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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. This dossier gathers the 11 products (9 approved), 51 trials, 2 pathways 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.
ALK is a receptor tyrosine kinase; the EML4-ALK fusion is most common. It is also altered in anaplastic large-cell lymphoma and neuroblastoma.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Neuroblastoma | 8-14% | Activating mutation/amplification | Higher at relapse | Wikipedia |
| Non-small-cell lung cancer | 3-6% | Rearrangement, usually EML4-ALK | cBioPortal structural variants: 109 of 2,422, 4.5%, in luad_mskcc_2023_met_organotropism (EML4 the partner in 94 of the events); 31 of 915, 3.4%, in lung_msk_2017; 75 of 2,621, 2.9%, in nsclc_ctdx_msk_2022; 13 of 232, 5.6%, in lung_nci_2022; 6 of 181, 3.3%, in luad_oncosg_2020. The original description found the fusion in 5 of 75 patients, 6.7% (Soda 2007), and the Lung Cancer Mutation Consortium found ALK rearrangement in 57 of 733, 8%, by fluorescence in situ hybridisation (Kris 2014). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 3-5% | Rearrangement | Younger never-smokers | cBioPortal (TCGA) |
| Pancreatic ductal adenocarcinoma | 0.2% | Gene fusion (EML4-ALK, STRN-ALK) | 5 of 3,170 profiled cancers, 0.16%, all KRAS wild-type and all under 50, where ALK fusions were 1.3% of tumours in patients under 50; 3 of 4 treated with an ALK inhibitor had stable disease, radiographic response or CA 19-9 normalisation (Singhi 2017); 1 of 2,336 (ASAP2-ALK) in pdac_msk_2024 (cBioPortal); 2.6% of 266 KRAS wild-type tumours (Philip 2022). | doi.org |
| Colorectal cancer | 0.1% | Gene fusion | cBioPortal structural variants: 9 of 7,237, 0.12%, in crc_msk_2026; 1 of 594 (PPP4R3B-ALK) in coadread_tcga_pan_can_atlas_2018. ALK point mutations read 388 of 7,237 in crc_msk_2026 but are overwhelmingly passengers in hypermutated tumours, not the fusions that matter. | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
| 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.
| Modality | Approved | Phase 3 | Phase 2 |
|---|---|---|---|
| Small molecule 4 | - | ||
| Small-molecule ALK TKI 2 | - | - | |
| Degrader 1 | - | - | |
| Small-molecule ALK/EGFR TKI 1 | - | - | |
| Small-molecule ALK/ROS1/MET TKI 1 | - | - | |
| Small-molecule TRK/ROS1/ALK TKI 1 | - | - | |
| Test or device 1 | - | - |
| Trial | 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. | |
eXalt3 NCT02767804 | 3 | Positive | Advanced ALK-positive non-small-cell lung cancer with no prior ALK inhibitor: ensartinib versus crizotinib | Median progression-free survival 25.8 vs 12.7 months (hazard ratio 0.51, blinded independent review, intent-to-treat); intracranial response 63.6% vs 21.1% in patients with target brain metastases. | |
CROWN NCT03052608 | 3 | Positive | First-line ALK-positive advanced NSCLC: lorlatinib vs crizotinib | 5-year PFS 60% vs 8%, HR 0.19 (JCO 2024). | |
ALESIA NCT02838420 | 3 | Positive | Untreated ALK-positive non-small-cell lung cancer in Asian patients: alectinib 600 mg twice daily versus crizotinib 250 mg twice daily, with investigator-assessed progression-free survival as the primary endpoint | Investigator-assessed progression-free survival significantly longer with alectinib than crizotinib, consistent with the global ALEX trial. | |
ALTA-1L NCT02737501 | 3 | Positive | Untreated advanced ALK-positive non-small-cell lung cancer: brigatinib versus crizotinib | Median progression-free survival 24.0 vs 11.1 months (hazard ratio 0.48, blinded independent review, final analysis). | |
ALEX NCT02075840 | 3 | Positive | Untreated advanced ALK-positive non-small-cell lung cancer: alectinib versus crizotinib | Median progression-free survival 34.8 vs 10.9 months (hazard ratio 0.43); 12-month brain progression 9.4% vs 41.4%; 5-year overall survival 62.5% vs 45.5%. | |
ASCEND-4 NCT01828099 | 3 | Positive | Untreated advanced ALK-rearranged non-squamous non-small-cell lung cancer: ceritinib versus platinum and pemetrexed chemotherapy | Median progression-free survival 16.6 vs 8.1 months (hazard ratio 0.55, blinded independent review); response rate 72.5% vs 26.7%; overall survival not significantly different at the interim analysis. | |
| J-ALEX | 3 | Positive | ALK inhibitor-naive Japanese patients with ALK-positive non-small-cell lung cancer, chemotherapy-naive or after one regimen: alectinib 300 mg twice daily versus crizotinib 250 mg twice daily, with progression-free survival by an independent review facility as the primary endpoint | Stopped at the second interim analysis for a large progression-free survival advantage of alectinib over crizotinib. | |
| 3 | Completed | A Phase III, Multicenter, Randomized, Open-label Study of Oral LDK378 Versus Standard Chemotherapy in Adult Patients With ALK-rearranged (ALK-positive) Advanced Non-small Cell Lung Cancer Who Have Been Treated Previously With Chemotherapy (Platinum Doublet) and Crizotinib | - | ||
PROFILE 1014 NCT01154140 | 3 | Positive | Untreated advanced ALK-positive non-squamous non-small-cell lung cancer: crizotinib 250 mg twice daily versus pemetrexed with cisplatin or carboplatin for up to six cycles, with progression-free survival by independent radiological review as the primary endpoint and crossover allowed | Median progression-free survival 10.9 against 7.0 months (hazard ratio 0.45, 95 percent confidence interval 0.35 to 0.60). | |
| 3 | Recruiting | A Phase 3 Multicenter Open-label Study of Taletrectinib Versus a Standard of Care ROS1-Tyrosine Kinase Inhibitor (Crizotinib) in TKI-Naïve Patients With ROS1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer (TRUST-III) | - | ||
| 3 | Active | A Phase I-III, Multicenter Study Evaluating the Efficacy and Safety of Multiple Therapies in Cohorts of Patients Selected According to Biomarker Status, With Locally Advanced, Unresectable, Stage III Non-Small Cell Lung Cancer | - | ||
| 3 | Active | Randomized, Open-label, Multicenter, Phase 3 Trial of Repotrectinib Versus Crizotinib in Participants With Locally Advanced or Metastatic Tyrosine Kinase Inhibitor (TKI)-naïve ROS1-positive Non-Small Cell Lung Cancer (NSCLC) (TRIDENT-3) | - | ||
| 3 | Active | Randomized, Open Label, Multicenter, Phase III Study of Entrectinib Versus Crizotinib in Patients With Locally-Advanced or Metastatic Non-Small Cell Lung Cancer Harboring ROS1 Gene Rearrangements With and Without Central Nervous System Metastases | - | ||
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) | - | |
| 3 | Planned | A Randomized, Open-label, Multicenter, Phase III Study of Lorlatinib Compared with Concurrent/ Sequential Chemoradiotherapy As Definitive Treatment in Patients with Locally Advanced, Unresectable Stage III ALK Positive Lung Adenocarcinoma | - | ||
| 3 | Completed | Molecular Profiling of Advanced Soft-tissue Sarcomas. A Phase III Study | - | ||
| 3 | Recruiting | A Phase 3 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 Compared to Alectinib in First-Line Treatment of Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer (ALKAZAR) | - | ||
| 3 | - | An Open-label, Randomized, Multicenter Phase 3 Study Comparing WX-0593 to Crizotinib in Anaplastic Lymphoma Kinase (ALK) Positive Non-Small Cell Lung Cancer (NSCLC) Patients | - | ||
| 3 | Planned | A Randomized, Phase III Umbrella Trial of Adjuvant Therapy Versus Observation in Completely Resected High-Risk Stage IA-IB Non-Small Cell Lung Cancer Based on Oncogenic Driver Mutations | - | ||
| 2/3 | Active | A Phase II/III Multicenter Study Evaluating the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Patients With Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) Harboring Actionable Somatic Mutations Detected in Blood (B-FAST: Blood-First Assay Screening Trial) | - | ||
| 2/3 | Active | IDE196 (Darovasertib) in Combination With Crizotinib Versus Investigator's Choice of Treatment as First-line Therapy in HLA-A2 Negative Metastatic Uveal Melanoma (DAR-UM-2) | - | ||
| 2/3 | Active | Explore the Relationship Between Single Nucleotide Polymorphisms and Alectinib Response and Toxicity in Patients With Non-Small Cell Lung Cancer. | - | ||
NCI-MATCH (EAY131) NCT02465060 | platform | Active | Advanced solid tumours, lymphomas and myeloma that have progressed on standard treatment: central tumour sequencing assigns patients to one of nearly 40 single-agent or doublet targeted-therapy arms by molecular alteration regardless of cancer type | 5,954 patients enrolled; 17.8 percent assigned to an arm. Dabrafenib plus trametinib in BRAF V600 tumours (38 percent response) and nivolumab in dMMR non-colorectal tumours (36 percent) were positive; most single-agent arms were not. | |
| platform | Active | Completely resected stage IB to IIIA non-small-cell lung cancer: central testing for EGFR mutations, ALK rearrangements and later PD-L1 feeds randomised adjuvant trials of erlotinib, crizotinib and nivolumab against observation or placebo | Screening and adjuvant trials completed accrual; the EGFR and ALK adjuvant questions were settled in practice by ADAURA (osimertinib) and ALINA (alectinib) while ALCHEMIST follow-up continues. | ||
DETERMINE NCT05722886 | platform | Recruiting | Adults, teenagers and children in the United Kingdom with rare cancers, or common cancers carrying rare alterations, matched to licensed targeted drugs and immunotherapies outside their approved indications, with a route to NHS access for arms that work | Recruiting; no arm has reported. | |
CUPISCO NCT03498521 | 2 | Positive | Newly diagnosed unfavourable cancer of unknown primary controlled by three cycles of platinum chemotherapy: randomised to molecularly guided therapy chosen from tissue and blood genomic profiling, or to continued chemotherapy | Median progression-free survival 6.1 months with molecularly guided therapy versus 4.4 months with continued chemotherapy (hazard ratio 0.72); overall survival immature. | |
INTUITT-NF2 NCT04374305 | 2 | Recruiting | NF2-related schwannomatosis with progressive vestibular or non-vestibular schwannomas, meningiomas or ependymomas: an adaptive platform trial testing targeted drugs in sub-studies (brigatinib, closed; neratinib; retifanlimab with bevacizumab), with radiographic response as the primary endpoint | Brigatinib produced radiographic responses in 10 percent of target tumours and 23 percent of all tumours, slowed growth of every tumour type and improved hearing in 35 percent of eligible ears in 40 heavily pretreated patients. | |
PAPMET (SWOG S1500) NCT02761057 | 2 | Positive | Metastatic papillary renal cell carcinoma: sunitinib against cabozantinib, crizotinib or savolitinib | Cabozantinib lengthened progression-free survival compared with sunitinib in metastatic papillary renal cell carcinoma; the crizotinib and savolitinib arms closed for futility. | |
GEOMETRY mono-1 NCT02414139 | 2 | Positive | Advanced non-small-cell lung cancer with MET exon 14 skipping or MET amplification: capmatinib monotherapy in cohorts by prior treatment and MET gene copy number | Response rate 68% (treatment-naive, n=28) and 41% (previously treated, n=69) in MET exon 14 skipping disease; about a third in high-level MET amplification. |
Steric clash blocks first- and second-generation inhibitors; compound mutations (G1202R + L1196M etc.) emerge after lorlatinib.
Alternative receptors or downstream mutations re-activate MAPK/PI3K.
KEGG's non-small cell lung cancer map shows a set of alternative on-switches (EGFR mutation, KRAS mutation, EML4-ALK, RET and MET alterations) that all feed the same RAS/ERK, PI3K/AKT and STAT relays, plus loss of the p16 and p53 brakes. Each on-switch now has its own targeted pill, which is why molecular testing comes before treatment.
Which nodes have drugs →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 →| 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 |
| 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. |
Why 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.
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.
The dossier as machine-readable JSON, at /api/v1/dossiers/alk.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-NC 4.0.