# ROS1-positive non-small-cell lung cancer

Source: https://onco.cc/cancers/ros1-positive-nsclc/  
OnCo record `ros1-positive-nsclc` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

ROS1-positive lung cancer is a rare fusion-driven adenocarcinoma treated with a pill. Crizotinib was the first, and the newer drugs repotrectinib and taletrectinib control the disease for about three years, reach the brain and work against the resistance mutation that defeated the older drugs.

## Summary

ROS1 fusions were identified in lung cancer in 2007 alongside ALK, and because the two kinases are closely related the ALK inhibitor crizotinib also blocked ROS1. In the ROS1 cohort of PROFILE 1001 the response rate was 72 percent and median progression-free survival 19.2 months, and crizotinib was approved for ROS1-positive lung cancer in March 2016 on that single-arm evidence. Its weaknesses were poor brain penetration and resistance through the G2032R solvent-front mutation.

Entrectinib, a ROS1, NTRK and ALK inhibitor with brain penetration, was approved in August 2019 on an integrated analysis of its phase 1 and 2 studies (STARTRK-2 among them) with a response rate of 77 percent and intracranial responses. Repotrectinib, a compact macrocycle designed to fit around solvent-front mutations, was approved in November 2023 on TRIDENT-1: a 79 percent response rate and median progression-free survival of 35.7 months in inhibitor-naive patients, and a 38 percent response rate after one prior inhibitor, including G2032R disease. Taletrectinib, tested in the TRUST-I and TRUST-II studies, was approved in June 2025 with high response rates in both inhibitor-naive and crizotinib-pretreated patients and less dizziness than repotrectinib.

Zidesamtinib (NVL-520) is designed to spare TRK and so avoid the dizziness and weight gain of the current drugs. Chemotherapy with platinum-pemetrexed remains effective once inhibitors are exhausted, and checkpoint inhibitors add little. Open questions are the best first drug now that three brain-penetrant inhibitors exist and how to treat bypass resistance through MET or KRAS.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: ROS1-rearranged lung cancer; ROS1 fusion NSCLC; CD74-ROS1 lung cancer
- Tags: subtype-page; lung
- Group: lung
- Burden: About 1 to 2 percent of non-small-cell lung cancers carry a ROS1 fusion, typically adenocarcinoma in younger patients who have never smoked; about a third have brain metastases at some point.
- Subtypes: ROS1 fusion adenocarcinoma, inhibitor-naive (repotrectinib, taletrectinib, entrectinib or crizotinib); ROS1-positive disease with brain metastases at diagnosis; Crizotinib-resistant ROS1 disease (G2032R solvent-front mutation; repotrectinib, taletrectinib); Bypass resistance through MET or KRAS after ROS1 inhibitors
- Biomarkers: ROS1 fusion by RNA sequencing, fluorescence in situ hybridisation or immunohistochemistry with confirmation; ROS1 resistance mutations at progression (G2032R, D2033N, L2026M); Brain MRI at diagnosis and during follow-up; Bypass alterations (MET amplification, KRAS) at progression

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/ros1-positive-nsclc/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/ros1-positive-nsclc/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/ros1-positive-nsclc/#what-it-is [4 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/ros1-positive-nsclc/#finding-it [4 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/ros1-positive-nsclc/#treating-it [3 settings, 3 decisions with options]
- Trials and papers (on the hub): 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. https://onco.cc/cancers/ros1-positive-nsclc/#evidence [17 trials, 3 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/ros1-positive-nsclc/#science [4 targets, 2 pathways]
- Countries and centres (own page): 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. https://onco.cc/cancers/ros1-positive-nsclc/where-you-are/ [34 UK centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/ros1-positive-nsclc/#living-with-it [16 questions, 6 red cards]
- Pipeline and open problems (own page): 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. https://onco.cc/cancers/ros1-positive-nsclc/coming/ [7 medicines, 17 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/ros1-positive-nsclc/data/ [55 connected records]

## Standard of care

- Advanced, first line: Repotrectinib (TRIDENT-1) or taletrectinib as preferred; entrectinib or crizotinib as alternatives, entrectinib when brain metastases are present. ([Repotrectinib](https://onco.cc/drugs/repotrectinib/), [A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements](https://onco.cc/trials/nct03093116/), [Taletrectinib](https://onco.cc/drugs/taletrectinib/), [A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene](https://onco.cc/trials/nct04395677/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme](https://onco.cc/trials/nct02568267/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))
- Advanced, after crizotinib or entrectinib: Repotrectinib or taletrectinib, which cover G2032R; zidesamtinib in trials; platinum-pemetrexed once inhibitors are exhausted. ([Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Taletrectinib](https://onco.cc/drugs/taletrectinib/), [Zidesamtinib](https://onco.cc/drugs/zidesamtinib/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Carboplatin](https://onco.cc/drugs/carboplatin/))
- Brain metastases: Brain-penetrant inhibitors (repotrectinib, taletrectinib, entrectinib) with stereotactic radiosurgery for large or symptomatic lesions. ([Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))

## State of the art

- Repotrectinib and taletrectinib give about three years of control first line and cover the G2032R mutation.
- Three brain-penetrant inhibitors approved between 2019 and 2025 after crizotinib's decade alone.
- Zidesamtinib designed to spare TRK and remove the dizziness and weight gain of dual ROS1/TRK inhibitors.

## Open problems

- No randomised trial compares the ROS1 inhibitors; choice rests on single-arm response rates and side-effect profiles.
- Dizziness, weight gain and paraesthesia from TRK inhibition limit the current brain-penetrant drugs.
- Resistance through MET, KRAS and other bypass routes has no approved targeted option.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/ROS1
- Wikipedia: https://en.wikipedia.org/wiki/ROS1
- NCCN Guidelines: Non-Small Cell Lung Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450

## Connected records

- cancers: [ALK-positive non-small-cell lung cancer](https://onco.cc/cancers/alk-positive-nsclc/), [BRAF V600E-mutant non-small-cell lung cancer](https://onco.cc/cancers/braf-v600e-nsclc/), [EGFR-mutated non-small-cell lung cancer](https://onco.cc/cancers/egfr-mutant-nsclc/), [MET exon 14 and MET-amplified non-small-cell lung cancer](https://onco.cc/cancers/met-altered-nsclc/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [NTRK fusion-positive non-small-cell lung cancer](https://onco.cc/cancers/ntrk-fusion-nsclc/), [RET fusion-positive non-small-cell lung cancer](https://onco.cc/cancers/ret-fusion-nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/)
- targets: [MET](https://onco.cc/targets/met/), [NTRK](https://onco.cc/targets/ntrk/), [ROS1](https://onco.cc/targets/ros1/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Crizotinib](https://onco.cc/drugs/crizotinib/), [Entrectinib](https://onco.cc/drugs/entrectinib/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Repotrectinib](https://onco.cc/drugs/repotrectinib/), [Taletrectinib](https://onco.cc/drugs/taletrectinib/), [Zidesamtinib](https://onco.cc/drugs/zidesamtinib/)
- companies: [Bristol Myers Squibb](https://onco.cc/companies/bms/), [Nuvalent](https://onco.cc/companies/nuvalent/), [Nuvation Bio](https://onco.cc/companies/nuvation-bio/), [Pfizer (incl. Seagen)](https://onco.cc/companies/pfizer/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [Receptor tyrosine kinase activation](https://onco.cc/pathways/rtk-activation/)
- terms: [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/), [Tyrosine kinase inhibitor (TKI)](https://onco.cc/terms/tki-term/)
- trials: [A Phase III Study Comparing Taletrectinib With Standard Therapy in ROS1 Positive Locally Advanced or Metastatic Non-small Cell Lung Cancer Patients](https://onco.cc/trials/nct06564324/), [A Phase III Study to Evaluate the Efficacy and Safety of JYP0322 in Previously Untreated ROS1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer](https://onco.cc/trials/nct07816380/), [A Study Evaluates the Safety and Efficacy of WX-0593 in ALK -Positive, or ROS1-positive Non-small Cell Lung Cancer](https://onco.cc/trials/nct04641754/), [A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene](https://onco.cc/trials/nct04395677/), [A Study of Lorlatinib in Subjects With ROS1-Positive Non-Small Cell Lung Cancer](https://onco.cc/trials/nct05297890/), [A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements](https://onco.cc/trials/nct03093116/), [A Study 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)](https://onco.cc/trials/nct06140836/), [A Study of XZP-5955 Tablets in Patients With NTRK or ROS1 Fusion Positive Locally Advanced or Metastatic Solid Tumors](https://onco.cc/trials/nct04996121/), [A Study to Compare the Efficacy and Safety of Entrectinib and Crizotinib in Participants With Advanced or Metastatic ROS1 Non-small Cell Lung Cancer (NSCLC) With and Without Central Nervous System (CNS) Metastases](https://onco.cc/trials/nct04603807/), [Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme](https://onco.cc/trials/nct02568267/), [Cabozantinib in Patients With RET Fusion-Positive Advanced Non-Small Cell Lung Cancer and Those With Other Genotypes: ROS1 or NTRK Fusions or Increased MET or A](https://onco.cc/trials/nct01639508/), [JYP0322 Versus Platinum Based Doublet Chemotherapy in ROS1 Positive Patients Previously Treated With ROS1-TKIs.](https://onco.cc/trials/nct07154368/), [Neoadjuvant WX-0593 in Resectable ALK-positive or ROS1-positive Non-small Cell Lung Cancer](https://onco.cc/trials/nct05765877/), [Phase 3 Study of Taletrectinib vs Placebo as an Adjuvant Therapy in ROS1 Positive NSCLC (TRUST-IV)](https://onco.cc/trials/nct07154706/), [PROFILE 1001 ROS1 expansion cohort](https://onco.cc/trials/profile-1001-ros1/), [Repotrectinib in ROS1-positive Non-small Cell Lung Cancer Patients With Active Brain Metastasis](https://onco.cc/trials/nct06315010/), [Taletrectinib Phase 2 Global Study in ROS1 Positive NSCLC](https://onco.cc/trials/nct04919811/)
- people: [Alexander Drilon](https://onco.cc/people/alexander-drilon/), [Alice T. Shaw](https://onco.cc/people/alice-shaw/), [Byoung Chul Cho](https://onco.cc/people/cho-byoung-chul/), [D. Ross Camidge](https://onco.cc/people/ross-camidge/), [Robert C. Doebele](https://onco.cc/people/robert-doebele/)
- key papers: [Crizotinib in ROS1-rearranged non-small-cell lung cancer](https://onco.cc/key-papers/paper-shaw-crizotinib-ros1-nejm-2014/), [Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three trials](https://onco.cc/key-papers/paper-drilon-entrectinib-ros1-lancet-oncol-2020/), [TRIDENT-1: repotrectinib in ROS1 fusion-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-trident-1-repotrectinib-nejm-2024/)

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JSON: https://onco.cc/api/v1/entities/ros1-positive-nsclc.json