ROS1-positive non-small-cell lung cancer

aka ROS1-rearranged lung cancer, ROS1 fusion NSCLC, CD74-ROS1 lung cancer

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.

Part ofNon-small-cell lung cancer

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.

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.

Red cards

From the labels and guidelines behind the standard of care. Your team's thresholds win.

Emergency services now
Fainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Crizotinib Entrectinib Repotrectinib Taletrectinib Zidesamtinib source
Emergency services now
Bleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
Carboplatin Pemetrexed source
Check before combining
Entrectinib with Crizotinib: major interaction
QT: both Entrectinib and Crizotinib prolong the QT interval (known and known risk).. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Crizotinib Entrectinib source
Check before combining
Food and drink: Entrectinib
Avoid grapefruit.
Entrectinib source
Check before combining
Heart rhythm (QT): Crizotinib
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Crizotinib source
Check before combining
Heart rhythm (QT): Entrectinib
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
Entrectinib source

See all on the product pages:Carboplatin Crizotinib Entrectinib Pemetrexed Repotrectinib Taletrectinib Zidesamtinib·Printable cards in the navigator

Anatomy and lymph node drainage

Lungs, pleura and mediastinum: subsites and node stations · wireframe schematic, not to scale

Organ atlas →

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.

Subsites

Central airways (squamous, small-cell)
Periphery (adenocarcinoma)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
Apex (Pancoast)
Pleura (mesothelioma)
Thymus (anterior mediastinum)ROS1 fusion adenocarcinoma, inhibitor-naive (repotrectinib, taletrectinib, entrectinib or crizotinib)

Regional lymph nodes

hilar (N1)
mediastinal (N2)
supraclavicular (N3)

Who gets it and what has changed

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.

Group

lung

Cases by country

Cases by country · GLOBOCAN 2022

All countries →

No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.

Standard of care

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Lines of therapy by subgroup →Staging and risk scores →

Decisions you may face

3 with more than one option · full decision page →

One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.

Advanced, first line4 Advanced, after crizotinib or entrectinib5 Brain metastases3

Advanced, first line

Repotrectinib (TRIDENT-1) or taletrectinib as preferred; entrectinib or crizotinib as alternatives, entrectinib when brain metastases are present.

NCCN Guidelines: Non-Small Cell Lung Cancer

RepotrectinibA Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 RearrangementsTaletrectinibA Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion GeneEntrectinibBasket 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 RearrangemeCrizotinibBrain metastases (intracranial disease)

Advanced, after crizotinib or entrectinib

Repotrectinib or taletrectinib, which cover G2032R; zidesamtinib in trials; platinum-pemetrexed once inhibitors are exhausted.

NCCN Guidelines: Non-Small Cell Lung Cancer

RepotrectinibTaletrectinibZidesamtinibOn-target resistance mutations (gatekeeper, solvent-front, compound)PemetrexedCarboplatin

Brain metastases

Brain-penetrant inhibitors (repotrectinib, taletrectinib, entrectinib) with stereotactic radiosurgery for large or symptomatic lesions.

NCCN Guidelines: Non-Small Cell Lung Cancer

RepotrectinibEntrectinibStereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)Brain metastases (intracranial disease)

Subtypes & biomarkers

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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 clinicians test

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

How often this target appears

History

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2007ROS1 fusions identified in lung cancer
ROS1 Gene fusion
2014PROFILE 1001 ROS1 cohort: crizotinib response rate 72 percent
Crizotinib
2016Crizotinib approved for ROS1-positive lung cancer
Crizotinib
2019Entrectinib approved for ROS1 lung cancer and NTRK fusion tumours
EntrectinibBasket 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 Alexander Drilon
2023TRIDENT-1: repotrectinib approved with activity against G2032R
RepotrectinibA Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements Alexander Drilon
2025Taletrectinib approved after TRUST-I and TRUST-II
TaletrectinibA Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene

What changed

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Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.

All 7 changes by month →

FollowWatch this cancer and Saved shows what changed since you last looked.Follow by feed

In development

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What is in development for ROS1-positive non-small-cell lung cancer, drawn from the whole corpus: 3 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.

Trials under way · 3

A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene · phase 2 · Nuvation Bio Inc.
A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements · phase 1/2 · Turning Point Therapeutics, Inc.
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 · phase 2 · Hoffmann-La Roche

Open problems and what is being done

No randomised trial compares the ROS1 inhibitors; choice rests on single-arm response rates and side-effect profiles.
What is being done about this
Rare cancers and small trials
and how the field plans to fix it →
Available now
Comprehensive genomic profilingStandard of care
In trials
Nothing recorded yet.
Ideas and roadmaps
Nothing recorded yet.
Also on OnCo: Find a trial · Expert centres.
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.
What is being done about this
Resistance to treatment
and how the field plans to fix it →
Available now
Comprehensive genomic profilingStandard of care
Small-molecule kinase inhibitorsStandard of care
In trials
Nothing recorded yet.
Ideas and roadmaps
Nothing recorded yet.
Background: On-target resistance mutations (gatekeeper, solvent-front, compound). Also on OnCo: Resistance atlas · Lines of therapy.

Trials

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Trials recruiting now

Recruiting trials near you · live from ClinicalTrials.gov

ROS1-positive non-small-cell lung cancer

condition: ROS1-positive non-small-cell lung cancer

Open on ClinicalTrials.gov →

within

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Landmark trials

A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements 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

Expert centres

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Where the expertise is

Expert centres

28 centres in 11 countries · 0 with a trial for this cancer on record · second-opinion finder →

Choose a region from the globe in the header to mark centres near you.

28 centres


Memorial Sloan Kettering Cancer Center New York · cancer center	United States	NCI comprehensive	5,100	94,456	Comprehensive genomic profiling CAR-T cell therapy Digital pathology & AI	#1
MD Anderson Cancer Center Houston · cancer center	United States	NCI comprehensive	6,724	95,007	CAR-NK & CAR-macrophage Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +2	#2
Samsung Medical Center Seoul · hospital Programme: Lung cancer trials	South Korea	none recorded	1,312	17,172	Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#3
Mayo Clinic Rochester, MN · hospital	United States	NCI comprehensive	4,511	44,748	Carbon-ion therapy Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +1	#5
Gustave Roussy Villejuif · cancer center	France	none recorded	1,855	31,182	ZAP-X gyroscopic radiosurgery Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#6
Seoul National University Hospital Seoul · hospital Programme: Lung cancer	South Korea	none recorded	1,607	24,676	Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#8
Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center Baltimore · cancer center	United States	NCI comprehensive	2,955	41,449	Multi-cancer early detection (MCED)Liquid biopsy (ctDNA)Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems +2	#10
Charité Universitätsmedizin Berlin Berlin · university	Germany	none recorded	1,563	17,749	Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems CyberKnife robotic radiosurgery Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#12
Massachusetts General Hospital Cancer Center Boston · hospital Programme: Targeted therapy (lung)	United States	NCI comprehensive	3,582	54,857	Proton therapy Small-molecule kinase inhibitors Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +1	#16
Cleveland Clinic Taussig Cancer Institute Cleveland · hospital	United States	NCI comprehensive	2,264	29,412	Off-the-shelf cancer vaccines Proton therapy Proton therapy machines: cyclotrons, synchrotrons and single-room systems Gamma Knife +1	#20
Severance Hospital, Yonsei University Seoul · hospital	South Korea	none recorded	464	3,248	Carbon-ion therapy Robotic & minimally invasive surgery Carbon-ion synchrotrons and facilities Gamma Knife +1	#22
Stanford Health Care / Stanford Cancer Institute Stanford · university	United States	NCI comprehensive	3,000	50,162	CAR-T cell therapy SBRT / SABR (stereotactic radiotherapy)CyberKnife robotic radiosurgery Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)+1	#30
UCSF Helen Diller Family Comprehensive Cancer Center San Francisco · cancer center	United States	NCI comprehensive	2,800	46,704	PSMA PET Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#33
Karolinska University Hospital Stockholm · university	Sweden	none recorded	987	12,440	Gamma Knife Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)	#39
University College London Hospitals / UCL Cancer Institute London · hospital	United Kingdom	none recorded	2,376	28,940	Proton therapy CAR-T cell therapy Liquid biopsy (ctDNA)Whole-exome & whole-genome sequencing +5	-

(showing the first 15)

These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with ROS1-positive non-small-cell lung cancer but is thinly recorded here will look small.

Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.

Seeking a second opinion: ask your oncologist for a referral to a high-volume centre; most accept records and pathology by mail or telehealth. In the US, use the NCI's Find a Cancer Center tool or the nonprofit Cancer Commons, which navigates options for advanced cancers at no cost. The second-opinion finder explains how referral works in your country.

Questions to ask

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Bring to your appointment

Questions to ask your oncologist about ROS1-positive non-small-cell lung cancer

Generated from this cancer's standard of care, biomarkers, and pipeline · 16 questions

Newly diagnosed

What is my exact diagnosis, stage, and grade, and which tests established them?
Why: Everything else follows from an accurate stage and subtype.
Which biomarkers have been tested on my tumour (for example ROS1 fusion by RNA sequencing, fluorescence in situ hybridisation or immunohistochemistry with confirmation, ROS1 resistance mutations at progression, Brain MRI at diagnosis and during follow-up, Bypass alterationsat progression), and what were the results?
Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
Which subtype is my cancer, and does that change the recommended treatment?
Why: Recognised subtypes for this cancer include ROS1 fusion adenocarcinoma, inhibitor-naive, ROS1-positive disease with brain metastases at diagnosis, Crizotinib-resistant ROS1 disease.
Is germline (inherited) genetic testing recommended for me or my family?
Why: Inherited variants can change treatment and matter for relatives.

Advanced, first line

For my situation (advanced, first line), which of the standard options do you recommend and why?
Why: Guideline options include: Repotrectinib (TRIDENT-1) or taletrectinib as preferred; entrectinib or crizotinib as alternatives, entrectinib when brain metastases are present.
Am I a candidate for Repotrectinib, Taletrectinib, Entrectinib or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
How do the results of A Study of Repotrectinib (TPX-0005) in Patients With Advanced Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements and A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene apply to someone like me?
Why: Trial populations differ from individual patients; ask how closely you match.

Advanced, after crizotinib or entrectinib

For my situation (advanced, after crizotinib or entrectinib), which of the standard options do you recommend and why?
Why: Guideline options include: Repotrectinib or taletrectinib, which cover G2032R; zidesamtinib in trials; platinum-pemetrexed once inhibitors are exhausted.
Am I a candidate for Repotrectinib, Taletrectinib, Zidesamtinib or related drugs, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Brain metastases

For my situation (brain metastases), which of the standard options do you recommend and why?
Why: Guideline options include: Brain-penetrant inhibitors (repotrectinib, taletrectinib, entrectinib) with stereotactic radiosurgery for large or symptomatic lesions.
Am I a candidate for Repotrectinib, Entrectinib, and what side effects should I expect?
Why: Knowing the expected toxicities helps you plan work, family, and supportive care.

Any stage

Are there clinical trials I could join, for example of Zidesamtinib, Taletrectinib, A Study of AB-106 in Subjects With Advanced NSCLC Harboring ROS1 Fusion Gene?
Why: Trials are how the next standard of care is set; asking early keeps options open.
Would a second opinion at a high-volume centre change anything, and can you help arrange it?
Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?
Why: Supportive care improves quality of life and helps patients complete treatment.
I read that “No randomised trial compares the ROS1 inhibitors; choice rests on single-arm response rates and side-effect profiles”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.
I read that “Dizziness, weight gain and paraesthesia from TRK inhibition limit the current brain-penetrant drugs”. How does that affect my plan?
Why: Open problems are where trials and second opinions matter most.