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A gene fusion in about 1-2% of lung cancers that responds for years to targeted pills, now in their third generation. This dossier gathers the 6 products (6 approved), 34 trials, 0 pathways and 0 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.
Receptor tyrosine kinase with homology to ALK; fusions constitutively activate MAPK, PI3K, and JAK-STAT.
| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Non-small-cell lung cancer | 1-3% | Rearrangement, commonly CD74-ROS1 | cBioPortal structural variants: 25 of 915, 2.7%, in lung_msk_2017 (CD74 in 13 events, EZR in 4, SDC4 in 3, SLC34A2 in 2); 44 of 2,621, 1.7%, in nsclc_ctdx_msk_2022; 40 of 2,422, 1.7%, in luad_mskcc_2023_met_organotropism; 5 of 232, 2.2%, in lung_nci_2022. In the founding series, 18 of 1,073 screened lung cancers, 1.7%, against 31 ALK-rearranged, 2.9% (Bergethon 2012). | cBioPortal (TCGA) |
| Non-small-cell lung cancer | 1.7% | FISH, ROS1 rearrangement (18 of 1,073 NSCLC) | Bergethon 2012; enriched in younger never-smokers with adenocarcinoma | doi.org |
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 |
|---|---|---|---|---|---|---|
| G2032R (solvent front) 2032 | Resistance | The most common ROS1 resistance mutation after crizotinib | Defeats crizotinib and entrectinib; repotrectinib and taletrectinib were designed to fit past it. | Gainor et al., JCO Precision Oncology 2017 | ||
| L2026M (gatekeeper) and D2033N, S1986F/Y 2026 | Resistance | not sourced | Less common escapes; sensitivity varies by drug. | - | Gainor et al., JCO Precision Oncology 2017 |
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: COSMIC: ROS1.
| Modality | Approved |
|---|---|
| Small molecule 2 | |
| Small-molecule ALK/ROS1/MET TKI 1 | |
| Small-molecule ROS1 TKI 1 | |
| Small-molecule TRK/ROS1/ALK TKI 1 | |
| Test or device 1 |
| Trial | Setting | Result | Products | ||
|---|---|---|---|---|---|
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. | |
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%. | |
| 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. | |
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 | - | ||
| 3 | Recruiting | A Phase 3 Multicenter Double-blind Randomized Study of Taletrectinib Versus Placebo in Patients With ROS1-Fusion Positive Stage IB-IIIA Non-Small Cell Lung Cancer Who Have Undergone Complete Tumor Resection | - | ||
| 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 | - | ||
| 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) | - | ||
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. | |
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. | |
National Lung Matrix Trial NCT02664935 | 2 | Completed | Advanced non-small-cell lung cancer after first-line treatment, screened nationally through the Cancer Research UK Stratified Medicine Programme: 22 biomarker-defined cohorts of eight targeted drugs | Most of the 22 biomarker-drug cohorts did not meet their pre-set efficacy thresholds; the trial demonstrated national molecular screening and the limits of single-agent matching. | |
| 2 | Recruiting | Advanced solid tumours, multiple myeloma and B-cell lymphoma with a genomic alteration that an approved targeted drug addresses in another cancer: the drug is given off-label in a pragmatic basket with cohorts by drug and tumour type | Continuous cohort reporting: positive signals for pembrolizumab in high tumour mutational burden cancers and trastuzumab plus pertuzumab in ERBB2-amplified colorectal cancer; palbociclib in CDKN2A-altered lung cancer and several other matches were negative. | ||
| 2 | - | Phase II Clinical Study to Evaluate the Efficacy and Safety of WX-0593 in Patients With Crizotinib-resistant ALK -Positive, or Crizotinib-resistant/Crizotinib-naive ROS1-positive Non-small Cell Lung Cancer (NSCLC) | - | ||
| 2 | Recruiting | NAUTIKA1: A Multicenter, Phase II, Neoadjuvant and Adjuvant Study of Multiple Therapies in Biomarker-selected Patients With Resectable Stages IB-III Non-small Cell Lung Cancer | - | ||
| 2 | Active | An Open-Label, Multicenter, Global Phase 2 Basket Study of Entrectinib for the Treatment of Patients With Locally Advanced or Metastatic Solid Tumors That Harbor NTRK1/2/3, ROS1, or ALK Gene Rearrangements | - | ||
| 2 | Recruiting | Neoadjuvant WX-0593 in Resectable ALK-positive or ROS1-positive Non-small Cell Lung Cancer: a Single-arm, Exploratory Trial | - | ||
| 2 | Recruiting | A Phase II Study Assessing Safety and Efficacy of Repotrectinib in ROS1-positive Non-small Cell Lung Cancer Patients With Active Brain Metastasis (The REPOSE Study) | - | ||
| 2 | Recruiting | Study to Investigate Outcome of Individualized Treatment Based on Pharmacogenomic Profiling & Ex Vivo Drug Sensitivity Testing of Patient-derived Organoids in Patients With Metastatic Colorectal Cancer | - | ||
| 2 | Active | A Single-Arm, Open-Label, Multicenter Phase 2 Study to Evaluate the Efficacy and Safety of Taletrectinib in Patients With Advanced or Metastatic ROS1 Positive NSCLC and Other Solid Tumors | - | ||
| 2 | Active | Tumor-agnostic Precision Immuno-oncology and Somatic Targeting Rational for You (TAPISTRY) Phase II Platform Trial | - | ||
| 1/2 | Recruiting | A Phase 1/2, Open-Label, Multi-Center, First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of TPX-0005 in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1) | Repotrectinib produced responses in 79 percent of ROS1 inhibitor-naive patients (median progression-free survival 35.7 months) and 38 percent after one ROS1 inhibitor, including 59 percent of those with the G2032R solvent-front mutation. |
No recorded escape route names this target.
No pathway diagram carries this target as a node.
| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| Oncomine Dx Target Test Thermo Fisher Scientific · FDA CDx 2017 | NGS tissue | Per companion claim: BRAF V600E (dabrafenib plus trametinib), ROS1 fusions (crizotinib), EGFR (gefitinib), RET fusions (pralsetinib), MET exon 14 (tepotinib), EGFR exon 20 insertions |
No model entry for this target yet; check the cancer entries on the models page.
No open questions recorded for this target yet. Suggest one.
Query for this target: (TITLE:"ROS1" OR ABSTRACT:"ROS1") 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 ROS1, not a curated reading list.
The dossier as machine-readable JSON, at /api/v1/dossiers/ros1.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/ros1.json. Licence CC BY-NC 4.0.