/neladalkib/), [TRI-611](https://onco.cc/drugs/tri-611/)
- companies: [Imagene AI](https://onco.cc/companies/imagene-ai/), [Inivata](https://onco.cc/companies/inivata/), [Lucence](https://onco.cc/companies/lucence/), [Triana Biomedicines](https://onco.cc/companies/triana-biomedicines/)
- pathways: [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [Drug efflux pumps (ABC transporters)](https://onco.cc/pathways/drug-efflux-pumps/), [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Organ tropism: seed and soil](https://onco.cc/pathways/organ-tropism-seed-soil/), [PI3K / AKT / mTOR](https://onco.cc/pathways/pi3k-akt-mtor/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [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/), [The blood-brain barrier & brain metastasis](https://onco.cc/pathways/blood-brain-barrier-metastasis/)
- terms: [Driver mutation](https://onco.cc/terms/driver-mutation/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [Hallmark: sustaining proliferative signalling](https://onco.cc/terms/sustaining-proliferative-signaling/), [Histologic transformation](https://onco.cc/terms/histologic-transformation/), [Kinase](https://onco.cc/terms/kinase/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Oncogene](https://onco.cc/terms/oncogene/), [Segmental chromosomal aberrations and ploidy (neuroblastoma)](https://onco.cc/terms/segmental-chromosomal-aberrations/)
- key papers: [Alectinib in resected ALK-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-wu-alina-adjuvant-alectinib-nejm-2024/), [Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-peters-alex-alectinib-crizotinib-nejm-2017/), [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/), [Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer](https://onco.cc/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/), [Brigatinib in patients with crizotinib-refractory ALK-positive non-small-cell lung cancer: a randomized, multicenter phase II trial (ALTA)](https://onco.cc/key-papers/paper-alta-jco-2017/), [Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer](https://onco.cc/key-papers/paper-aggarwal-plasma-genotyping-personalised-therapy-jama-oncol-2019/), [First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study](https://onco.cc/key-papers/paper-ascend-4-lancet-2017/), [First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer](https://onco.cc/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/), [Genomic and evolutionary classification of lung cancer in never smokers](https://onco.cc/key-papers/paper-zhang-lung-cancer-never-smokers-nat-genet-2021/), [Identification of targetable ALK rearrangements in pancreatic ductal adenocarcinoma](https://onco.cc/key-papers/paper-singhi-alk-rearrangements-pancreatic-jnccn-2017/), [Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer](https://onco.cc/key-papers/paper-soda-eml4-alk-fusion-nature-2007/), [Lemmon and Schlessinger 2010: cell signalling by receptor tyrosine kinases](https://onco.cc/key-papers/paper-lemmon-schlessinger-rtk-signalling-cell-2010/), [Molecular characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma](https://onco.cc/key-papers/paper-philip-kras-wild-type-pancreatic-ccr-2022/), [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/), [NILE: clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer](https://onco.cc/key-papers/paper-leighl-nile-cfdna-tissue-genotyping-ccr-2019/), [Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies](https://onco.cc/key-papers/paper-jordan-prospective-lung-adenocarcinoma-msk-cancer-discov-2017/), [Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F](https://onco.cc/key-papers/paper-shaw-alk-l1198f-resensitisation-nejm-2016/), [ROS1 rearrangements define a unique molecular class of lung cancers](https://onco.cc/key-papers/paper-bergethon-ros1-rearrangements-lung-jco-2012/), [Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors](https://onco.cc/key-papers/paper-lindeman-lung-molecular-testing-guideline-jto-2018/), [Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs](https://onco.cc/key-papers/paper-kris-lung-cancer-mutation-consortium-jama-2014/)
- trials: [ALESIA](https://onco.cc/trials/alesia/), [ALEX](https://onco.cc/trials/alex/), [ALINA](https://onco.cc/trials/alina/), [ALKOVE-1](https://onco.cc/trials/alkove-1/), [ALTA](https://onco.cc/trials/alta/), [ALTA-1L](https://onco.cc/trials/alta-1l/), [ASCEND-4](https://onco.cc/trials/nct01828099/), [COG ANBL1531](https://onco.cc/trials/anbl1531/), [CROWN](https://onco.cc/trials/crown/), [eXalt3](https://onco.cc/trials/nct02767804/), [J-ALEX](https://onco.cc/trials/j-alex/), [PROFILE 1014](https://onco.cc/trials/profile-1014/)
- pairings: [Sequence: targeted therapy before immunotherapy in driver-positive NSCLC](https://onco.cc/pairings/targeted-before-io-nsclc/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- people: [Benjamin Solomon](https://onco.cc/people/solomon-benjamin/), [D. Ross Camidge](https://onco.cc/people/ross-camidge/), [Dong-Wan Kim](https://onco.cc/people/kim-dong-wan/), [Enriqueta Felip](https://onco.cc/people/enriqueta-felip/), [John M. Maris](https://onco.cc/people/john-maris/), [Justin F. Gainor](https://onco.cc/people/justin-gainor/), [Myung-Ju Ahn](https://onco.cc/people/ahn-myung-ju/), [Yael P. Mossé](https://onco.cc/people/yael-mosse/)
- ideas: [Kill drug-tolerant persisters through ferroptosis](https://onco.cc/ideas/idea-ferroptosis-persisters/), [Test intermittent dosing of targeted drugs to delay resistance, with honest priors](https://onco.cc/ideas/idea-tr1-intermittent-dosing-to-delay-resistance/)
- collections: [LUNGevity Foundation (and GO2 for Lung Cancer)](https://onco.cc/collections/lungevity/)
- institutions: [Aichi Cancer Center](https://onco.cc/institutions/aichi-cancer-center/), [Children's Hospital of Philadelphia](https://onco.cc/institutions/chop/), [Ghent University Hospital / Cancer Research Institute Ghent](https://onco.cc/institutions/uz-gent/), [Guangdong Provincial People's Hospital](https://onco.cc/institutions/guangdong-provincial-peoples-hospital/), [National Cancer Center Hospital East](https://onco.cc/institutions/ncc-hospital-east/), [nationales Netzwerk Genomische Medizin Lungenkrebs](https://onco.cc/institutions/nngm/), [Shanghai Chest Hospital](https://onco.cc/institutions/shanghai-chest-hospital/), [Shanghai Pulmonary Hospital](https://onco.cc/institutions/shanghai-pulmonary-hospital/), [University of Colorado Cancer Center](https://onco.cc/institutions/colorado-cancer-center/)
- roadmaps: [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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JSON: https://onco.cc/api/v1/entities/alk.json