ALK-positive non-small-cell lung cancer
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowFainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Check before combiningFood and drink: Alectinib
Take with food; exposure roughly triples with a high-fat meal, and the trials dosed with food.
- Check before combiningKidneys: Carboplatin
Dose by Calvert formula using GFR (see the calculators).
- Check before combiningKidneys: Pemetrexed
Not recommended for CrCl below 45.
- Check before combiningLiver: Alectinib
Start at 450 mg twice daily in severe impairment (Child-Pugh C).
See all on the product pages:AlectinibBrigatinibCarboplatinLorlatinibNeladalkibPemetrexed·Printable cards in the navigator
Anatomy and lymph node drainage
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)
- Nodes: hilar (N1)
- Nodes: mediastinal (N2)
- Nodes: supraclavicular (N3)
Central tumours arise in the large airways, peripheral ones in the alveoli; both drain to hilar then mediastinal nodes, and the pleural lining is a separate cancer site.
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)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) · Compound ALK mutations after lorlatinib (neladalkib)
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)EML4-ALK fusion adenocarcinoma (variants 1, 2 and 3 differ in resistance patterns) · ALK-positive adenocarcinoma with brain metastases at diagnosis
- hilar (N1)
- mediastinal (N2)
- supraclavicular (N3)
Same organ: Non-small-cell lung cancer, Lung cancer (all types), Small-cell lung cancer, Mesothelioma, Pleural mesothelioma, Thymoma and thymic carcinoma, Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Inflammatory myofibroblastic tumour (IMT), EGFR-mutated non-small-cell lung cancer, KRAS G12C-mutant non-small-cell lung cancer, ROS1-positive non-small-cell lung cancer, MET exon 14 and MET-amplified non-small-cell lung cancer, RET fusion-positive non-small-cell lung cancer, BRAF V600E-mutant non-small-cell lung cancer, HER2-mutant non-small-cell lung cancer, NTRK fusion-positive non-small-cell lung cancer, PD-L1-high non-small-cell lung cancer without a driver mutation, Resectable stage I to III non-small-cell lung cancer, Unresectable stage III non-small-cell lung cancer, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer, Lung neuroendocrine tumours (typical and atypical carcinoid)
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.
- Liquid biopsy (ctDNA)Standard of care
Nothing recorded yet.
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
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.
Lorlatinib, guided where possible by the resistance mutation; local radiotherapy for oligoprogression; platinum-pemetrexed once inhibitors are exhausted.
Neladalkib in trials (ALKOVE-1); chemotherapy; clinical trial.
Surgery then two years of adjuvant alectinib (ALINA) in place of platinum chemotherapy.
Next-generation inhibitors control most brain metastases without radiotherapy; stereotactic radiosurgery for large or symptomatic lesions; whole-brain radiotherapy avoided.
Subtypes & biomarkers
top- 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)
- 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
How often this target appears
- 2007EML4-ALK fusion discovered in lung cancer (Soda and Mano, Japan)
- 2011Crizotinib approved four years after the fusion was found
- 2014PROFILE 1014: crizotinib beats chemotherapy first line
- 2017ALEX: alectinib beats crizotinib first line with far less brain progression
- 2018ALTA-1L: brigatinib beats crizotinib first line
- 2020CROWN: lorlatinib first line; five-year update in 2024 shows 60 percent progression-free
- 2024ALINA: two years of adjuvant alectinib cuts recurrence by 76 percent
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 21 changes by month →- 2026-09-17This recordALK-positive non-small-cell lung cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2025Trial resultALKOVE-1ALKOVE-1 reported
ORR 31% in heavily pretreated ALK+ NSCLC; NDA under priority review.
- 2024ApprovalAlectinibAlectinib approved in US
Adjuvant ALK+ NSCLC after resection (stage IB ≥4 cm to IIIA)
- 2024MilestoneALINAALINA: two years of adjuvant alectinib cuts recurrence by 76 percent
A milestone in how this cancer is treated.
- 2023ApprovalIruplinalkibIruplinalkib approved in CN
ALK-positive non-small-cell lung cancer after crizotinib; first line from 2024
- 2023Trial resultALINAALINA reported
DFS HR 0.
What is in development for ALK-positive non-small-cell lung cancer, drawn from the whole corpus: 7 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 3 · 1
Trials reported · 5
Ideas not yet in a trial · 1
Open problems and what is being done
Whether any sequence of inhibitors cures metastatic ALK-positive disease or only holds it is unknown.
and how the field plans to fix it →What is being done about thisAdvanced and metastatic diseaseAvailable now- Liquid biopsy (ctDNA)Standard of care
- SBRT / SABR (stereotactic radiotherapy)Standard of care
- Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)Established
In trials- ALTA-1LPositive
Ideas and roadmapsNothing recorded yet.
Background: Oligoprogression. Also on OnCo: Atlas of advanced disease · Invasion and metastasis.
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.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- Comprehensive genomic profilingStandard of care
- Liquid biopsy (ctDNA)Standard of care
- LorlatinibApproved
- Small-molecule kinase inhibitorsStandard of care
In trialsNothing recorded yet.
Ideas and roadmapsBackground: Drug resistance (primary and acquired), Oligoprogression, On-target resistance mutations (gatekeeper, solvent-front, compound). Also on OnCo: Resistance atlas · Lines of therapy.
The right duration of adjuvant alectinib is untested; recurrences after stopping are being watched.
and how the field plans to fix it →What is being done about thisRecurrence and residual diseaseAvailable now- Liquid biopsy (ctDNA)Standard of care
In trials- ALINAPositive
Ideas and roadmapsNothing recorded yet.
Background: Neoadjuvant / adjuvant / perioperative. Also on OnCo: Treatment journeys · Survivorship planner.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Houston · cancer center | United States | 0 | 6,724 | 95,007 | #2 | ||
| South Korea | none recorded | 0 | 1,312 | 17,172 | #3 | ||
Rochester, MN · hospital | United States | 0 | 4,511 | 44,748 | #5 | ||
Villejuif · cancer center | France | none recorded | 0 | 1,855 | 31,182 | #6 | |
| South Korea | none recorded | 0 | 1,607 | 24,676 | #8 | ||
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Berlin · university | Germany | none recorded | 0 | 1,563 | 17,749 | #12 | |
Melbourne · cancer center | Australia | none recorded | 0 | 1,547 | 24,196 | #14 | |
| United States | 0 | 3,582 | 54,857 | #16 | |||
Cleveland · hospital | United States | 0 | 2,264 | 29,412 | #20 | ||
Seoul · hospital | South Korea | none recorded | 0 | 464 | 3,248 | #22 | |
Stanford · university | United States | 0 | 3,000 | 50,162 | #30 | ||
San Francisco · cancer center | United States | 0 | 2,800 | 46,704 | #33 | ||
Stockholm · university | Sweden | none recorded | 0 | 987 | 12,440 | #39 | |
Amsterdam · cancer center | Netherlands | none recorded | 0 | 1,451 | 25,873 | #45 |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with ALK-positive non-small-cell lung cancer but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about ALK-positive non-small-cell lung cancer
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example ALK fusion by immunohistochemistry, fluorescence in situ hybridisation or RNA sequencing, ALK resistance mutations at progressionby tissue or plasma sequencing, EML4-ALK variant, TP53 co-mutation, Brain MRI at diagnosis and during follow-up), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include EML4-ALK fusion adenocarcinoma, ALK-positive adenocarcinoma with brain metastases at diagnosis, Crizotinib-resistant ALK-positive disease.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Advanced, first line
- For my situation (advanced, first line), which of the standard options do you recommend and why?Why: Guideline options include: 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.
- Am I a candidate for Alectinib, Brigatinib, Lorlatinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of ALEX and ALTA-1L apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Advanced, after a second-generation inhibitor
- For my situation (advanced, after a second-generation inhibitor), which of the standard options do you recommend and why?Why: Guideline options include: Lorlatinib, guided where possible by the resistance mutation; local radiotherapy for oligoprogression; platinum-pemetrexed once inhibitors are exhausted.
- Am I a candidate for Lorlatinib, Pemetrexed, Carboplatin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Advanced, after lorlatinib
- For my situation (advanced, after lorlatinib), which of the standard options do you recommend and why?Why: Guideline options include: Neladalkib in trials (ALKOVE-1); chemotherapy; clinical trial.
- Am I a candidate for Neladalkib, Pemetrexed, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of ALKOVE-1 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Resected stage IB to IIIA
- For my situation (resected stage ib to iiia), which of the standard options do you recommend and why?Why: Guideline options include: Surgery then two years of adjuvant alectinib (ALINA) in place of platinum chemotherapy.
- Am I a candidate for Alectinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of ALINA apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Brain metastases
- For my situation (brain metastases), which of the standard options do you recommend and why?Why: Guideline options include: Next-generation inhibitors control most brain metastases without radiotherapy; stereotactic radiosurgery for large or symptomatic lesions; whole-brain radiotherapy avoided.
- Am I a candidate for Lorlatinib, Alectinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Neladalkib, ALKOVE-1, Iruplinalkib, Ensartinib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Whether any sequence of inhibitors cures metastatic ALK-positive disease or only holds it is unknown”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Lorlatinib's cognitive, mood and metabolic effects are managed by dose reduction without trials of the optimal dose”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with ALK-positive non-small-cell lung cancer, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
7targets
3drugs
10companies
6pathways
2terms
9trials
5ideas
1people
7key papers
1Latest papers
topQuery for this cancer: (TITLE:"ALK-positive non-small-cell lung cancer" OR ABSTRACT:"ALK-positive non-small-cell lung cancer" OR TITLE:"ALK-rearranged lung cancer" OR ABSTRACT:"ALK-rearranged lung cancer" OR TITLE:"ALK fusion NSCLC" OR ABSTRACT:"ALK fusion NSCLC" OR TITLE:"EML4-ALK lung cancer" OR ABSTRACT:"EML4-ALK lung cancer" OR TITLE:"ALK+ NSCLC" OR ABSTRACT:"ALK+ NSCLC") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about ALK-positive non-small-cell lung cancer, not a curated reading list.
Similar pages
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