RET Fusions in Lung Cancer

by Matthew Cecchini, MD PhD FRCPC
March 20, 2026

RET is a gene that encodes a receptor protein involved in signalling pathways that regulate cell growth, survival, and differentiation during normal development. In healthy adult lung tissue, RET activity is minimal. In approximately 1–2% of non-small cell lung cancers, a chromosomal rearrangement fuses the RET gene to a partner gene, creating an abnormal fusion protein that is permanently switched on and continuously drives cancer cell growth. Although RET fusions are relatively uncommon, they are highly important to identify: patients whose tumours carry a RET fusion can achieve substantial and durable responses to a new generation of RET-specific targeted drugs called selective RET inhibitors — a significant advance over older, less selective treatments. Like several other fusion-driven lung cancers, RET-rearranged NSCLC tends to occur in younger patients and in never-smokers or light smokers, making the identification of an effective targeted therapy especially meaningful for this group.

What the test looks for

The RET gene sits on chromosome 10. In a small subset of lung cancers, a structural rearrangement causes RET to fuse with a partner gene, producing a hybrid fusion protein in which the kinase signalling domain of RET is constitutively active — permanently transmitting growth and survival signals without the normal regulatory controls that would switch it off.

The most common fusion partner in lung cancer is KIF5B, a kinesin motor protein gene, which accounts for approximately 70% of RET fusions in this setting. Other partners include CCDC6, NCOA4, TRIM33, and others. As with ALK and ROS1 rearrangements, the specific fusion partner does not change the fundamental treatment approach — all RET fusions activate the same signalling pathway, and all predict sensitivity to selective RET inhibitor drugs. Knowing the partner may be relevant to prognosis and resistance patterns, but the primary actionable finding is simply the presence of a RET fusion.

It is important to distinguish RET fusions from RET point mutations. Point mutations in RET are the primary driver of several thyroid cancers (particularly medullary thyroid carcinoma) and are also found in a small proportion of other cancers. In lung cancer, the relevant alteration is almost always a fusion, not a point mutation, and the two types of RET alteration have different therapeutic implications. The selective RET inhibitors approved for lung cancer were developed specifically to target RET fusions, and their activity against RET point mutations varies.

Why is the test done

To determine eligibility for selective RET inhibitor therapy. Pralsetinib (Gavreto) and selpercatinib (Retevmo) are both approved for RET fusion-positive advanced NSCLC, including in the first-line setting. These drugs achieve high response rates and durable disease control, specifically in RET fusion-positive tumours, and have essentially no activity in RET-negative cancers. Testing is necessary to identify who will benefit.
To avoid less effective treatment. In patients with RET fusions, selective RET inhibitors are substantially more effective than standard chemotherapy as initial treatment, with higher response rates and a more favourable tolerability profile. Identifying the fusion at diagnosis ensures these patients receive the most appropriate therapy from the outset.
To distinguish RET fusions from older, non-selective RET-targeting drugs. Before selective RET inhibitors were developed, some oncologists used multikinase inhibitors such as cabozantinib or vandetanib — drugs that inhibit RET among many other targets — in RET fusion-positive lung cancer. These older drugs achieved only modest response rates and came with significant toxicity. The availability of selective, potent RET inhibitors has made these earlier agents largely obsolete for this indication.
To support clinical trial eligibility. The RET field continues to evolve, with ongoing trials investigating RET inhibitors in earlier disease stages, in combination with other agents, and in patients who have developed resistance to first-line RET inhibitor therapy.

Who should be tested

Current guidelines recommend RET fusion testing for:

All patients with advanced or metastatic non-small cell lung cancer, as part of comprehensive molecular profiling at diagnosis, regardless of histological subtype, though RET fusions are most common in lung adenocarcinoma.
Never-smokers or light smokers with NSCLC, in whom RET fusions are proportionally more prevalent than in heavy smokers.
Younger patients with lung adenocarcinoma in whom other driver alterations have not been identified.

In practice, RET testing is performed simultaneously with all other major lung cancer biomarker tests as part of a comprehensive NGS panel at diagnosis. It is not ordered in isolation at most major cancer centres.

How the test is performed

RET fusion testing uses the same platforms employed for other lung cancer fusions — primarily NGS, with FISH and IHC playing supplementary roles at some centres.

Next-generation sequencing (NGS)

RNA-based next-generation sequencing is the preferred and most sensitive method for detecting RET fusions. By directly sequencing the messenger RNA produced by tumour cells, RNA-based NGS identifies the fusion transcript, confirms the partner gene, and characterises the specific breakpoint — providing the most complete picture of the rearrangement. DNA-based NGS can also detect RET rearrangements by identifying structural variants at the genomic level. However, RNA-based approaches are generally more sensitive for fusion detection and less likely to miss novel or complex rearrangements.

Fluorescence in situ hybridization (FISH)

FISH uses fluorescent probes flanking the RET gene to detect rearrangements. Separation of the probe signals (a split signal) indicates that a structural rearrangement has disrupted the RET gene. FISH is highly specific but cannot identify the fusion partner and is less sensitive than RNA-based NGS for complex or atypical rearrangements. It may be used as a confirmatory test when NGS results are equivocal or when tissue is limited.

Immunohistochemistry (IHC)

Unlike ALK and ROS1, for which IHC has well-validated, widely used antibodies, RET IHC is less reliably standardised for lung cancer and is not recommended as a standalone diagnostic test by most guidelines. It may be used at some centres as a preliminary screening tool, but a positive IHC result requires confirmation with a molecular method before treatment decisions are made.

Liquid biopsy

Cell-free circulating tumour DNA testing can detect RET fusions, though — as with other structural rearrangements — sensitivity is lower than for point mutations. Liquid biopsy is most useful when tissue is unavailable or insufficient, or for monitoring disease during treatment and identifying resistance mechanisms at progression. A negative liquid biopsy result does not exclude a RET fusion, and tissue testing should be performed when clinically indicated.

How results are reported

RET results are reported as positive (fusion detected) or negative (no fusion detected), with the fusion partner and variant identified on NGS specified where available. A typical positive report might read: “KIF5B-RET fusion detected” or “CCDC6-RET fusion, exon 1-12 breakpoint confirmed.” FISH reports will note the percentage of cells showing split signals and whether the result meets the laboratory’s positivity threshold.

The report should specify that the alteration is a fusion — not a point mutation — since the therapeutic implications differ. If a RET point mutation is incidentally identified rather than a fusion, this should prompt discussion with a thoracic oncologist regarding its significance in the context of lung cancer.

What the result means

RET fusion positive. A RET fusion gene is present in the cancer cells. The tumour is driven at least in part by the constitutively active RET fusion protein and is expected to respond to selective RET inhibitor therapy. This is a highly actionable finding. Both pralsetinib (Gavreto) and selpercatinib (Retevmo) are approved for RET fusion-positive advanced NSCLC in the first-line setting and beyond. In clinical trials, response rates among treatment-naive patients exceeded 70%, with a meaningful proportion achieving durable responses lasting well over a year. Selpercatinib in particular demonstrated strong intracranial activity in patients with brain metastases in the LIBRETTO-001 trial, and pralsetinib showed comparable systemic efficacy in the ARROW trial. Both drugs are taken as daily oral capsules or tablets. Your oncologist will discuss which drug is most appropriate based on your overall clinical situation, local approval and availability, and any prior treatments received.
RET fusion negative. No RET fusion was detected in the regions assessed. RET inhibitor therapy is not indicated. The full molecular profile and PD-L1 expression will guide treatment. If all major driver alterations are absent, treatment typically involves immunotherapy with or without chemotherapy, based on PD-L1 expression level.
Equivocal result. In rare cases, a result may be indeterminate — for example, a FISH result showing borderline split-signal frequency, or an NGS result identifying a structural variant involving RET with an uncertain partner or breakpoint. Confirmatory testing with an alternative platform, preferably RNA-based NGS, should be performed before treatment decisions are made.

Selective RET inhibitors and resistance

The approval of selpercatinib and pralsetinib represented a major advance for patients with RET fusion-positive lung cancer. Earlier multikinase inhibitors that also inhibited RET — such as cabozantinib and vandetanib — achieved response rates of only 15–30% in this population and were associated with considerable off-target toxicity. The selective RET inhibitors were purpose-built to block RET with high potency and precision, achieving dramatically better efficacy and tolerability.

As with other targeted therapies, resistance to selective RET inhibitors eventually develops in most patients. Resistance mechanisms include:

On-target resistance: Mutations within the RET kinase domain — most commonly at the solvent front (G810 mutations) or gatekeeper position — that reduce drug binding. These are detected by repeated molecular testing at progression.
Off-target resistance: Activation of bypass signalling pathways (such as MET amplification, KRAS mutations, or other alterations) that allow the cancer cell to continue growing independently of RET signalling.

Repeat molecular testing — with both liquid biopsy and tissue biopsy where feasible — is recommended when a RET fusion-positive cancer progresses on selective RET inhibitor therapy, to identify the resistance mechanism and guide the next treatment step. Next-generation RET inhibitors designed to overcome specific resistance mutations are in clinical development.

RET fusions and brain metastases

Like ALK- and ROS1-rearranged lung cancers, RET fusion-positive NSCLC has a meaningful propensity for brain metastases. Both selpercatinib and pralsetinib demonstrate CNS activity in patients with brain metastases, with selpercatinib having particularly robust intracranial response data from the LIBRETTO-001 trial. Brain MRI is typically recommended as part of initial staging for patients with RET fusion-positive NSCLC and is included in ongoing monitoring during treatment.

RET fusions vs. RET mutations: an important distinction

Patients with RET fusion-positive lung cancer may come across information about RET mutations in the context of thyroid cancer — particularly medullary thyroid carcinoma, where point mutations in RET are the primary driver and where RET-targeted drugs are also used. It is worth understanding that these are different types of RET alteration:

RET fusions (structural rearrangements) are the relevant alteration in lung cancer. They are somatic and not inherited.
RET point mutations are the relevant alteration in hereditary and sporadic medullary thyroid carcinoma. Germline RET mutations cause multiple endocrine neoplasia type 2 (MEN2), a hereditary syndrome associated with medullary thyroid carcinoma, pheochromocytoma, and parathyroid disease.

A RET fusion found in a lung cancer does not indicate MEN2 or a hereditary RET syndrome. These are somatic rearrangements arising within the lung cancer cells and are not inherited. Family members do not require RET screening based on a somatic RET fusion in a relative’s lung cancer.

What happens next

If a RET fusion is found: Your oncologist will recommend selective RET inhibitor therapy — selpercatinib or pralsetinib — for advanced disease. Brain imaging is typically performed before starting treatment to assess for CNS involvement, as this may influence drug selection and monitoring. Both drugs are taken orally once or twice daily. Your oncologist will review expected side effects — which are generally manageable and differ from those of chemotherapy — and set up a monitoring schedule.
If the result is negative, RET inhibitor therapy is not indicated. The full molecular profile, PD-L1 expression, and disease stage will guide treatment.
If the result is equivocal, Confirmatory testing will be arranged before treatment decisions are finalised.
At progression on selective RET inhibitor therapy, repeat molecular testing is recommended to identify the resistance mechanism. Clinical trials investigating next-generation RET inhibitors and combination strategies are increasingly available for patients whose cancers have progressed on first-generation selective RET inhibitors.

Questions to ask your doctor

Has my tumour been tested for RET fusions, and what method was used?
If my RET test is positive, which drug — selpercatinib or pralsetinib — is recommended for me, and why?
Do I have brain metastases, and how does that affect the choice of treatment?
Will I need a brain MRI as part of my initial staging?
What side effects should I expect from selective RET inhibitor therapy, and how are they managed?
If my cancer progresses on a RET inhibitor, will re-testing be done to identify the resistance mechanism?
Are there clinical trials studying new RET-targeted treatments that I might qualify for?
What other biomarkers have been tested in my tumour, and were any other actionable alterations found?