A gene fusion found in about 5% of lung cancers that responds spectacularly to pills, now for many years. This dossier gathers the 8 products (7 approved), 4 trials, 1 pathway and 2 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
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.
- NSCLC (~5%)
- Anaplastic large-cell lymphoma
- Neuroblastoma
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Neuroblastoma | 8-14% | Activating mutation/amplification | Higher at relapse | Wikipedia |
| Non-small-cell lung cancer | 3-5% | Rearrangement | Younger never-smokers | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| F1174L / R1275Q 1174 | Activating | not sourced | Point mutations in neuroblastoma (rather than the fusions seen in lung cancer). F1174L is relatively crizotinib-resistant; lorlatinib is being tested up front. | — | Mossé et al., Nature 2008 | |
| L1196M 1196 | Resistance | not sourced | Gatekeeper; the classic crizotinib escape, covered by every later-generation inhibitor. | Gainor et al., Cancer Discov 2016 | ||
| G1202R 1202 | Resistance | About 40% of biopsies at progression on second-generation ALK TKIs | Solvent-front mutation that clashes with most inhibitors; lorlatinib was designed to fit, and G1202R-containing compound mutations drive resistance to lorlatinib itself. | Gainor et al., Cancer Discov 2016 | ||
| I1171N/T/S and G1269A 1171 | Resistance | not sourced | Alectinib-associated (I1171) and crizotinib-associated (G1269A) escapes with differing sensitivity profiles; sequencing decisions depend on which is present. | — | Gainor et al., Cancer Discov 2016 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: ALK.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 |
|---|---|---|
| Small molecule 3 | ||
| Small-molecule ALK TKI 2 | — | |
| Small-molecule ALK/EGFR TKI 1 | — | |
| Small-molecule ALK/ROS1/MET TKI 1 | — | |
| Small-molecule TRK/ROS1/ALK TKI 1 | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| ALINA NCT03456076 | 3 | Positive | Adjuvant alectinib 2 years vs platinum chemotherapy after resection of stage IB (≥4 cm)-IIIA ALK-positive NSCLC | DFS HR 0.24. | |
| CROWN NCT03052608 | 3 | Positive | First-line ALK-positive advanced NSCLC: lorlatinib vs crizotinib | 5-year PFS 60% vs 8%, HR 0.19 (JCO 2024). | |
| COG ANBL1531 NCT03126916 | 3 | Active | Newly diagnosed high-risk neuroblastoma: 131I-MIBG added to induction (randomised, MIBG-avid); lorlatinib added for ALK-aberrant tumours (non-randomised arm) | ||
| ALKOVE-1 NCT05384626 | 1/2 | Positive | ALK-positive NSCLC after prior ALK TKIs (including lorlatinib): neladalkib single arm | ORR 31% in heavily pretreated ALK+ NSCLC; NDA under priority review. |
Resistance routes that involve this target
Unaddressed routes →Steric clash blocks first- and second-generation inhibitors; compound mutations (G1202R + L1196M etc.) emerge after lorlatinib.
- Lorlatinib covers G1202R; fourth-generation neladalkib for compound mutations
Alternative receptors or downstream mutations re-activate MAPK/PI3K.
- Combination with MET or MEK inhibitors (trials); chemotherapy; ADCs
Pathways where it is a node
Pathway-to-drug matrix →- Receptor tyrosine kinase activationNode: Mutation, amp, fusion · 5 druggable nodes
Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| Vysis ALK Break Apart FISH Probe Kit Abbott Molecular · FDA CDx 2011 | FISH/ISH | At least 15% of tumour cells with split or isolated 3' signals (at least 50 cells scored) | |
| VENTANA ALK (D5F3) CDx Assay Roche Diagnostics · FDA CDx 2015 | IHC | Binary: strong granular cytoplasmic staining in any tumour cells is positive | |
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| FoundationOne Liquid CDx Foundation Medicine (Roche) · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib, erlotinib, gefitinib), ALK (alectinib), BRCA1/2 and ATM (olaparib, rucaparib), PIK3CA (alpelisib), FGFR3 (erdafitinib), NTRK and RET; negative plasma results reflex to tissue |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| NCI-H3122 | CVCL_5160 · ACH-000337 | Lung, EML4::ALK variant 1. |
| NCI-H2228 | CVCL_1543 · ACH-000447 | Lung, EML4::ALK variant 3. |
| Karpas-299 | CVCL_1324 · ACH-000053 | Anaplastic large-cell lymphoma, NPM1::ALK. |
| SU-DHL-1 | CVCL_0538 · ACH-000664 | Anaplastic large-cell lymphoma, NPM1::ALK. |
| Kelly | CVCL_2092 · ACH-000259 | Neuroblastoma, ALK F1174L. |
| SH-SY5Y | CVCL_0019 · ACH-001188 | Neuroblastoma, ALK F1174L. |
| NB-1 | CVCL_1440 · ACH-000804 | Neuroblastoma, ALK-amplified. |
| Ba/F3 EML4-ALK mutants | not resolved | G1202R, L1196M, compound mutations; the lorlatinib and neladalkib profiling panel. |
- Eml4-Alk (CRISPR) (Somatic Cas9-induced inversion) Maddalo et al., Nature 2014
Open questions
All open questions →- 01
Will fourth-generation ALK inhibitors extend the more than five-year progression-free survival seen with lorlatinib, or is lorlatinib the ceiling for on-target therapy?
clinicalindustryWhy unresolved. CROWN's five-year data made lorlatinib the first-line standard; resistance now runs through compound mutations and bypass pathways that neladalkib targets, but the incremental benefit after lorlatinib is unknown.
What would answer it. ALKOVE-1 and randomised post-lorlatinib trials with resistance-mechanism stratification.
Source: CROWN five-year update, J Clin Oncol 2024
Ideas and companies
Key papers and the live literature
Preprints →- CROWN: lorlatinib versus crizotinib as first treatment for ALK-positive lung cancer · New England Journal of Medicine 2020
Query for this target: (TITLE:"ALK" OR ABSTRACT:"ALK") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about ALK, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/alk.json. Licence CC BY 4.0.