# 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

## 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

- 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 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/), [LIBRETTO-431](https://onco.cc/trials/libretto-431/), [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/)
- cancers: [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/)

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