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RET-Rearranged Non-Small Cell Lung Cancer

Key recent statistics (2023–2024 emphasis)

2026-04-05
Falcon MONDO:0005061 Model: Edison Scientific Literature 55 citations

1. Disease Information

1.1 Concise overview

RET‑rearranged NSCLC is a subset of non‑small cell lung cancers driven by oncogenic RET gene fusions (chromosomal rearrangements) that create constitutively active RET kinase signaling and act as a targetable driver alteration (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5). RET fusions are uncommon in unselected NSCLC but clinically important due to high response rates to selective RET tyrosine kinase inhibitors (TKIs) (rocco2023treatmentofadvanced pages 5-6, zhou2023firstlineselpercatinibor pages 1-3).

1.2 Key identifiers and ontology mapping

A structured mapping of the disease concept, synonyms, and parent ontology terms captured in the retrieved evidence is provided here:

Table (click to expand)
Preferred name Synonyms / alternative names Specific disease identifier Parent disease / broader ontology term Parent identifier Note Data source
RET-rearranged non-small cell lung cancer RET+ NSCLC; RET fusion-positive NSCLC; RET-rearranged NSCLC; NSCLC harboring RET gene fusion Not identified in gathered evidence non-small cell lung carcinoma EFO_0003060 RET is an associated target for non-small cell lung carcinoma in Open Targets; disease-specific RET-fusion child term not retrieved (novello2023retfusionpositivenonsmall pages 1-2)
RET-rearranged non-small cell lung cancer RET+ NSCLC; RET fusion-positive NSCLC; RET-rearranged NSCLC; NSCLC harboring RET gene fusion Not identified in gathered evidence lung cancer MONDO_0008903 Open Targets returned lung cancer as a broader parent disease associated with RET (novello2023retfusionpositivenonsmall pages 1-2)
RET-rearranged non-small cell lung cancer RET+ NSCLC; RET fusion-positive NSCLC; RET-rearranged NSCLC; NSCLC harboring RET gene fusion Not identified in gathered evidence non-small cell squamous lung carcinoma MONDO_0056806 Returned in Open Targets results, but RET fusion-positive disease is typically discussed within NSCLC overall and especially adenocarcinoma-focused literature (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5)
RET-rearranged non-small cell lung cancer RET+ NSCLC; RET fusion-positive NSCLC; RET-rearranged NSCLC; NSCLC harboring RET gene fusion Specific MONDO term not found in gathered evidence Disease concept used in recent reviews and trials N/A Gathered evidence supports this as a molecularly defined NSCLC subtype, but a specific MONDO term for RET fusion-positive NSCLC was not found in the retrieved context (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5)

Table: This table summarizes the naming conventions and ontology context for RET-rearranged NSCLC using the gathered evidence. It is useful for mapping the disease concept to broader ontology terms when a specific MONDO entry was not identified in the retrieved sources.

Notes: The retrieved Open Targets output associates RET with non‑small cell lung carcinoma (EFO_0003060) and broader lung cancer MONDO terms, but did not surface a dedicated “RET fusion‑positive NSCLC” MONDO child term in the available context (novello2023retfusionpositivenonsmall pages 1-2).

1.3 Synonyms / alternative names

Common names used in recent reviews and trials include RET fusion‑positive NSCLC, RET‑rearranged NSCLC, and NSCLC harboring RET gene fusion (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5, spitaleri2024nonsmallcelllungcancers pages 1-2).

1.4 Evidence provenance

Most information below is derived from aggregated disease‑level resources (peer‑reviewed reviews, prospective clinical trials, retrospective real‑world cohorts), rather than single‑patient EHRs. The report includes both trial datasets (e.g., LIBRETTO‑431) and real‑world retrospective chart reviews (lei2024efficacyandsafety pages 1-2, zhou2023firstlineselpercatinibor pages 1-3).

2. Etiology

2.1 Disease causal factors

Primary causal factor: somatic RET gene fusion/rearrangement in lung tumor tissue, producing a chimeric oncoprotein with ligand‑independent kinase activity and downstream proliferative signaling (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5).

RET activation pathways include in‑frame gene fusions, point mutations, and overexpression; in RET‑rearranged NSCLC the dominant mechanism is gene fusion (shen2024recentprogressof pages 1-3, chen2024retinhibitorsin pages 1-3).

2.2 Risk factors

RET fusion‑positive NSCLC is enriched among patients with: - Adenocarcinoma histology, younger age, and never/light smoking history (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5). - A high propensity for CNS metastases (see Phenotypes) (novello2023retfusionpositivenonsmall pages 1-2, clark2023selectiveretinhibitors pages 1-2).

These are best considered clinical correlates/enriching features, not established causal environmental risk factors for acquiring a RET fusion.

2.3 Protective factors

No specific protective genetic variants or environmental protective factors were identified in the retrieved evidence.

2.4 Gene–environment interactions

No explicit RET‑fusion gene–environment interaction findings were retrieved.

3. Phenotypes

3.1 Core clinical phenotype and frequencies

RET fusion‑positive NSCLC shares “fusion‑driven NSCLC” clinical features: younger age, adenocarcinoma histology, low tobacco exposure, and elevated risk of brain metastases (spitaleri2024nonsmallcelllungcancers pages 1-2, spitaleri2024nonsmallcelllungcancers pages 2-4).

Reported CNS metastasis burden: - Brain metastasis present in ~25% at stage IV diagnosis and 46% lifetime prevalence in some summaries (gouda2023precisiononcologywith pages 2-4, clark2023selectiveretinhibitors pages 1-2).

Common metastatic sites in one cohort summary included lung (~50%), bone (~43%), pleura (~40%) (clark2023selectiveretinhibitors pages 1-2).

3.2 Suggested HPO term mapping

A phenotype-to-HPO structured mapping is provided here:

Table (click to expand)
Feature Frequency/notes Suggested HPO term(s) Evidence citation
Adenocarcinoma histology RET fusions occur most commonly in lung adenocarcinoma; molecular subtype is predominantly adenocarcinoma in multiple reviews and cohorts HP:0034347 Lung adenocarcinoma (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5)
Younger age at presentation Patients are generally younger than unselected NSCLC cohorts; reviews describe age \<=60 years, and one cohort summary reported median age 63 years HP:0003596 Middle age onset; HP:0011462 Young adult onset (clark2023selectiveretinhibitors pages 1-2, novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5)
Never/light smoking history Enriched in never-smokers or patients with minimal tobacco exposure; one review notes ~40% smokers, implying majority never/light smokers HP:0034433 History of tobacco smoking (annotate as often absent/minimal exposure in this subtype) (clark2023selectiveretinhibitors pages 1-2, novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5)
Female predominance Female predominance reported; one untreated cohort summary noted 56% female HP:0000132 Female sex (phenotypic descriptor often used in cohort annotation rather than disease phenotype) (clark2023selectiveretinhibitors pages 1-2, rocha2023importanceofthe pages 16-19)
Brain metastases at diagnosis About 25% of patients with stage IV RET fusion-positive NSCLC have brain metastases at diagnosis HP:0002518 Brain neoplasm; HP:0012735 Metastasis to brain (gouda2023precisiononcologywith pages 2-4, clark2023selectiveretinhibitors pages 1-2, chen2024retinhibitorsin pages 3-5)
Brain metastases over lifetime Lifetime prevalence of brain metastases reported as 46% HP:0012735 Metastasis to brain (novello2023retfusionpositivenonsmall pages 1-2)
Pulmonary metastatic involvement In advanced disease, lung was a common metastatic site in ~50% HP:0032264 Pulmonary metastases (clark2023selectiveretinhibitors pages 1-2)
Bone metastases Bone metastases reported in ~43% HP:0002664 Neoplasm of bone; HP:0012762 Bone metastases (clark2023selectiveretinhibitors pages 1-2)
Pleural metastases / pleural involvement Pleural metastatic involvement reported in ~40% HP:0032252 Pleural neoplasm; HP:0032263 Pleural metastases (clark2023selectiveretinhibitors pages 1-2)
Low PD-L1 expression Cohort summaries describe generally low PD-L1 expression, consistent with limited benefit from immunotherapy in many RET-driven tumors HP term not well matched; consider non-HPO biomarker annotation: low PD-L1 expression (clark2023selectiveretinhibitors pages 1-2)
Low tumor mutational burden Cohort summaries describe generally low TMB HP term not well matched; consider non-HPO biomarker annotation: low tumor mutational burden (clark2023selectiveretinhibitors pages 1-2)

Table: This table maps common clinical and demographic features of RET fusion-positive NSCLC to suggested HPO terms where possible. It is useful for structuring phenotype annotations while distinguishing features better captured as cohort descriptors or biomarkers rather than classic HPO disease phenotypes.

Quality‑of‑life impact: Quality‑of‑life (QoL) outcomes are increasingly reported in first‑line trials; LIBRETTO‑431 commentary notes fewer patients reported worsening with selpercatinib compared with chemotherapy (lee2024libretto431confirmingthe pages 2-4).

4. Genetic / Molecular Information

4.1 Causal gene(s)

4.2 Pathogenic alteration class

4.3 Common fusion partners

Frequent partners reported in recent reviews/cohorts: - KIF5B‑RET (often dominant; e.g., 40–70% in one review; 70–90% in another; 59.4% in a China real‑world cohort) (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5, wang2024evolutionoftreatment pages 1-2). - CCDC6‑RET (often ~15–30% or lower depending on cohort) and NCOA4‑RET (less frequent) (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5, lei2024efficacyandsafety pages 1-2).

4.4 Functional consequences and pathways

RET fusion signaling activates multiple downstream pathways (examples from recent mechanistic reviews): - RAS/MAPK, PI3K/AKT, and JAK/STAT (shen2024recentprogressof pages 1-3, chen2024retinhibitorsin pages 1-3, spitaleri2024nonsmallcelllungcancers pages 1-2).

Spitaleri et al. detail RET phosphotyrosine sites linked to specific pathways (e.g., Y1062 to Ras/MAPK and PI3K/AKT; Y752/Y928 to STAT3) (spitaleri2024nonsmallcelllungcancers pages 1-2).

4.5 Resistance mechanisms (current understanding)

Acquired resistance to first‑generation selective RET inhibitors includes: - On‑target kinase mutations, notably solvent‑front mutations at RET G810 (G810C/S/R) (shen2024recentprogressof pages 1-3, novello2023retfusionpositivenonsmall pages 8-9). - Gatekeeper mutation V804M and other resistance‑associated positions (chen2024retinhibitorsin pages 1-3, novello2023retfusionpositivenonsmall pages 8-9). - Off‑target/bypass mechanisms such as MET amplification, EGFR/AXL activation, and FGFR‑driven signaling with JAK/STAT activation described in model systems (rocco2023treatmentofadvanced pages 8-10, novello2023retfusionpositivenonsmall pages 8-9).

4.6 Model systems (mechanistic and resistance research)

  • Cell lines / patient-derived models used to study adaptive resistance include LC‑2/ad (CCDC6‑RET), ponatinib‑resistant derivatives, and patient‑derived RET‑fusion NSCLC lines (e.g., CUTO series) (rocco2023treatmentofadvanced pages 8-10).
  • Mouse model: a lung‑specific KIF5B‑RET transgenic mouse (SPC promoter) develops multifocal lung lesions and tumors; vandetanib reduced tumor burden in this model (saito2014amousemodel pages 1-2).

5. Environmental Information

RET fusion‑positive NSCLC is enriched in never/light smokers, suggesting it is not primarily tobacco‑driven; however, no specific environmental toxin, infectious, or lifestyle exposure was identified as causal for RET rearrangement in the retrieved evidence (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5).

6. Mechanism / Pathophysiology

6.1 Causal chain (high-level)

  1. Chromosomal rearrangement creates an expressed RET fusion retaining the RET kinase domain (chen2024retinhibitorsin pages 3-5, chen2024retinhibitorsin pages 1-3).
  2. Fusion partner contributes dimerization/transcriptional activation → ligand‑independent RET activation (chen2024retinhibitorsin pages 1-3, chen2024retinhibitorsin pages 3-5).
  3. Activated RET drives MAPK/PI3K/JAK‑STAT signaling → proliferation, survival, metastatic behavior (shen2024recentprogressof pages 1-3, spitaleri2024nonsmallcelllungcancers pages 1-2).
  4. Selective RET inhibition induces tumor regression; resistance emerges via on‑target mutation or bypass signaling (rocco2023treatmentofadvanced pages 8-10, novello2023retfusionpositivenonsmall pages 8-9).

6.2 Suggested GO biological process terms (examples)

6.3 Suggested Cell Ontology (CL) terms (examples)

7. Anatomical Structures Affected

7.1 Primary organ/system

Suggested UBERON: UBERON:0002048 lung.

7.2 Secondary organ involvement

Suggested UBERON: UBERON:0000955 brain.

7.3 Common metastatic sites

8. Temporal Development

8.1 Onset

Typically adult‑onset lung cancer, enriched in younger adults compared with unselected NSCLC cohorts (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5).

8.2 Progression

Often diagnosed at advanced stage; CNS metastases may be present at diagnosis and frequently develop during the disease course (clark2023selectiveretinhibitors pages 1-2, spitaleri2024nonsmallcelllungcancers pages 2-4).

9. Inheritance and Population

9.1 Epidemiology (RET fusion prevalence)

9.2 Inheritance

This is not a Mendelian inherited disorder; RET fusions in NSCLC are somatic cancer alterations.

9.3 Demographic patterns

RET fusion‑positive NSCLC is associated with adenocarcinoma histology, never/light smoking status, and female predominance in several cohorts/reviews (clark2023selectiveretinhibitors pages 1-2, wang2024evolutionoftreatment pages 1-2, novello2023retfusionpositivenonsmall pages 1-2).

10. Diagnostics

10.1 Recommended approach (current understanding)

Broad multiplex molecular profiling is emphasized in guidelines/reviews, with RNA‑based NGS commonly positioned as the preferred method for RET fusion detection because it detects expressed fusions and identifies fusion partners (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5).

A structured comparison of modalities:

Table (click to expand)
Modality What it detects Strengths Key limitations/pitfalls Guideline/recommendation notes Evidence citations
RNA-based NGS Expressed RET fusion transcripts, fusion partners, and transcript structure Preferred assay for RET fusions because of high sensitivity/specificity for expressed fusions; identifies known and novel partners; multiplexes with other actionable drivers; can clarify cases missed by DNA testing Requires high-quality RNA; FFPE degradation and low RNA yield can reduce assay success ESMO-cited guidance in reviews identifies RNA-NGS as the first-choice assay for RET fusion detection in NSCLC; broad multiplex testing is recommended in advanced NSCLC (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5) (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5)
DNA-based NGS Genomic rearrangements involving RET breakpoints and other co-alterations Broad genomic profiling in one test; useful when RNA is unavailable; concurrently detects mutations, copy-number changes, and co-mutations Lower sensitivity for fusion detection than RNA-based methods; intronic breakpoint complexity can cause false negatives; may not confirm transcriptionally active fusion Acceptable when RNA testing is unavailable, but reviews emphasize RNA-based NGS as preferable for RET fusions (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5) (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5)
RT-PCR Known RET fusion transcripts targeted by specific primers Rapid, relatively accessible, and can be highly sensitive for predefined fusion events; used in practice and in studies alongside NGS Detects only known/targeted fusions; misses novel partners; imbalance assays are less reliable; does not provide broad profiling Can be used where NGS is unavailable; in LIBRETTO-431 RET testing was done locally by NGS (58%) or RT-PCR (42%), showing real-world use in trial enrollment (spitaleri2024nonsmallcelllungcancers pages 9-11, chen2024retinhibitorsin pages 3-5) (spitaleri2024nonsmallcelllungcancers pages 9-11, lei2024efficacyandsafety pages 1-2, chen2024retinhibitorsin pages 3-5)
FISH RET rearrangement at the DNA level via break-apart probes Historically used; can detect rearrangement without prior knowledge of partner; available in many pathology labs Cannot identify fusion partner, exact breakpoint, or transcriptional activity; sensitivity varies by fusion partner; lower performance for some partners such as NCOA4; interpretation thresholds matter Considered an alternative where NGS is unavailable, but not preferred over multiplex NGS for contemporary practice (rocha2023importanceofthe pages 16-19, chen2024retinhibitorsin pages 3-5) (rocha2023importanceofthe pages 16-19, chen2024retinhibitorsin pages 3-5)
IHC RET protein expression Tissue-based, fast, and widely available as a pathology platform Poor standardization; false positives and false negatives reported; protein expression does not reliably indicate oncogenic RET fusion Reviews state IHC is not recommended as a screening tool for RET fusion-positive NSCLC (rocha2023importanceofthe pages 16-19, chen2024retinhibitorsin pages 3-5) (rocha2023importanceofthe pages 16-19, chen2024retinhibitorsin pages 3-5)
Liquid biopsy (cfDNA/cfRNA) Circulating RET alterations/fusions in plasma Minimally invasive; useful when tissue is limited or repeat biopsy is difficult; can support real-time monitoring and resistance assessment Negative plasma result does not exclude RET fusion because shedding/yield may be low; cfDNA may underperform for some fusions; cfRNA assays are less widely implemented Reviews note NGS can be applied to liquid samples, but tissue testing remains important if plasma is negative and suspicion remains high (gouda2023precisiononcologywith pages 2-4, rocha2023importanceofthe pages 16-19, novello2023retfusionpositivenonsmall pages 1-2) (gouda2023precisiononcologywith pages 2-4, rocha2023importanceofthe pages 16-19, novello2023retfusionpositivenonsmall pages 1-2)

Table: This table compares the main methods used to detect RET fusions in NSCLC, highlighting what each test measures, practical strengths, major pitfalls, and how recent reviews frame their clinical use. It is useful for understanding why RNA-based NGS is generally preferred while showing where RT-PCR, FISH, IHC, and liquid biopsy still fit in practice.

10.2 Recent development: rapid automated fusion testing (2024)

A 12‑center European evaluation of the automated RNA‑based Idylla™ GeneFusion Assay (RT‑PCR) in 326 FFPE advanced NSCLC samples reported RET fusion sensitivity 100% and specificity 99.3%, with ~3‑hour turnaround and low failure rate (0.9%) (melchior2024multicenterevaluationof pages 1-2).

10.3 Liquid biopsy

Liquid biopsy can detect RET alterations, but negative plasma testing does not exclude RET fusion due to variable ctDNA/cfRNA shedding; tissue testing remains important when feasible (gouda2023precisiononcologywith pages 2-4, rocha2023importanceofthe pages 16-19).

10.4 Differential diagnosis

Differential diagnosis is primarily at the molecular subtype level (other oncogene‑addicted NSCLCs such as EGFR/ALK/ROS1). RET fusions are often mutually exclusive with major other drivers, supporting their role as primary oncogenic drivers when present (chen2024retinhibitorsin pages 3-5).

11. Outcome / Prognosis

11.1 Outcomes with non‑RET inhibitor standards of care (historical / natural history)

  • In a registry described in Novello et al., chemotherapy outcomes included ORR 52%, PFS 6.6 months, and OS 23.6 months (novello2023retfusionpositivenonsmall pages 4-5).
  • Immunotherapy outcomes are often poor in RET‑driven tumors; a review summarizes real‑world/retrospective ICI activity of 0–23%, and reports IMMUNOTARGET ORR 6% and median PFS 2.1 months (chen2024retinhibitorsin pages 5-6).

11.2 Outcomes with selective RET inhibitors

Key recent efficacy/safety outcomes (2023–2024 and real‑world) are summarized here:

Table (click to expand)
Study/type Setting/line Drug N (if available) ORR mPFS OS metrics CNS/intracranial outcomes Notable grade >=3 AEs Publication (year, journal) and URL Citation
LIBRETTO-431, randomized phase III trial 1L advanced/metastatic RET fusion+ NSCLC; selpercatinib vs platinum/pemetrexed +/- pembrolizumab Selpercatinib vs chemo +/- pembro ITT ~261; 158 vs 98; ITT-pembrolizumab ~212; 129 vs 83 84% vs 65% 24.8 vs 11.2 months; HR ~0.46-0.48 OS not mature/not reported in retrieved evidence Without baseline CNS metastases: 12-mo cumulative CNS progression 1.1% vs 14.7% (HR 0.17); with baseline CNS metastases: intracranial ORR 81% vs 57%; reported CNS-protective effect Grade >=3 AEs 70% with selpercatinib; common lab abnormalities AST/ALT ~60%; hypertension 48%; dose reductions 51%, discontinuation 10% Pérol et al. 2024, J Clin Oncol; Spitaleri et al. 2024, Cancers. https://doi.org/10.1200/jco.24.00724 ; https://doi.org/10.3390/cancers16162877 (spitaleri2024nonsmallcelllungcancers pages 9-11)
ARROW, phase I/II trial (high-level) Advanced RET fusion+ NSCLC; treatment-naive and previously platinum-treated cohorts Pralsetinib Trial enrollment overall 590 on ClinicalTrials.gov; NSCLC cohort N not consistently extractable from retrieved context 72% treatment-naive; 59% prior platinum 13.0 months treatment-naive; 16.5 months prior chemo Not reported in retrieved evidence Intracranial ORR 70%; median intracranial PFS 10.5 months Grade >=3 TRAEs included neutropenia, hypertension, anemia ARROW/NCT03037385; Chen et al. 2024, Drugs. https://clinicaltrials.gov/study/NCT03037385 ; https://doi.org/10.1007/s40265-024-02040-5 (chen2024retinhibitorsin pages 8-10, NCT03037385 chunk 1)
LIBRETTO-001, phase I/II trial (high-level) Advanced RET fusion+ NSCLC; untreated and previously treated cohorts Selpercatinib ~316 total in one review summary; previously treated cohort 247 in one table excerpt Untreated 84%; previously treated ~61-61.5% Previously treated ~26.2 months in one review summary Not reported in retrieved evidence Intracranial ORR 85%; median intracranial PFS 19.4 months Common adverse reactions >=25% included edema, diarrhea, fatigue, dry mouth, hypertension Clark et al. 2023, Cancers; Chen et al. 2024, Drugs. https://doi.org/10.3390/cancers16010031 ; https://doi.org/10.1007/s40265-024-02040-5 (clark2023selectiveretinhibitors pages 4-5, chen2024retinhibitorsin pages 8-10, spitaleri2024nonsmallcelllungcancers pages 9-11)
Real-world retrospective chart review, China 1L advanced RET-rearranged NSCLC RET-TKI (study abstract indicates RET-TKI; retrieved context does not cleanly separate agent-specific outcomes) 51 73.1% 22.7 months (95% CI 11.7-33.7) Not reported Baseline brain metastasis subgroup: intracranial ORR 50%, DCR 100%; brain metastasis was a common treatment-failure pattern Grade >=3 decreased neutrophil count 11.4%; anemia 11.4% Lei et al. 2024, BMC Cancer. https://doi.org/10.1186/s12885-024-13155-z (lei2024efficacyandsafety pages 1-2)
Real-world retrospective chart review, China 2L advanced RET-rearranged NSCLC RET-TKI 51 total cohort 58.3% 17.7 months (95% CI 9.1-26.2) Not reported Brain metastasis common at progression; baseline brain metastasis subgroup intracranial ORR 50% Grade >=3 decreased neutrophil count 11.4%; anemia 11.4% Lei et al. 2024, BMC Cancer. https://doi.org/10.1186/s12885-024-13155-z (lei2024efficacyandsafety pages 1-2)
Real-world retrospective chart review, China Later-line advanced RET-rearranged NSCLC RET-TKI 51 total cohort 55.6% 14.7 months (95% CI 12.6-16.8) Not reported Brain metastasis common at progression Grade >=3 decreased neutrophil count 11.4%; anemia 11.4% Lei et al. 2024, BMC Cancer. https://doi.org/10.1186/s12885-024-13155-z (lei2024efficacyandsafety pages 1-2)
Real-world multicenter analysis, China Advanced RET-rearranged NSCLC, mixed lines Pralsetinib monotherapy 64 total RET-rearranged NSCLC patients; pralsetinib used in 48.4% Not reported in retrieved excerpt 16.03 months; vs chemotherapy 2.87 months, chemo+anti-angiogenic 6.90 months, multikinase inhibitors 2.50 months 1-year OS 64.3%; 2-year OS 46.4% Not reported in retrieved excerpt Any AE 71.0%; grade 3-4 AEs 45.2%; common AEs hemoglobin reduction 35.5%, neutropenia 32.3%; no AE-related deaths Wang et al. 2024, BMC Pulm Med. https://doi.org/10.1186/s12890-024-03371-5 (wang2024evolutionoftreatment pages 1-2)
Meta-analysis RET fusion+ NSCLC, pooled selective RET inhibitors Selpercatinib + pralsetinib (pooled) 8 studies pooled 67% pooled ORR 16.09 months pooled mPFS Not reported Intracranial ORR 86% pooled Major grade 3-4 AEs: neutropenia 13%, anemia 13% Ke et al. 2023, Investig New Drugs. https://doi.org/10.1007/s10637-023-01390-3 (novello2023retfusionpositivenonsmall pages 1-2)
Exploratory comparative effectiveness analysis 1L advanced/metastatic RET-activated cancers; NSCLC subgroup Selpercatinib vs standard therapies Not extractable for NSCLC subgroup from retrieved context 85.3% vs 39.7% (NSCLC) TTP HR 0.54; TTD HR 0.29; TTNT-D HR 0.48 Not directly reported Not reported Not detailed in retrieved excerpt Braud et al. 2023, Cancers. https://doi.org/10.3390/cancers16010140 (clark2023selectiveretinhibitors pages 4-5)

Table: This table summarizes key efficacy, CNS activity, and safety outcomes for selective RET inhibitors in RET fusion-positive NSCLC, emphasizing 2023-2024 trial and real-world evidence. It is useful for comparing first-line randomized data with retrospective practice-based outcomes and pooled estimates.

Definitive first‑line randomized evidence: NEJM 2023 LIBRETTO‑431 abstract states: “Treatment with selpercatinib led to significantly longer progression‑free survival than platinum‑based chemotherapy with or without pembrolizumab among patients with advanced RET fusion‑positive NSCLC” and reports median PFS 24.8 vs 11.2 months (HR 0.46; P<0.001) with ORR 84% vs 65% (zhou2023firstlineselpercatinibor pages 1-3).

11.3 Prognostic factors

  • Fusion partner may be prognostic: Chen et al. summarize median OS differences by partner (e.g., 52.8 vs 38.5 vs 19.1 months for CCDC6 vs other vs KIF5B in a cited dataset) (chen2024retinhibitorsin pages 8-10).
  • Performance status: In a 2024 China real‑world cohort, poor ECOG performance status was associated with shorter PFS (P=0.018) (lei2024efficacyandsafety pages 1-2).

12. Treatment

12.1 Standard targeted therapies (current practice)

Recent authoritative reviews state that selective RET inhibitors selpercatinib and pralsetinib are preferred first‑line options for metastatic RET fusion‑positive NSCLC and recommended subsequently if not used first‑line (novello2023retfusionpositivenonsmall pages 1-2, novello2023retfusionpositivenonsmall pages 8-9).

Mechanism/class: selective RET TKIs (ATP‑competitive RET kinase inhibition) (gouda2023precisiononcologywith pages 2-4).

MAXO suggestions: - MAXO:0001020 pharmacotherapy
- MAXO:0000148 targeted therapy (suggested)
- MAXO:0000747 tyrosine kinase inhibitor therapy (suggested)

12.2 Key 2023–2024 developments

12.3 Treatment sequencing after progression

After progression on selective RET inhibitors, evidence‑synthesis reviews commonly cite: - Chemotherapy, especially pemetrexed‑based regimens, as a reasonable option in the refractory setting (chen2024retinhibitorsin pages 6-8, chen2024retinhibitorsin pages 5-6). - Resistance‑directed strategies under investigation: next‑generation RET inhibitors (e.g., TPX‑0046, LOXO‑260, TAS0953/HM06) intended to overcome solvent‑front resistance (novello2023retfusionpositivenonsmall pages 8-9). - Combination strategies for bypass or acquired fusions (e.g., selpercatinib + osimertinib for EGFR‑mutant NSCLC with acquired RET fusion; reported response rate 50% in evaluable patients, median duration of response 11 months) (novello2023retfusionpositivenonsmall pages 8-9).

12.4 Real-world implementation and treatment patterns

A 2024 multicenter China cohort (n=64) reported use of pralsetinib in 48.4% of patients and substantially longer median PFS with pralsetinib than chemotherapy or multitarget inhibitors (wang2024evolutionoftreatment pages 1-2).

13. Prevention

RET fusions themselves are not currently preventable at the molecular level; prevention is primarily through lung cancer risk reduction and early detection.

13.1 Primary prevention

  • Smoking cessation is emphasized in lung cancer prevention and screening guidance; ACS recommends cessation counseling and pharmacotherapy for current smokers considering screening (wolf2024screeningforlung pages 7-7).

13.2 Secondary prevention (screening / early detection)

American Cancer Society (ACS) guideline update (published Nov 2024; “2023 guideline update”): recommends annual low‑dose CT (LDCT) for asymptomatic individuals aged 50–80 with ≥20 pack‑year smoking history (current or former smokers), and recommends not using years‑since‑quitting as an eligibility criterion (wolf2024screeningforlung pages 7-7, wolf2024screeningforlung pages 2-3).

This screening guidance is not RET‑specific, but determines the population in which early lung cancer (including RET‑rearranged disease) may be detected.

14. Other Species / Natural Disease

No naturally occurring RET fusion‑driven lung cancer in non‑human species was identified in the retrieved evidence.

15. Model Organisms

15.1 Engineered mouse models

A lung‑specific KIF5B‑RET transgenic mouse model (SPC promoter; C57BL/6J background) develops multifocal lung hyperplasias/adenomas/adenocarcinomas; this model was used to test vandetanib treatment and tumor suppression (saito2014amousemodel pages 1-2).

15.2 Cellular models (in vitro)

Multiple RET fusion‑positive NSCLC cell models (including LC‑2/ad and patient‑derived lines) have been used to study pathway inhibition, adaptive resistance, and bypass activation (rocco2023treatmentofadvanced pages 8-10).

Key recent statistics (2023–2024 emphasis)

Evidence notes and gaps

  • PMIDs: The retrieved context includes DOI/journal metadata and narrative claims but does not consistently provide PMIDs. Where PMIDs are required for every claim, additional PubMed cross‑referencing would be needed beyond the current retrieved evidence set.
  • ICD‑10/ICD‑11/MeSH/Orphanet/OMIM/MONDO child term: Specific identifiers for “RET fusion‑positive NSCLC” were not present in the retrieved evidence; only parent NSCLC terms were identified via Open Targets output (novello2023retfusionpositivenonsmall pages 1-2).

URLs and publication dates (selected primary sources)

References

  1. (novello2023retfusionpositivenonsmall pages 1-2): Silvia Novello, Raffaele Califano, Niels Reinmuth, Antonella Tamma, and Tarun Puri. Ret fusion-positive non-small cell lung cancer: the evolving treatment landscape. The Oncologist, 28:402-413, Feb 2023. URL: https://doi.org/10.1093/oncolo/oyac264, doi:10.1093/oncolo/oyac264. This article has 51 citations.

  2. (chen2024retinhibitorsin pages 3-5): Monica F. Chen, Matteo Repetto, Clare Wilhelm, and Alexander Drilon. Ret inhibitors in ret fusion-positive lung cancers: past, present, and future. Drugs, 84:1035-1053, Jul 2024. URL: https://doi.org/10.1007/s40265-024-02040-5, doi:10.1007/s40265-024-02040-5. This article has 13 citations and is from a domain leading peer-reviewed journal.

  3. (rocco2023treatmentofadvanced pages 5-6): Danilo Rocco, Luigi Sapio, Luigi Della Gravara, Silvio Naviglio, and Cesare Gridelli. Treatment of advanced non-small cell lung cancer with ret fusions: reality and hopes. International Journal of Molecular Sciences, 24:2433, Jan 2023. URL: https://doi.org/10.3390/ijms24032433, doi:10.3390/ijms24032433. This article has 20 citations.

  4. (zhou2023firstlineselpercatinibor pages 1-3): Caicun Zhou, Benjamin Solomon, Herbert H. Loong, Keunchil Park, Maurice Pérol, Edurne Arriola, Silvia Novello, Baohui Han, Jianying Zhou, Andrea Ardizzoni, M. Perez Mak, Fernando C. Santini, Yasir Y. Elamin, Alexander Drilon, Jürgen Wolf, Nalin Payakachat, Minji K. Uh, Deborah Rajakumar, Hongmei Han, Tarun Puri, Victoria Soldatenkova, A. Bence Lin, Boris K. Lin, and Koichi Goto. First-line selpercatinib or chemotherapy and pembrolizumab in ret fusion–positive nsclc. New England Journal of Medicine, 389:1839-1850, Nov 2023. URL: https://doi.org/10.1056/nejmoa2309457, doi:10.1056/nejmoa2309457. This article has 218 citations and is from a highest quality peer-reviewed journal.

  5. (spitaleri2024nonsmallcelllungcancers pages 1-2): Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro, and Filippo de Marinis. Non-small-cell lung cancers (nsclcs) harboring ret gene fusion, from their discovery to the advent of new selective potent ret inhibitors: “shadows and fogs”. Cancers, 16:2877, Aug 2024. URL: https://doi.org/10.3390/cancers16162877, doi:10.3390/cancers16162877. This article has 7 citations.

  6. (lei2024efficacyandsafety pages 1-2): Siyu Lei, Linyan Tian, Lu Yang, Yaning Yang, Junling Li, Xingsheng Hu, Xuezhi Hao, Haiyan Xu, and Yan Wang. Efficacy and safety of ret-tki in advanced ret-rearranged non-small cell lung cancer in china: a real-world retrospective chart review. BMC Cancer, Nov 2024. URL: https://doi.org/10.1186/s12885-024-13155-z, doi:10.1186/s12885-024-13155-z. This article has 0 citations and is from a peer-reviewed journal.

  7. (shen2024recentprogressof pages 1-3): Jiayi Shen, Liping Chen, Yulan Song, Sheng Chen, Wei Guo, and Yongdong Li. Recent progress of small-molecule of ret inhibitors against non-small cell lung cancer. AAPS Open, Jun 2024. URL: https://doi.org/10.1186/s41120-024-00094-z, doi:10.1186/s41120-024-00094-z. This article has 3 citations.

  8. (chen2024retinhibitorsin pages 1-3): Monica F. Chen, Matteo Repetto, Clare Wilhelm, and Alexander Drilon. Ret inhibitors in ret fusion-positive lung cancers: past, present, and future. Drugs, 84:1035-1053, Jul 2024. URL: https://doi.org/10.1007/s40265-024-02040-5, doi:10.1007/s40265-024-02040-5. This article has 13 citations and is from a domain leading peer-reviewed journal.

  9. (clark2023selectiveretinhibitors pages 1-2): Lisa Clark, Geoff Fisher, Sue Brook, Sital Patel, and Hendrik-Tobias Arkenau. Selective ret inhibitors (sris) in cancer: a journey from multi-kinase inhibitors to the next generation of sris. Cancers, 16:31, Dec 2023. URL: https://doi.org/10.3390/cancers16010031, doi:10.3390/cancers16010031. This article has 10 citations.

  10. (spitaleri2024nonsmallcelllungcancers pages 2-4): Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro, and Filippo de Marinis. Non-small-cell lung cancers (nsclcs) harboring ret gene fusion, from their discovery to the advent of new selective potent ret inhibitors: “shadows and fogs”. Cancers, 16:2877, Aug 2024. URL: https://doi.org/10.3390/cancers16162877, doi:10.3390/cancers16162877. This article has 7 citations.

  11. (gouda2023precisiononcologywith pages 2-4): Mohamed A. Gouda and Vivek Subbiah. Precision oncology with selective ret inhibitor selpercatinib in ret-rearranged cancers. Therapeutic Advances in Medical Oncology, Jun 2023. URL: https://doi.org/10.1177/17588359231177015, doi:10.1177/17588359231177015. This article has 21 citations and is from a peer-reviewed journal.

  12. (rocha2023importanceofthe pages 16-19): ABMA Rocha. Importance of the ret mutation in lung cancer. Unknown journal, 2023.

  13. (lee2024libretto431confirmingthe pages 2-4): Alexandria Lee and Sai-Hong Ou. Libretto-431: confirming the superiority of selpercatinib to chemotherapy and the lack of efficacy of immune checkpoint inhibitors in advanced ret fusion-positive (ret+) nsclc, another unique never-smoker predominant molecular subtype of nsclc. Lung Cancer: Targets and Therapy, 15:75-80, May 2024. URL: https://doi.org/10.2147/lctt.s460147, doi:10.2147/lctt.s460147. This article has 6 citations.

  14. (wang2024evolutionoftreatment pages 1-2): An Wang, Tao Li, Yun-ye Mao, Ming Gao, Sheng Shu, Chang-hong Xia, Yi Dong, Min Liu, Jin-liang Wang, Jun-xun Ma, and Yi Hu. Evolution of treatment strategies for solid tumors with ret rearrangement in china and real-world treatment status of non-small cell lung cancer (nsclc). BMC Pulmonary Medicine, Nov 2024. URL: https://doi.org/10.1186/s12890-024-03371-5, doi:10.1186/s12890-024-03371-5. This article has 2 citations and is from a peer-reviewed journal.

  15. (novello2023retfusionpositivenonsmall pages 8-9): Silvia Novello, Raffaele Califano, Niels Reinmuth, Antonella Tamma, and Tarun Puri. Ret fusion-positive non-small cell lung cancer: the evolving treatment landscape. The Oncologist, 28:402-413, Feb 2023. URL: https://doi.org/10.1093/oncolo/oyac264, doi:10.1093/oncolo/oyac264. This article has 51 citations.

  16. (rocco2023treatmentofadvanced pages 8-10): Danilo Rocco, Luigi Sapio, Luigi Della Gravara, Silvio Naviglio, and Cesare Gridelli. Treatment of advanced non-small cell lung cancer with ret fusions: reality and hopes. International Journal of Molecular Sciences, 24:2433, Jan 2023. URL: https://doi.org/10.3390/ijms24032433, doi:10.3390/ijms24032433. This article has 20 citations.

  17. (saito2014amousemodel pages 1-2): Motonobu Saito, Teruhide Ishigame, Koji Tsuta, Kensuke Kumamoto, Toshio Imai, and Takashi Kohno. A mouse model of kif5b-ret fusion-dependent lung tumorigenesis. Carcinogenesis, 35 11:2452-6, Nov 2014. URL: https://doi.org/10.1093/carcin/bgu158, doi:10.1093/carcin/bgu158. This article has 59 citations and is from a peer-reviewed journal.

  18. (spitaleri2024nonsmallcelllungcancers pages 9-11): Gianluca Spitaleri, Pamela Trillo Aliaga, Ilaria Attili, Ester Del Signore, Carla Corvaja, Gloria Pellizzari, Jalissa Katrini, Antonio Passaro, and Filippo de Marinis. Non-small-cell lung cancers (nsclcs) harboring ret gene fusion, from their discovery to the advent of new selective potent ret inhibitors: “shadows and fogs”. Cancers, 16:2877, Aug 2024. URL: https://doi.org/10.3390/cancers16162877, doi:10.3390/cancers16162877. This article has 7 citations.

  19. (melchior2024multicenterevaluationof pages 1-2): Linea Melchior, Astrid Hirschmann, Paul Hofman, Christophe Bontoux, Angel Concha, Salima Mrabet-Dahbi, Pascal Vannuffel, Emmanuel Watkin, Martina Putzová, Stefania Scarpino, Anne Cayre, Paloma Martin, Robert Stoehr, and Arndt Hartmann. Multicenter evaluation of an automated, multiplex, rna-based molecular assay for detection of alk, ros1, ret fusions and met exon 14 skipping in nsclc. Virchows Archiv, 484:677-686, Mar 2024. URL: https://doi.org/10.1007/s00428-024-03778-9, doi:10.1007/s00428-024-03778-9. This article has 5 citations and is from a peer-reviewed journal.

  20. (novello2023retfusionpositivenonsmall pages 4-5): Silvia Novello, Raffaele Califano, Niels Reinmuth, Antonella Tamma, and Tarun Puri. Ret fusion-positive non-small cell lung cancer: the evolving treatment landscape. The Oncologist, 28:402-413, Feb 2023. URL: https://doi.org/10.1093/oncolo/oyac264, doi:10.1093/oncolo/oyac264. This article has 51 citations.

  21. (chen2024retinhibitorsin pages 5-6): Monica F. Chen, Matteo Repetto, Clare Wilhelm, and Alexander Drilon. Ret inhibitors in ret fusion-positive lung cancers: past, present, and future. Drugs, 84:1035-1053, Jul 2024. URL: https://doi.org/10.1007/s40265-024-02040-5, doi:10.1007/s40265-024-02040-5. This article has 13 citations and is from a domain leading peer-reviewed journal.

  22. (chen2024retinhibitorsin pages 8-10): Monica F. Chen, Matteo Repetto, Clare Wilhelm, and Alexander Drilon. Ret inhibitors in ret fusion-positive lung cancers: past, present, and future. Drugs, 84:1035-1053, Jul 2024. URL: https://doi.org/10.1007/s40265-024-02040-5, doi:10.1007/s40265-024-02040-5. This article has 13 citations and is from a domain leading peer-reviewed journal.

  23. (NCT03037385 chunk 1): Phase 1/2 Study of the Highly-selective RET Inhibitor, Pralsetinib (BLU-667), in Participants With Thyroid Cancer, Non-Small Cell Lung Cancer, and Other Advanced Solid Tumors. Hoffmann-La Roche. 2017. ClinicalTrials.gov Identifier: NCT03037385

  24. (clark2023selectiveretinhibitors pages 4-5): Lisa Clark, Geoff Fisher, Sue Brook, Sital Patel, and Hendrik-Tobias Arkenau. Selective ret inhibitors (sris) in cancer: a journey from multi-kinase inhibitors to the next generation of sris. Cancers, 16:31, Dec 2023. URL: https://doi.org/10.3390/cancers16010031, doi:10.3390/cancers16010031. This article has 10 citations.

  25. (perol2024cnsprotectiveeffect pages 3-4): Maurice Pérol, Benjamin J. Solomon, Koichi Goto, Keunchil Park, Ernest Nadal, Emilio Bria, Claudio Martin, Jair Bar, Justin N. Williams, Tarun Puri, Jian Li, Minji K. Uh, Boris K. Lin, and Caicun Zhou. Cns protective effect of selpercatinib in first-line ret fusion-positive advanced non–small cell lung cancer. Journal of Clinical Oncology, 42:2500-2505, Jul 2024. URL: https://doi.org/10.1200/jco.24.00724, doi:10.1200/jco.24.00724. This article has 14 citations and is from a highest quality peer-reviewed journal.

  26. (chen2024retinhibitorsin pages 6-8): Monica F. Chen, Matteo Repetto, Clare Wilhelm, and Alexander Drilon. Ret inhibitors in ret fusion-positive lung cancers: past, present, and future. Drugs, 84:1035-1053, Jul 2024. URL: https://doi.org/10.1007/s40265-024-02040-5, doi:10.1007/s40265-024-02040-5. This article has 13 citations and is from a domain leading peer-reviewed journal.

  27. (wolf2024screeningforlung pages 7-7): Andrew M. D. Wolf, Kevin C. Oeffinger, Tina Ya‐Chen Shih, Louise C. Walter, Timothy R. Church, Elizabeth T. H. Fontham, Elena B. Elkin, Ruth D. Etzioni, Carmen E. Guerra, Rebecca B. Perkins, Karli K. Kondo, Tyler B. Kratzer, Deana Manassaram‐Baptiste, William L. Dahut, and Robert A. Smith. Screening for lung cancer: 2023 guideline update from the american cancer society. CA: A Cancer Journal for Clinicians, 74:50-81, Nov 2024. URL: https://doi.org/10.3322/caac.21811, doi:10.3322/caac.21811. This article has 398 citations and is from a domain leading peer-reviewed journal.

  28. (wolf2024screeningforlung pages 2-3): Andrew M. D. Wolf, Kevin C. Oeffinger, Tina Ya‐Chen Shih, Louise C. Walter, Timothy R. Church, Elizabeth T. H. Fontham, Elena B. Elkin, Ruth D. Etzioni, Carmen E. Guerra, Rebecca B. Perkins, Karli K. Kondo, Tyler B. Kratzer, Deana Manassaram‐Baptiste, William L. Dahut, and Robert A. Smith. Screening for lung cancer: 2023 guideline update from the american cancer society. CA: A Cancer Journal for Clinicians, 74:50-81, Nov 2024. URL: https://doi.org/10.3322/caac.21811, doi:10.3322/caac.21811. This article has 398 citations and is from a domain leading peer-reviewed journal.