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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.
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.
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.
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.
Same organ: Mediastinal germ cell tumour, Pleuropulmonary blastoma (types I, Ir, II and III), Type A and type AB thymoma, Type B1 and type B2 thymoma, Type B3 thymoma, Micronodular thymoma with lymphoid stroma, Adenocarcinoma of the lung, Squamous cell carcinoma of the lung, Large cell carcinoma of the lung, Sarcomatoid carcinoma of the lung, Adenosquamous carcinoma of the lung, Invasive mucinous adenocarcinoma of the lung, Adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung, Basaloid squamous cell carcinoma of the lung, Lymphoepithelial carcinoma of the lung, Pulmonary blastoma (adult), 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), Large cell neuroendocrine carcinoma of the lung, Thymoma (WHO types A, AB, B1, B2 and B3), Thymic carcinoma
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Also on OnCo: Symptoms and red flags · Early detection roadmap.
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.
Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year.
The targets of this cancer's medicines and the ones linked to it directly.
Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Take with food; exposure roughly triples with a high-fat meal, and the trials dosed with food.
Dose by Calvert formula using GFR (see the calculators).
Not recommended for CrCl below 45.
Start at 450 mg twice daily in severe impairment (Child-Pugh C).
See all on the product pages:AlectinibBrigatinibCarboplatinLorlatinibNeladalkibPemetrexed·Printable cards in the navigator
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Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record.
Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked.