# RET fusion-positive non-small-cell lung cancer

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

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: RET-rearranged lung cancer; KIF5B-RET lung cancer; RET+ NSCLC
- Tags: subtype-page; lung
- Group: lung
- Burden: 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.
- Subtypes: 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
- Biomarkers: 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

## 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/ret-fusion-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/ret-fusion-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/ret-fusion-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/ret-fusion-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/ret-fusion-nsclc/#treating-it [2 settings, 2 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/ret-fusion-nsclc/#evidence [10 trials, 3 key papers, 3 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/ret-fusion-nsclc/#science [2 targets, 3 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/ret-fusion-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/ret-fusion-nsclc/#living-with-it [14 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/ret-fusion-nsclc/coming/ [5 medicines, 10 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/ret-fusion-nsclc/data/ [45 connected records]

## Standard of care

- Advanced, first line: Selpercatinib (LIBRETTO-431) as preferred; pralsetinib as an alternative. ([Selpercatinib](https://onco.cc/drugs/selpercatinib/), [LIBRETTO-431](https://onco.cc/trials/libretto-431/), [A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRET](https://onco.cc/trials/nct03157128/), [Pralsetinib](https://onco.cc/drugs/pralsetinib/), [Brain metastases (intracranial disease)](https://onco.cc/terms/brain-metastases/))
- Advanced, after a RET inhibitor: Platinum-pemetrexed with or without pembrolizumab; clinical trial of a next-generation RET inhibitor; local radiotherapy for oligoprogression. ([Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Oligoprogression](https://onco.cc/terms/oligoprogression/), [On-target resistance mutations (gatekeeper, solvent-front, compound)](https://onco.cc/terms/gatekeeper-mutation/))

## State of the art

- Selpercatinib first line: progression-free survival 24.8 versus 11.2 months against chemoimmunotherapy in LIBRETTO-431.
- Two approved selective RET inhibitors with brain activity after years of poor results from multikinase drugs.
- Adjuvant selpercatinib under test after resection.

## Open problems

- Solvent-front resistance mutations have no approved inhibitor.
- Whether adjuvant selpercatinib prevents recurrence is not yet known.
- RNA-based testing is needed to find all fusions but is not universally available.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/RET_proto-oncogene
- Wikipedia: https://en.wikipedia.org/wiki/RET_proto-oncogene
- 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/), [ROS1-positive non-small-cell lung cancer](https://onco.cc/cancers/ros1-positive-nsclc/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)](https://onco.cc/technologies/radiosurgery-srs/)
- targets: [RET](https://onco.cc/targets/ret/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Pemetrexed](https://onco.cc/drugs/pemetrexed/), [Pralsetinib](https://onco.cc/drugs/pralsetinib/), [Selpercatinib](https://onco.cc/drugs/selpercatinib/)
- companies: [Blueprint Medicines](https://onco.cc/companies/blueprint-medicines/), [Eli Lilly (incl. Loxo)](https://onco.cc/companies/eli-lilly/), [Roche / Genentech](https://onco.cc/companies/roche-genentech/)
- pathways: [Non-small cell lung cancer (KEGG map)](https://onco.cc/pathways/nsclc-signalling/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [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/), [Oligoprogression](https://onco.cc/terms/oligoprogression/), [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 Prospective, Single-center, Non-randomized, Interventional Study on the Effectiveness and Safety of Combined Immunotargeted Therapy in Patients With Metastati](https://onco.cc/trials/nct07809256/), [A Study of EP0031 (Lunbotinib) in Patients With Advanced RET-altered Malignancies](https://onco.cc/trials/nct05443126/), [A Study of HS-10365 in Patients With Advanced or Metastatic RET Fusion-Positive Non-Small Cell Lung Cancer](https://onco.cc/trials/nct06147570/), [A Study of Selpercatinib (LOXO-292) in Participants With Advanced Solid Tumors, RET Fusion-Positive Solid Tumors, and Medullary Thyroid Cancer (LIBRET](https://onco.cc/trials/nct03157128/), [A Study of Selpercatinib After Surgery or Radiation in Participants With Non-Small Cell Lung Cancer (NSCLC)](https://onco.cc/trials/nct04819100/), [ARROW (thyroid cohorts)](https://onco.cc/trials/arrow-thyroid/), [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/), [LIBRETTO-431](https://onco.cc/trials/libretto-431/), [Phase III Study of SY-5007, a RET Inhibitor, in Patients With Locally Advanced or Metastatic RET Fusion-positive NSCLC](https://onco.cc/trials/nct06031558/), [Study of RET Inhibitor TAS0953/HM06 in Patients With Advanced Solid Tumors With RET Gene Abnormalities](https://onco.cc/trials/nct04683250/)
- people: [Alexander Drilon](https://onco.cc/people/alexander-drilon/), [Caicun Zhou](https://onco.cc/people/zhou-caicun/), [Justin F. Gainor](https://onco.cc/people/justin-gainor/)
- key papers: [ARROW: pralsetinib for RET fusion-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-arrow-pralsetinib-gainor-lancet-oncol-2021/), [LIBRETTO-001: selpercatinib in RET fusion-positive non-small-cell lung cancer](https://onco.cc/key-papers/paper-libretto-001-selpercatinib-nsclc-nejm-2020/), [LIBRETTO-431: first-line selpercatinib versus chemotherapy with or without pembrolizumab in RET fusion-positive lung cancer](https://onco.cc/key-papers/paper-libretto-431-nejm-2023/)

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JSON: https://onco.cc/api/v1/entities/ret-fusion-nsclc.json