RET fusion-positive non-small-cell lung cancer
RET fusion lung cancer is a rare adenocarcinoma driven by a fused RET gene. The selective pill selpercatinib shrinks most tumours and more than doubles the time to progression compared with chemotherapy and immunotherapy, and pralsetinib is a second option.
Overview
RET fusions were found in lung cancer in 2012, but the first drugs tried, the multikinase inhibitors cabozantinib and vandetanib, produced responses in fewer than a third of patients with heavy off-target toxicity. Selective RET inhibitors designed from 2014 onward changed that: in LIBRETTO-001 selpercatinib produced a 64 percent response rate in patients who had received platinum chemotherapy and 85 percent in treatment-naive patients, with intracranial responses in most patients with measurable brain disease, and it received accelerated approval in May 2020. Pralsetinib followed in September 2020 on the ARROW study, with response rates of 61 percent after platinum and 70 percent in treatment-naive patients.
LIBRETTO-431 (2023) was the randomised confirmation: selpercatinib against platinum-pemetrexed with or without pembrolizumab first line gave median progression-free survival of 24.8 versus 11.2 months (hazard ratio 0.46) and far fewer brain progressions, so selective RET inhibition became the first-line standard. Side effects are hypertension, liver enzyme rises, dry mouth, oedema and, rarely, hypersensitivity; QT prolongation is monitored. Checkpoint inhibitors work poorly in RET fusion disease.
Resistance arises through solvent-front mutations (G810) and through bypass via MET amplification or KRAS; next-generation RET inhibitors designed for G810 are in early trials, and chemotherapy remains active. Open questions are how to treat resistance, and whether adjuvant selpercatinib (LIBRETTO-432) prevents recurrence after surgery.
State of the art
- Two approved selective RET inhibitors with brain activity after years of poor results from multikinase drugs.
- Adjuvant selpercatinib under test after resection.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Selpercatinib first line: progression-free survival 24.8 versus 11.2 months against chemoimmunotherapy in LIBRETTO-431.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowFainting 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.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
- Check before combiningFood and drink: Pralsetinib
Take on an empty stomach.
- Check before combiningHeart rhythm (QT): Selpercatinib
Known QT prolongation. Avoid other QT-prolonging drugs where possible; check ECG and correct potassium and magnesium before and during treatment.
See all on the product pages:CarboplatinPembrolizumabPemetrexedPralsetinibSelpercatinib·Printable cards in the navigator
Anatomy and lymph node drainage
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)
- Nodes: hilar (N1)
- Nodes: mediastinal (N2)
- Nodes: supraclavicular (N3)
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.
- Central airways (squamous, small-cell)
- Periphery (adenocarcinoma)KIF5B-RET fusion adenocarcinoma (about 70 percent of RET fusions) · CCDC6-RET and other RET fusion adenocarcinoma · RET fusion disease with brain metastases at diagnosis
- Apex (Pancoast)
- Pleura (mesothelioma)
- Thymus (anterior mediastinum)KIF5B-RET fusion adenocarcinoma (about 70 percent of RET fusions) · CCDC6-RET and other RET fusion adenocarcinoma
- hilar (N1)
- mediastinal (N2)
- supraclavicular (N3)
Same organ: Non-small-cell lung cancer, Lung cancer (all types), Small-cell lung cancer, Mesothelioma, Pleural mesothelioma, Thymoma and thymic carcinoma, Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Inflammatory myofibroblastic tumour (IMT), EGFR-mutated non-small-cell lung cancer, ALK-positive non-small-cell lung cancer, KRAS G12C-mutant non-small-cell lung cancer, ROS1-positive non-small-cell lung cancer, MET exon 14 and MET-amplified non-small-cell lung cancer, BRAF V600E-mutant non-small-cell lung cancer, HER2-mutant non-small-cell lung cancer, NTRK fusion-positive non-small-cell lung cancer, PD-L1-high non-small-cell lung cancer without a driver mutation, Resectable stage I to III non-small-cell lung cancer, Unresectable stage III non-small-cell lung cancer, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer, Lung neuroendocrine tumours (typical and atypical carcinoid)
About 1 to 2 percent of non-small-cell lung cancers carry a RET fusion, most often KIF5B-RET, in adenocarcinomas of younger patients who have never smoked; brain metastases are common.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Selpercatinib (LIBRETTO-431) as preferred; pralsetinib as an alternative.
Platinum-pemetrexed with or without pembrolizumab; clinical trial of a next-generation RET inhibitor; local radiotherapy for oligoprogression.
Subtypes & biomarkers
top- KIF5B-RET fusion adenocarcinoma (about 70 percent of RET fusions)
- CCDC6-RET and other RET fusion adenocarcinoma
- RET fusion disease with brain metastases at diagnosis
- Solvent-front (G810) resistance after selpercatinib or pralsetinib
- RET fusion by RNA sequencing or DNA panel (RNA preferred; fluorescence in situ hybridisation less reliable)
- RET resistance mutations (G810) and bypass alterations at progression
- Brain MRI at diagnosis and during follow-up
- Blood pressure, liver enzymes and QT interval on RET inhibitors
How often this target appears
- 2012RET fusions (KIF5B-RET) found in lung adenocarcinoma
- 2020Selpercatinib (LIBRETTO-001) and pralsetinib (ARROW) approved
- 2023LIBRETTO-431: selpercatinib beats chemotherapy plus pembrolizumab first line
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 5 changes by month →- 2026-09-17This recordRET fusion-positive non-small-cell lung cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2023Trial resultLIBRETTO-431LIBRETTO-431 reported
PFS HR 0.
- 2023MilestoneLIBRETTO-431LIBRETTO-431: selpercatinib beats chemotherapy plus pembrolizumab first line
A milestone in how this cancer is treated.
- 2020MilestoneSelpercatinibSelpercatinib (LIBRETTO-001) and pralsetinib (ARROW) approved
A milestone in how this cancer is treated.
- 2012MilestoneRETRET fusions (KIF5B-RET) found in lung adenocarcinoma
A milestone in how this cancer is treated.
What is in development for RET fusion-positive non-small-cell lung cancer, drawn from the whole corpus: 2 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 · 1
Trials reported · 1
- LIBRETTO-431 · phase 3 · 2023 · positive
Open problems and what is being done
Solvent-front resistance mutations have no approved inhibitor.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- Comprehensive genomic profilingStandard of care
- Small-molecule kinase inhibitorsStandard of care
In trialsNothing recorded yet.
Ideas and roadmapsNothing recorded yet.
Background: Oligoprogression, On-target resistance mutations (gatekeeper, solvent-front, compound). Also on OnCo: Resistance atlas · Lines of therapy.
Whether adjuvant selpercatinib prevents recurrence is not yet known.
RNA-based testing is needed to find all fusions but is not universally available.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
New York · cancer center | United States | 0 | 5,100 | 94,456 | #1 | ||
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
| United States | 0 | 3,582 | 54,857 | #16 | |||
Stanford · university | United States | 0 | 3,000 | 50,162 | #30 | ||
Dallas, TX · cancer center | United States | 0 | 1,744 | 19,757 | - | ||
Utrecht · cancer center | Netherlands | none recorded | 0 | 1,422 | 20,323 | - | |
Rozzano (Milan) · hospital | Italy | none recorded | 0 | 1,031 | 10,720 | - | |
Jinan · cancer center | China | none recorded | 0 | 920 | 7,804 | - | |
Aarhus · hospital | Denmark | none recorded | 0 | 624 | 4,497 | - | |
Freiburg im Breisgau · cancer center | Germany | none recorded | 0 | 549 | 5,261 | - | |
| China | none recorded | 0 | 539 | 6,491 | - | ||
Lausanne · hospital | Switzerland | none recorded | 0 | 509 | 9,176 | - | |
Brussels · cancer center | Belgium | none recorded | 0 | 489 | 8,689 | - | |
Aurora, CO · cancer center Programme: Oncogene-driven lung cancer, Lung cancer SPORE | United States | 0 | 483 | 13,480 | - | ||
| Switzerland | none recorded | 0 | 470 | 4,598 | - |
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 RET fusion-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.
Questions to ask
topQuestions to ask your oncologist about RET fusion-positive non-small-cell lung cancer
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 RET fusion by RNA sequencing or DNA panel, RET resistance mutationsand bypass alterations at progression, Brain MRI at diagnosis and during follow-up, Blood pressure, liver enzymes and QT interval on RET inhibitors), 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 KIF5B-RET fusion adenocarcinoma, CCDC6-RET and other RET fusion adenocarcinoma, RET fusion disease with brain metastases at diagnosis.
- 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: Selpercatinib (LIBRETTO-431) as preferred; pralsetinib as an alternative.
- Am I a candidate for Selpercatinib, Pralsetinib, 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 LIBRETTO-431 and A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRET apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Advanced, after a RET inhibitor
- For my situation (advanced, after a ret inhibitor), which of the standard options do you recommend and why?Why: Guideline options include: Platinum-pemetrexed with or without pembrolizumab; clinical trial of a next-generation RET inhibitor; local radiotherapy for oligoprogression.
- Am I a candidate for Pemetrexed, Carboplatin, Pembrolizumab, 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 Selpercatinib, LIBRETTO-431?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 “Solvent-front resistance mutations have no approved inhibitor”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Whether adjuvant selpercatinib prevents recurrence is not yet known”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with RET fusion-positive non-small-cell lung cancer, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
7targets
2drugs
5companies
4pathways
3terms
6trials
2people
3Latest papers
topQuery for this cancer: (TITLE:"RET fusion-positive non-small-cell lung cancer" OR ABSTRACT:"RET fusion-positive non-small-cell lung cancer" OR TITLE:"RET-rearranged lung cancer" OR ABSTRACT:"RET-rearranged lung cancer" OR TITLE:"KIF5B-RET lung cancer" OR ABSTRACT:"KIF5B-RET lung cancer" OR TITLE:"RET+ NSCLC" OR ABSTRACT:"RET+ NSCLC") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about RET fusion-positive non-small-cell lung cancer, not a curated reading list.
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