# ALK-positive non-small-cell lung cancer

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

## TL;DR

ALK-positive lung cancer is driven by a fused ALK gene and is treated with a pill from the start. The newest inhibitors keep the disease under control for years, with lorlatinib holding six in ten patients progression-free at five years, and two years of alectinib after surgery cuts recurrence by three quarters.

## Summary

The EML4-ALK fusion was found in lung cancer in Japan in 2007, and crizotinib, a MET inhibitor that happened to block ALK, was approved four years later on the strength of response rates around 60 percent, one of the fastest paths from discovery to approval in oncology. PROFILE 1014 (2014) showed crizotinib beat chemotherapy first line, but most patients progressed within a year, frequently in the brain, which crizotinib penetrates poorly. Ceritinib, alectinib and brigatinib were developed against crizotinib-resistant disease and then moved to the front.

ALEX (2017) showed alectinib beat crizotinib first line, with median progression-free survival of 34.8 versus 10.9 months, brain progression cut from 41 to 9 percent at one year and five-year survival of 62.5 versus 45.5 percent. ALTA-1L (2018) showed the same for brigatinib (24.0 versus 11.1 months), and CROWN (2020) for lorlatinib, a third-generation inhibitor designed to cover every known resistance mutation and to enter the brain: at five years 60 percent of lorlatinib patients were progression-free against 8 percent with crizotinib (hazard ratio 0.19), a result without precedent in metastatic lung cancer, though lorlatinib's cognitive, mood, weight and lipid effects need active management. Resistance to second-generation drugs is dominated by the G1202R solvent-front mutation, which lorlatinib covers; resistance to lorlatinib produces compound mutations that neladalkib (NVL-655, ALKOVE-1) is designed to overcome. Oligoprogression is often treated with local radiotherapy while the inhibitor continues.

In resected stage IB to IIIA disease ALINA (2024) showed that two years of adjuvant alectinib cut recurrence by 76 percent compared with platinum chemotherapy (hazard ratio 0.24), and it was approved in April 2024. Checkpoint inhibitors are ineffective in ALK-positive disease and carry excess liver toxicity with ALK inhibitors. Open questions are the sequence of inhibitors, whether ALK-positive cancers can be cured with prolonged therapy, and how long adjuvant treatment should last.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: ALK-rearranged lung cancer; ALK fusion NSCLC; EML4-ALK lung cancer; ALK+ NSCLC
- Tags: subtype-page; lung
- Group: lung
- Burden: About 3 to 5 percent of non-small-cell lung cancers carry an ALK fusion, most often EML4-ALK; patients are on average a decade younger than other lung cancer patients and most have never smoked or smoked lightly. Brain metastases develop in over half over the course of the disease.
- Subtypes: EML4-ALK fusion adenocarcinoma (variants 1, 2 and 3 differ in resistance patterns); ALK-positive adenocarcinoma with brain metastases at diagnosis; Crizotinib-resistant ALK-positive disease (second-generation inhibitors); G1202R solvent-front resistance (lorlatinib); Compound ALK mutations after lorlatinib (neladalkib)
- Biomarkers: ALK fusion by immunohistochemistry, fluorescence in situ hybridisation or RNA sequencing; ALK resistance mutations at progression (G1202R, compound mutations) by tissue or plasma sequencing; EML4-ALK variant (prognostic, research); TP53 co-mutation (worse outcome); Brain MRI at diagnosis and during follow-up; Lipids, weight and mood on lorlatinib

## Standard of care

- Advanced, first line: Alectinib (ALEX), brigatinib (ALTA-1L) or lorlatinib (CROWN); lorlatinib gives the longest control and the best brain protection, with dose adjustment for cognitive, mood and metabolic effects. ([Alectinib](https://onco.cc/drugs/alectinib/), [ALEX](https://onco.cc/trials/alex/), [Brigatinib](https://onco.cc/drugs/brigatinib/), [ALTA-1L](https://onco.cc/trials/alta-1l/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [CROWN](https://onco.cc/trials/crown/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))
- Advanced, after a second-generation inhibitor: Lorlatinib, guided where possible by the resistance mutation; local radiotherapy for oligoprogression; platinum-pemetrexed once inhibitors are exhausted. ([Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Oligoprogression](https://onco.cc/terms/oligoprogression/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/))
- Advanced, after lorlatinib: Neladalkib in trials (ALKOVE-1); chemotherapy; clinical trial. ([Neladalkib](https://onco.cc/drugs/neladalkib/), [ALKOVE-1](https://onco.cc/trials/alkove-1/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/))
- Resected stage IB to IIIA: Surgery then two years of adjuvant alectinib (ALINA) in place of platinum chemotherapy. ([Alectinib](https://onco.cc/drugs/alectinib/), [ALINA](https://onco.cc/trials/alina/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/))
- Brain metastases: Next-generation inhibitors control most brain metastases without radiotherapy; stereotactic radiosurgery for large or symptomatic lesions; whole-brain radiotherapy avoided. ([Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Alectinib](https://onco.cc/drugs/alectinib/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Whole-brain radiotherapy (WBRT)](https://onco.cc/terms/wbrt/))

## State of the art

- Lorlatinib first line: 60 percent progression-free at five years in CROWN, the longest control reported in any metastatic lung cancer trial.
- Adjuvant alectinib (ALINA) replaces chemotherapy after resection.
- Sequencing of inhibitors by resistance mutation, with neladalkib designed for compound mutations after lorlatinib.
- Brain metastases managed largely with drugs rather than radiotherapy.

## Open problems

- Whether any sequence of inhibitors cures metastatic ALK-positive disease or only holds it is unknown.
- Lorlatinib's cognitive, mood and metabolic effects are managed by dose reduction without trials of the optimal dose.
- Resistance after lorlatinib is compound mutations and bypass pathways with no approved option.
- The right duration of adjuvant alectinib is untested; recurrences after stopping are being watched.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase
- Wikipedia: https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase
- NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

## Connected records

- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/)
- targets: [ALK](https://onco.cc/targets/alk/)
- drugs: [Alectinib](https://onco.cc/drugs/alectinib/), [Brigatinib](https://onco.cc/drugs/brigatinib/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Ceritinib](https://onco.cc/drugs/ceritinib/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Ensartinib](https://onco.cc/drugs/ensartinib/), [Iruplinalkib](https://onco.cc/drugs/iruplinalkib/), [Lorlatinib](https://onco.cc/drugs/lorlatinib/), [Neladalkib](https://onco.cc/drugs/neladalkib/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/)
- companies: [Novartis](https://onco.cc/companies/novartis/), [Nuvalent](https://onco.cc/companies/nuvalent/), [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/), [Takeda](https://onco.cc/companies/takeda/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [Neoadjuvant / adjuvant / perioperative](https://onco.cc/terms/neoadjuvant-adjuvant/), [Oligoprogression](https://onco.cc/terms/oligoprogression/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/), [Tyrosine kinase inhibitor (TKI)](https://onco.cc/terms/tki-term/), [Whole-brain radiotherapy (WBRT)](https://onco.cc/terms/wbrt/)
- trials: [ALEX](https://onco.cc/trials/alex/), [ALINA](https://onco.cc/trials/alina/), [ALKOVE-1](https://onco.cc/trials/alkove-1/), [ALTA-1L](https://onco.cc/trials/alta-1l/), [CROWN](https://onco.cc/trials/crown/)
- people: [Benjamin Solomon](https://onco.cc/people/solomon-benjamin/), [D. Ross Camidge](https://onco.cc/people/ross-camidge/), [Justin F. Gainor](https://onco.cc/people/justin-gainor/), [Myung-Ju Ahn](https://onco.cc/people/ahn-myung-ju/), [Solange Peters](https://onco.cc/people/solange-peters/), [Tony S. K. Mok](https://onco.cc/people/tony-mok/), [Yi-Long Wu](https://onco.cc/people/wu-yi-long/)
- key papers: [CROWN: lorlatinib versus crizotinib as first treatment for ALK-positive lung cancer](https://onco.cc/key-papers/paper-crown-nejm-2020/)
- ideas: [ctDNA-guided dose holidays for lung cancer targeted therapy](https://onco.cc/ideas/idea-bio1-ctdna-adaptive-tki/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)

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