RET-rearranged non-small cell lung cancer (NSCLC) is a molecularly-defined lung cancer subtype driven by chromosomal rearrangements involving the RET proto-oncogene. RET fusions occur in approximately 1-2% of NSCLC and result in constitutive activation of the RET receptor tyrosine kinase. Like ALK and ROS1 fusions, RET-positive NSCLC occurs predominantly in younger patients with minimal smoking history. Selpercatinib and pralsetinib are highly selective RET inhibitors that have transformed outcomes for patients with RET-driven cancers.
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name: RET-Rearranged Non-Small Cell Lung Cancer
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-06T15:56:14Z'
description: >-
RET-rearranged non-small cell lung cancer (NSCLC) is a molecularly-defined lung
cancer subtype driven by chromosomal rearrangements involving the RET proto-oncogene.
RET fusions occur in approximately 1-2% of NSCLC and result in constitutive activation
of the RET receptor tyrosine kinase. Like ALK and ROS1 fusions, RET-positive NSCLC
occurs predominantly in younger patients with minimal smoking history. Selpercatinib
and pralsetinib are highly selective RET inhibitors that have transformed outcomes
for patients with RET-driven cancers.
categories:
- Molecularly-Defined Cancer
- Lung Cancer Subtype
- Fusion Gene-Driven Cancer
- Solid Tumor
parents:
- non-small cell lung carcinoma
has_subtypes:
- name: KIF5B-RET NSCLC
description: >-
KIF5B-RET is the most common RET fusion in NSCLC (~70-90%), resulting from a
pericentric inversion on chromosome 10. The kinesin family member provides a
coiled-coil dimerization domain.
- name: CCDC6-RET NSCLC
description: >-
CCDC6-RET accounts for approximately 15-20% of RET fusions in NSCLC. Also
common in papillary thyroid carcinoma (PTC1).
- name: NCOA4-RET NSCLC
description: >-
NCOA4-RET is a less common fusion variant, also found in thyroid cancer
(PTC3).
pathophysiology:
- name: RET Gene Rearrangement
description: >-
RET rearrangements result from chromosomal inversions or translocations that
fuse the RET kinase domain (10q11.21) to an N-terminal partner gene. The partner
gene provides a dimerization domain, causing constitutive RET kinase activation
independent of ligand. RET normally signals through GDNF family ligands and
GFR-alpha co-receptors.
evidence:
- reference: PMID:38110308
reference_title: "[Chinese expert consensus on the diagnosis and treatment of advanced RET fusion-positive non-small cell lung cancer (2023 edition)]."
supports: PARTIAL
snippet: "Nearly 1% to 2% of NSCLCs harbor RET fusions, and this patient population may not respond well to traditional treatments like chemotherapy or radiation therapy."
explanation: "Supports the presence of RET fusions in a subset of NSCLC."
cell_types:
- preferred_term: type II pneumocyte
term:
id: CL:0002063
label: pulmonary alveolar type 2 cell
biological_processes:
- preferred_term: protein phosphorylation
modifier: INCREASED
term:
id: GO:0006468
label: protein phosphorylation
downstream:
- target: Constitutive RET Signaling
description: Fusion protein is constitutively active
- name: Constitutive RET Signaling
description: >-
RET fusion proteins are constitutively dimerized and auto-phosphorylated,
activating downstream signaling including RAS-MAPK, PI3K-AKT, and PLCgamma
pathways. RET also activates SRC family kinases and JAK-STAT signaling.
biological_processes:
- preferred_term: MAPK cascade
modifier: INCREASED
term:
id: GO:0000165
label: MAPK cascade
- preferred_term: phosphatidylinositol 3-kinase signaling
modifier: INCREASED
term:
id: GO:0043491
label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
downstream:
- target: Oncogene Addiction
description: Tumor survival dependent on RET activity
- name: Oncogene Addiction
description: >-
RET-rearranged tumors exhibit oncogene addiction, becoming dependent on
continued RET signaling for survival. Selective RET inhibition leads to
rapid and durable tumor responses.
biological_processes:
- preferred_term: cell population proliferation
modifier: INCREASED
term:
id: GO:0008283
label: cell population proliferation
downstream:
- target: RET Inhibitor Resistance
description: Selective pressure from RET-targeted therapy drives emergence of resistance mutations and bypass pathways.
- name: RET Inhibitor Resistance
description: >-
Resistance to selective RET inhibitors can develop through secondary RET
kinase mutations (G810R/S/C solvent front mutations, V804L/M gatekeeper),
RET amplification, or bypass pathway activation (MET, KRAS, BRAF, SRC).
RET-independent bypass resistance such as acquired MET or KRAS amplification
is common, so post-progression molecular profiling is important.
evidence:
- reference: PMID:31988000
reference_title: RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: G810R, G810S, and G810C mutations
explanation: Supports RET G810 solvent-front mutations as acquired resistance mechanisms after selective RET inhibition.
- reference: PMID:33007380
reference_title: Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Three resistant cases (15%) harbored acquired MET amplification
explanation: Supports acquired MET amplification as a RET-independent bypass resistance mechanism.
- reference: PMID:41194587
reference_title: Dual targeting of RET and SRC synergizes in RET fusion-positive cancer cells.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: multitargeted SRC TKI dasatinib significantly enhanced
explanation: Supports SRC as a targetable bypass interaction with RET inhibition in RET fusion-positive NSCLC cells.
biological_processes:
- preferred_term: response to drug
modifier: ABNORMAL
term:
id: GO:0009410
label: response to xenobiotic stimulus
histopathology:
- name: Adenocarcinoma Predominance
finding_term:
preferred_term: Lung Adenocarcinoma
term:
id: NCIT:C3512
label: Lung Adenocarcinoma
frequency: VERY_FREQUENT
description: Adenocarcinoma is the most common histologic subtype in NSCLC.
evidence:
- reference: PMID:32657049
reference_title: "Genetic profile of non-small cell lung cancer (NSCLC): A hospital-based survey in Jinhua."
supports: PARTIAL
snippet: "Of 256 patients with NSCLC, 219 were adenocarcinoma"
explanation: Abstract reports a NSCLC cohort dominated by adenocarcinoma.
phenotypes:
- category: Neoplastic
name: Lung Adenocarcinoma
frequency: VERY_FREQUENT
description: >-
RET-rearranged NSCLC is almost exclusively adenocarcinoma histology.
Typically presents in younger patients.
phenotype_term:
preferred_term: Lung adenocarcinoma
term:
id: HP:0030078
label: Lung adenocarcinoma
- category: Clinical
name: Young Age at Diagnosis
frequency: VERY_FREQUENT
description: >-
RET-positive patients are typically younger than average NSCLC patients,
similar to ALK/ROS1 demographics (median age ~60).
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
- category: Clinical
name: Never/Light Smoker
frequency: VERY_FREQUENT
description: >-
Like other fusion-driven NSCLC, RET-positive tumors occur predominantly
in never-smokers or light smokers.
phenotype_term:
preferred_term: Neoplasm of the lung
term:
id: HP:0100526
label: Neoplasm of the lung
- category: Clinical
name: Brain Metastases
frequency: FREQUENT
description: >-
Brain metastases occur in approximately 25-45% of RET-positive NSCLC patients.
Selpercatinib has excellent CNS penetration and demonstrated intracranial
activity.
phenotype_term:
preferred_term: Neoplasm of the nervous system
term:
id: HP:0004375
label: Neoplasm of the nervous system
biochemical:
- name: RET Testing
notes: >-
RET testing is recommended for all advanced non-squamous NSCLC. Methods include
FISH, immunohistochemistry (screening), and next-generation sequencing (identifies
fusion partner). RNA-based NGS is preferred as it detects expressed fusions.
RET fusions are mutually exclusive with EGFR, ALK, ROS1, and KRAS alterations.
genetic:
- name: RET
association: Somatic Rearrangement
inheritance:
- name: Somatic
notes: >-
RET (10q11.21) encodes the rearranged during transfection receptor tyrosine
kinase. Gene rearrangements occur somatically. Common fusion partners in NSCLC
include KIF5B (~70-90%), CCDC6 (~15-20%), and NCOA4. Germline RET mutations
cause MEN2 syndrome; somatic RET fusions drive lung and thyroid cancers.
Resistance mutations include G810R/S/C (solvent front) and V804L/M (gatekeeper).
evidence:
- reference: PMID:35220468
reference_title: "The genomic characteristics of RET fusion positive tumors in Chinese non-small cell lung cancer (NSCLC) patients."
supports: PARTIAL
snippet: "Approximately 1-2% of non-small cell lung cancer (NSCLC) patients harbor RET (rearranged during transfection) fusions."
explanation: "Abstract reports the frequency of RET fusions in NSCLC."
- name: KIF5B
association: Fusion Partner
inheritance:
- name: Somatic
notes: >-
KIF5B (10p11.22) encodes kinesin family member 5B. Most common RET fusion partner
in NSCLC. The pericentric inversion on chromosome 10 brings KIF5B coiled-coil
domain to RET kinase domain.
treatments:
- name: Selpercatinib
description: >-
Highly selective RET inhibitor approved for RET fusion-positive NSCLC based
on LIBRETTO-001 and supported as first-line therapy by LIBRETTO-431. Excellent
CNS penetration with demonstrated intracranial activity. Well-tolerated with
manageable side effects (hypertension, LFT elevation).
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: selpercatinib
term:
id: NCIT:C134987
label: Selpercatinib
evidence:
- reference: PMID:37870973
reference_title: First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: median progression-free survival was 24.8 months
explanation: LIBRETTO-431 supports first-line selpercatinib over platinum chemotherapy with or without pembrolizumab.
- reference: PMID:36122315
reference_title: "Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: intracranial ORR was 85%
explanation: LIBRETTO-001 updated analysis supports intracranial activity of selpercatinib in measurable CNS metastases.
- name: Pralsetinib
description: >-
Selective RET inhibitor approved for RET fusion-positive NSCLC based on
ARROW trial. Active in treatment-naive and previously treated patients,
including intracranial responses in patients with measurable CNS metastases.
Side effects include hypertension and pneumonitis.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: pralsetinib
term:
id: NCIT:C132295
label: Pralsetinib
evidence:
- reference: PMID:35973665
reference_title: "Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The ORR was 72%
explanation: ARROW update supports pralsetinib activity in treatment-naive RET fusion-positive NSCLC.
- reference: PMID:35973665
reference_title: "Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: intracranial response rate was 70%
explanation: ARROW update supports intracranial activity of pralsetinib.
- name: Cabozantinib
description: >-
Multi-kinase inhibitor (RET/VEGFR/MET) with RET activity. Less selective
than selpercatinib/pralsetinib, used historically before selective inhibitors
were available. More toxicity due to VEGFR inhibition.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: cabozantinib
term:
id: CHEBI:72317
label: cabozantinib
- name: Immunotherapy
description: >-
Checkpoint inhibitors may be used for RET-positive NSCLC at progression,
though driver-positive tumors often have lower response rates and retrospective
RET-fusion cohorts have not shown the same survival improvement seen with
selective RET inhibitors.
treatment_term:
preferred_term: immunotherapy
term:
id: NCIT:C15262
label: Immunotherapy
evidence:
- reference: PMID:35838839
reference_title: Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: treated with immunotherapy versus untreated patients
explanation: Retrospective RET fusion-positive cohort did not show a survival difference for immunotherapy versus untreated patients.
- name: Chemotherapy
description: >-
Platinum-based chemotherapy (pemetrexed-based) used at progression on
RET inhibitors or historically before RET inhibitors were available.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
disease_term:
preferred_term: lung adenocarcinoma
term:
id: MONDO:0005061
label: lung adenocarcinoma
classifications:
icdo_morphology:
classification_value: Carcinoma
harrisons_chapter:
- classification_value: cancer
- classification_value: solid tumor
references:
- reference: PMID:37603207
title: 'The efficacy and safety of selective RET inhibitors in RET fusion-positive non-small cell lung cancer: a meta-analysis.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Selective RET inhibitors have clinical activity in RET fusion-positive NSCLC.
supporting_text: selective RET inhibitors in treating RET fusion-positive NSCLC
evidence:
- reference: PMID:37603207
reference_title: 'The efficacy and safety of selective RET inhibitors in RET fusion-positive non-small cell lung cancer: a meta-analysis.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: selective RET inhibitors in treating RET fusion-positive NSCLC
explanation: OpenScientist cited this meta-analysis as relevant evidence for selective RET inhibitor activity in RET fusion-positive NSCLC.
- reference: PMID:38807655
title: '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.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: LIBRETTO-431 supports first-line selpercatinib over chemotherapy in advanced RET fusion-positive NSCLC.
supporting_text: significant improvement in progression-free
evidence:
- reference: PMID:38807655
reference_title: '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.'
supports: SUPPORT
evidence_source: OTHER
snippet: significant improvement in progression-free
explanation: OpenScientist cited this LIBRETTO-431 commentary for targeted therapy and immunotherapy context in RET fusion-positive NSCLC.
- reference: PMID:39497173
title: Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC).
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Real-world data support pralsetinib activity in advanced RET rearranged NSCLC.
supporting_text: Pralsetinib monotherapy demonstrated a median
evidence:
- reference: PMID:39497173
reference_title: Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC).
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Pralsetinib monotherapy demonstrated a median
explanation: OpenScientist cited this real-world analysis as evidence for RET inhibitor effectiveness in advanced RET rearranged NSCLC.
- reference: PMID:39563271
title: 'Efficacy and safety of RET-TKI in advanced RET-rearranged non-small cell lung cancer in China: a real-world retrospective chart review.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Real-world RET-TKI treatment produced objective responses in advanced RET-rearranged NSCLC.
supporting_text: RET-TKI induced an ORR
evidence:
- reference: PMID:39563271
reference_title: 'Efficacy and safety of RET-TKI in advanced RET-rearranged non-small cell lung cancer in China: a real-world retrospective chart review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: RET-TKI induced an ORR
explanation: OpenScientist cited this real-world chart review for RET-TKI efficacy and safety in advanced RET-rearranged NSCLC.
- reference: DOI:10.1007/s00428-024-03778-9
title: Multicenter evaluation of an automated, multiplex, RNA-based molecular assay for detection of ALK, ROS1, RET fusions and MET exon 14 skipping in NSCLC
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: Multicenter evaluation of an automated, multiplex, RNA-based molecular assay for detection of ALK, ROS1, RET fusions and MET exon 14 skipping in NSCLC
supporting_text: The current study assessed the performance of the fully automated RT-PCR-based Idylla™ GeneFusion Assay, which simultaneously covers the advanced non-small cell lung carcinoma (aNSCLC) actionable ALK, ROS1, RET, and MET exon 14 rearrangements, in a routine clinical setting involving 12 European clinical centers.
evidence:
- reference: DOI:10.1007/s00428-024-03778-9
reference_title: Multicenter evaluation of an automated, multiplex, RNA-based molecular assay for detection of ALK, ROS1, RET fusions and MET exon 14 skipping in NSCLC
supports: SUPPORT
evidence_source: OTHER
snippet: The current study assessed the performance of the fully automated RT-PCR-based Idylla™ GeneFusion Assay, which simultaneously covers the advanced non-small cell lung carcinoma (aNSCLC) actionable ALK, ROS1, RET, and MET exon 14 rearrangements, in a routine clinical setting involving 12 European clinical centers.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.1007/s10637-023-01390-3
title: 'The efficacy and safety of selective RET inhibitors in RET fusion-positive non-small cell lung cancer: a meta-analysis'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Rearranged during transfection (RET) fusion-positive occurs in approximately 2% of non-small cell lung cancer (NSCLC).
supporting_text: Rearranged during transfection (RET) fusion-positive occurs in approximately 2% of non-small cell lung cancer (NSCLC).
evidence:
- reference: DOI:10.1007/s10637-023-01390-3
reference_title: 'The efficacy and safety of selective RET inhibitors in RET fusion-positive non-small cell lung cancer: a meta-analysis'
supports: SUPPORT
evidence_source: OTHER
snippet: Rearranged during transfection (RET) fusion-positive occurs in approximately 2% of non-small cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.1007/s40265-024-02040-5
title: 'RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: 'RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future'
supporting_text: 'RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future'
- reference: DOI:10.1056/nejmoa2309457
title: First-Line Selpercatinib or Chemotherapy and Pembrolizumab in <i>RET</i> Fusion–Positive NSCLC
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: First-Line Selpercatinib or Chemotherapy and Pembrolizumab in <i>RET</i> Fusion–Positive NSCLC
supporting_text: First-Line Selpercatinib or Chemotherapy and Pembrolizumab in <i>RET</i> Fusion–Positive NSCLC
- reference: DOI:10.1093/carcin/bgu158
title: A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis
supporting_text: A mouse model of KIF5B-RET fusion-dependent lung tumorigenesis
- reference: DOI:10.1093/oncolo/oyac264
title: '<i>RET</i> Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: '<i>RET</i> Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape'
supporting_text: The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases.
evidence:
- reference: DOI:10.1093/oncolo/oyac264
reference_title: '<i>RET</i> Fusion-Positive Non-small Cell Lung Cancer: The Evolving Treatment Landscape'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The objective of this narrative review is to summarize the efficacy and safety of available therapies for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), including in patients with central nervous system (CNS) metastases.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.1177/17588359231177015
title: Precision oncology with selective RET inhibitor selpercatinib in <i>RET</i>-rearranged cancers
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: Rearranged during transfection ( RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways.
supporting_text: Rearranged during transfection ( RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways.
evidence:
- reference: DOI:10.1177/17588359231177015
reference_title: Precision oncology with selective RET inhibitor selpercatinib in <i>RET</i>-rearranged cancers
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Rearranged during transfection ( RET) is a protooncogene that encodes for receptor tyrosine kinase with downstream effects on multiple cellular pathways.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.1186/s12885-024-13155-z
title: 'Efficacy and safety of RET-TKI in advanced RET-rearranged non-small cell lung cancer in China: a real-world retrospective chart review'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: 'Efficacy and safety of RET-TKI in advanced RET-rearranged non-small cell lung cancer in China: a real-world retrospective chart review'
supporting_text: 'Efficacy and safety of RET-TKI in advanced RET-rearranged non-small cell lung cancer in China: a real-world retrospective chart review'
- reference: DOI:10.1186/s12890-024-03371-5
title: Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC)
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC)
supporting_text: Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC)
- reference: DOI:10.1186/s41120-024-00094-z
title: Recent progress of small-molecule of RET inhibitors against Non-small cell lung cancer
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: Recent progress of small-molecule of RET inhibitors against Non-small cell lung cancer
supporting_text: Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients.
evidence:
- reference: DOI:10.1186/s41120-024-00094-z
reference_title: Recent progress of small-molecule of RET inhibitors against Non-small cell lung cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Since the oncogenic rearranged during transfection (RET) gene fusion was discovered in non-small cell lung cancer (NSCLC) in 2012, multiple-targeted kinase inhibitors (MKIs) cabozantinib and vandetanib have been explored in the clinic for RET positive NSCLC patients.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.1200/jco.24.00724
title: CNS Protective Effect of Selpercatinib in First-Line <i>RET</i> Fusion-Positive Advanced Non–Small Cell Lung Cancer
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: Clinical trials frequently include multiple end points that mature at different times.
supporting_text: Clinical trials frequently include multiple end points that mature at different times.
evidence:
- reference: DOI:10.1200/jco.24.00724
reference_title: CNS Protective Effect of Selpercatinib in First-Line <i>RET</i> Fusion-Positive Advanced Non–Small Cell Lung Cancer
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Clinical trials frequently include multiple end points that mature at different times.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.2147/lctt.s460147
title: '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'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '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'
supporting_text: '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'
- reference: DOI:10.3322/caac.21811
title: 'Screening for lung cancer: 2023 guideline update from the American Cancer Society'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women.
supporting_text: Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women.
evidence:
- reference: DOI:10.3322/caac.21811
reference_title: 'Screening for lung cancer: 2023 guideline update from the American Cancer Society'
supports: SUPPORT
evidence_source: OTHER
snippet: Lung cancer is the leading cause of mortality and person‐years of life lost from cancer among US men and women.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.3390/cancers16010031
title: 'Selective RET Inhibitors (SRIs) in Cancer: A Journey from Multi-Kinase Inhibitors to the Next Generation of SRIs'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: RET is a receptor tyrosine kinase that plays an important role in the development of neurons and kidneys.
supporting_text: RET is a receptor tyrosine kinase that plays an important role in the development of neurons and kidneys.
evidence:
- reference: DOI:10.3390/cancers16010031
reference_title: 'Selective RET Inhibitors (SRIs) in Cancer: A Journey from Multi-Kinase Inhibitors to the Next Generation of SRIs'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: RET is a receptor tyrosine kinase that plays an important role in the development of neurons and kidneys.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.3390/cancers16010140
title: 'Comparative Effectiveness of First-Line Selpercatinib versus Standard Therapies in Patients with RET-Activated Cancers: An Exploratory Interpatient Analysis of LIBRETTO-001'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies.
supporting_text: Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies.
evidence:
- reference: DOI:10.3390/cancers16010140
reference_title: 'Comparative Effectiveness of First-Line Selpercatinib versus Standard Therapies in Patients with RET-Activated Cancers: An Exploratory Interpatient Analysis of LIBRETTO-001'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Selpercatinib is indicated for locally advanced/metastatic RET-activated solid tumors after progression or following prior systemic therapies.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.3390/cancers16162877
title: '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”'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs.
supporting_text: RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs.
evidence:
- reference: DOI:10.3390/cancers16162877
reference_title: '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”'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: RET fusions are relatively rare in Non-Small-Cell Lung Cancers (NSCLCs), being around 1–2% of all NSCLCs.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: DOI:10.3390/ijms24032433
title: 'Treatment of Advanced Non-Small Cell Lung Cancer with RET Fusions: Reality and Hopes'
found_in:
- RET_Rearranged_NSCLC-deep-research-falcon.md
findings:
- statement: RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles.
supporting_text: RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles.
evidence:
- reference: DOI:10.3390/ijms24032433
reference_title: 'Treatment of Advanced Non-Small Cell Lung Cancer with RET Fusions: Reality and Hopes'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: RET-selective tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib have revolutionized the landscape of RET-positive (RET+) advanced non-small cell lung cancer (NSCLC) treatment, thanks to their efficacy and safety profiles.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:17934909
title: 'Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2007;39(8):572-80. doi: 10.1080/07853890701646256.'
supporting_text: '2007;39(8):572-80. doi: 10.1080/07853890701646256.'
evidence:
- reference: PMID:17934909
reference_title: 'Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2007;39(8):572-80. doi: 10.1080/07853890701646256.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:22194472
title: A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2012 Mar;22(3):436-45. doi: 10.1101/gr.133645.111.'
supporting_text: '2012 Mar;22(3):436-45. doi: 10.1101/gr.133645.111.'
evidence:
- reference: PMID:22194472
reference_title: A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2012 Mar;22(3):436-45. doi: 10.1101/gr.133645.111.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:23052255
title: Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist.
supporting_text: The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist.
evidence:
- reference: PMID:23052255
reference_title: Identification of KIF5B-RET and GOPC-ROS1 fusions in lung adenocarcinomas through a comprehensive mRNA-based screen for tyrosine kinase fusions.
supports: SUPPORT
evidence_source: OTHER
snippet: The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:24022366
title: 'To bud or not to bud: the RET perspective in CAKUT.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2014 Apr;29(4):597-608. doi: 10.1007/s00467-013-2606-5.'
supporting_text: '2014 Apr;29(4):597-608. doi: 10.1007/s00467-013-2606-5.'
evidence:
- reference: PMID:24022366
reference_title: 'To bud or not to bud: the RET perspective in CAKUT.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2014 Apr;29(4):597-608. doi: 10.1007/s00467-013-2606-5.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:28177518
title: Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood.
supporting_text: Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood.
evidence:
- reference: PMID:28177518
reference_title: Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Lung adenocarcinoma in the young is a rare entity, and the oncogenic genetic alterations (GAs) and clinical characteristics associated with this disease are poorly understood.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:28428274
title: EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2017 Jul 1;77(13):3551-3563. doi: 10.1158/0008-5472.CAN-17-0109.'
supporting_text: '2017 Jul 1;77(13):3551-3563. doi: 10.1158/0008-5472.CAN-17-0109.'
evidence:
- reference: PMID:28428274
reference_title: EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases.
supports: SUPPORT
evidence_source: OTHER
snippet: '2017 Jul 1;77(13):3551-3563. doi: 10.1158/0008-5472.CAN-17-0109.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:31988000
title: RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2020 Apr;15(4):541-549. doi: 10.1016/j.jtho.2020.01.006.'
supporting_text: '2020 Apr;15(4):541-549. doi: 10.1016/j.jtho.2020.01.006.'
evidence:
- reference: PMID:31988000
reference_title: RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2020 Apr;15(4):541-549. doi: 10.1016/j.jtho.2020.01.006.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:33007380
title: Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC).
supporting_text: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC).
evidence:
- reference: PMID:33007380
reference_title: Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:33655698
title: Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649.'
supporting_text: '2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649.'
evidence:
- reference: PMID:33655698
reference_title: Integration of comprehensive genomic profiling, tumor mutational burden, and PD-L1 expression to identify novel biomarkers of immunotherapy in non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2021 Apr;10(7):2216-2231. doi: 10.1002/cam4.3649.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:34523767
title: Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-Small Cell Lung Cancer in the Phase I/II LIBRETTO-001 Trial.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: LIBRETTO-001 is an ongoing, global, open-label, phase I/II study of selpercatinib in patients with advanced or metastatic solid tumors.
supporting_text: LIBRETTO-001 is an ongoing, global, open-label, phase I/II study of selpercatinib in patients with advanced or metastatic solid tumors.
evidence:
- reference: PMID:34523767
reference_title: Patient-Reported Outcomes with Selpercatinib Among Patients with RET Fusion-Positive Non-Small Cell Lung Cancer in the Phase I/II LIBRETTO-001 Trial.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: LIBRETTO-001 is an ongoing, global, open-label, phase I/II study of selpercatinib in patients with advanced or metastatic solid tumors.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:34536732
title: Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2021 Nov;161:55-59. doi: 10.1016/j.lungcan.2021.08.008.'
supporting_text: '2021 Nov;161:55-59. doi: 10.1016/j.lungcan.2021.08.008.'
evidence:
- reference: PMID:34536732
reference_title: Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2021 Nov;161:55-59. doi: 10.1016/j.lungcan.2021.08.008.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:35242632
title: 'Use of on-therapy ctDNA monitoring in a patient with KIF5B-RET fusion positive advanced non-small cell lung cancer: a case report.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2022 Jan;11(1):111-116. doi: 10.21037/tlcr-21-571.'
supporting_text: '2022 Jan;11(1):111-116. doi: 10.21037/tlcr-21-571.'
evidence:
- reference: PMID:35242632
reference_title: 'Use of on-therapy ctDNA monitoring in a patient with KIF5B-RET fusion positive advanced non-small cell lung cancer: a case report.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2022 Jan;11(1):111-116. doi: 10.21037/tlcr-21-571.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:35838839
title: Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Jul;149(7):2987-2995. doi: 10.1007/s00432-022-04188-7.'
supporting_text: '2023 Jul;149(7):2987-2995. doi: 10.1007/s00432-022-04188-7.'
evidence:
- reference: PMID:35838839
reference_title: Selective RET inhibitors shift the treatment pattern of RET fusion-positive NSCLC and improve survival outcomes.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Jul;149(7):2987-2995. doi: 10.1007/s00432-022-04188-7.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:35973665
title: 'Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC).
supporting_text: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC).
evidence:
- reference: PMID:35973665
reference_title: 'Safety and efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.'
supports: SUPPORT
evidence_source: OTHER
snippet: RET fusions are present in 1%-2% of non-small-cell lung cancer (NSCLC).
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:36122315
title: 'Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Jan 10;41(2):385-394. doi: 10.1200/JCO.22.00393.'
supporting_text: '2023 Jan 10;41(2):385-394. doi: 10.1200/JCO.22.00393.'
evidence:
- reference: PMID:36122315
reference_title: 'Selpercatinib in Patients With RET Fusion-Positive Non-Small-Cell Lung Cancer: Updated Safety and Efficacy From the Registrational LIBRETTO-001 Phase I/II Trial.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Jan 10;41(2):385-394. doi: 10.1200/JCO.22.00393.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37070927
title: Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Jun 1;22(6):717-725. doi: 10.1158/1535-7163.MCT-22-0629.'
supporting_text: '2023 Jun 1;22(6):717-725. doi: 10.1158/1535-7163.MCT-22-0629.'
evidence:
- reference: PMID:37070927
reference_title: Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Jun 1;22(6):717-725. doi: 10.1158/1535-7163.MCT-22-0629.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37190044
title: 'Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135.'
supporting_text: '2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135.'
evidence:
- reference: PMID:37190044
reference_title: 'Gene Fusion Detection in NSCLC Routine Clinical Practice: Targeted-NGS or FISH?'
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Apr 11;12(8):1135. doi: 10.3390/cells12081135.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37282666
title: Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations.
supporting_text: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations.
evidence:
- reference: PMID:37282666
reference_title: Efficacy and safety of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Pralsetinib is a potent, selective RET inhibitor targeting oncogenic RET alterations.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37516008
title: Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET fusion positive colorectal carcinoma as a unique molecular subset.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: RET fusions are driver alterations in cancer and are most commonly found in non-small cell lung cancer and well-differentiated thyroid cancer.
supporting_text: RET fusions are driver alterations in cancer and are most commonly found in non-small cell lung cancer and well-differentiated thyroid cancer.
evidence:
- reference: PMID:37516008
reference_title: Pan-tumor survey of RET fusions as detected by next-generation RNA sequencing identified RET fusion positive colorectal carcinoma as a unique molecular subset.
supports: SUPPORT
evidence_source: OTHER
snippet: RET fusions are driver alterations in cancer and are most commonly found in non-small cell lung cancer and well-differentiated thyroid cancer.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37655205
title: Patient-reported outcomes following selpercatinib treatment in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer and thyroid cancer, and RET-mutant medullary thyroid cancer in the phase II LIBRETTO-321 trial.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Patient-reported outcomes (PROs) are increasingly becoming an important part of clinical trials as they are helpful in analyzing the safety and efficacy of treatment in chronic diseases like cancer.
supporting_text: Patient-reported outcomes (PROs) are increasingly becoming an important part of clinical trials as they are helpful in analyzing the safety and efficacy of treatment in chronic diseases like cancer.
evidence:
- reference: PMID:37655205
reference_title: Patient-reported outcomes following selpercatinib treatment in Chinese patients with advanced RET fusion-positive non-small-cell lung cancer and thyroid cancer, and RET-mutant medullary thyroid cancer in the phase II LIBRETTO-321 trial.
supports: SUPPORT
evidence_source: OTHER
snippet: Patient-reported outcomes (PROs) are increasingly becoming an important part of clinical trials as they are helpful in analyzing the safety and efficacy of treatment in chronic diseases like cancer.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37718634
title: Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Nov;14(31):3166-3177. doi: 10.1111/1759-7714.15105.'
supporting_text: '2023 Nov;14(31):3166-3177. doi: 10.1111/1759-7714.15105.'
evidence:
- reference: PMID:37718634
reference_title: Expert consensus on the diagnosis and treatment of RET gene fusion non-small cell lung cancer in China.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Nov;14(31):3166-3177. doi: 10.1111/1759-7714.15105.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37729688
title: Prevalence of oncogenic driver mutations in Hispanics/Latin patients with lung cancer. A systematic review and meta-analysis.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Nov;185:107378. doi: 10.1016/j.lungcan.2023.107378.'
supporting_text: '2023 Nov;185:107378. doi: 10.1016/j.lungcan.2023.107378.'
evidence:
- reference: PMID:37729688
reference_title: Prevalence of oncogenic driver mutations in Hispanics/Latin patients with lung cancer. A systematic review and meta-analysis.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Nov;185:107378. doi: 10.1016/j.lungcan.2023.107378.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37743366
title: Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023 Sep;4(9):1345-1361. doi: 10.1038/s43018-023-00630-y.'
supporting_text: '2023 Sep;4(9):1345-1361. doi: 10.1038/s43018-023-00630-y.'
evidence:
- reference: PMID:37743366
reference_title: Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023 Sep;4(9):1345-1361. doi: 10.1038/s43018-023-00630-y.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37854153
title: 'First-line versus second-line use of pralsetinib in treatment of rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer: a cost-effectiveness analysis.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: The ARROW study demonstrated favorable clinical efficacy and safety of pralsetinib (PRL) in treating rearranged during transfection (RET) fusion positive non-small cell lung cancer (NSCLC) in clinical trials.
supporting_text: The ARROW study demonstrated favorable clinical efficacy and safety of pralsetinib (PRL) in treating rearranged during transfection (RET) fusion positive non-small cell lung cancer (NSCLC) in clinical trials.
evidence:
- reference: PMID:37854153
reference_title: 'First-line versus second-line use of pralsetinib in treatment of rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer: a cost-effectiveness analysis.'
supports: SUPPORT
evidence_source: OTHER
snippet: The ARROW study demonstrated favorable clinical efficacy and safety of pralsetinib (PRL) in treating rearranged during transfection (RET) fusion positive non-small cell lung cancer (NSCLC) in clinical trials.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:37870973
title: First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study.
supporting_text: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study.
evidence:
- reference: PMID:37870973
reference_title: First-Line Selpercatinib or Chemotherapy and Pembrolizumab in RET Fusion-Positive NSCLC.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:38372058
title: 'The emerging perioperative treatment paradigm for non-small cell lung cancer: a narrative review.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Feb;13(1):12. doi: 10.21037/cco-23-137.'
supporting_text: '2024 Feb;13(1):12. doi: 10.21037/cco-23-137.'
evidence:
- reference: PMID:38372058
reference_title: 'The emerging perioperative treatment paradigm for non-small cell lung cancer: a narrative review.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2024 Feb;13(1):12. doi: 10.21037/cco-23-137.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:38405208
title: High-dose alectinib for RET fusion-positive non-small cell lung cancer in the Blood First Assay Screening Trial.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2023;27(4):217-223. doi: 10.5114/wo.2023.135246.'
supporting_text: '2023;27(4):217-223. doi: 10.5114/wo.2023.135246.'
evidence:
- reference: PMID:38405208
reference_title: High-dose alectinib for RET fusion-positive non-small cell lung cancer in the Blood First Assay Screening Trial.
supports: SUPPORT
evidence_source: OTHER
snippet: '2023;27(4):217-223. doi: 10.5114/wo.2023.135246.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:38768929
title: Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2024 Aug;1870(6):167249. doi: 10.1016/j.bbadis.2024.167249.'
supporting_text: '2024 Aug;1870(6):167249. doi: 10.1016/j.bbadis.2024.167249.'
evidence:
- reference: PMID:38768929
reference_title: Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC.
supports: SUPPORT
evidence_source: OTHER
snippet: '2024 Aug;1870(6):167249. doi: 10.1016/j.bbadis.2024.167249.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:39879936
title: Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R).
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Mar 15;286:117294. doi: 10.1016/j.ejmech.2025.117294.'
supporting_text: '2025 Mar 15;286:117294. doi: 10.1016/j.ejmech.2025.117294.'
evidence:
- reference: PMID:39879936
reference_title: Design, synthesis and evaluation of (E)-1-(4-(2-(1H-pyrazol-5-yl)vinyl)phenyl) derivatives as next generation selective RET inhibitors overcoming RET solvent front mutations (G810C/R).
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Mar 15;286:117294. doi: 10.1016/j.ejmech.2025.117294.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:39926433
title: Previous treatment decreases efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Pralsetinib is a selective RET inhibitor.
supporting_text: Pralsetinib is a selective RET inhibitor.
evidence:
- reference: PMID:39926433
reference_title: Previous treatment decreases efficacy of pralsetinib in RET fusion-positive non-small-cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: Pralsetinib is a selective RET inhibitor.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40021042
title: A single-cell map of patients with non-small cell lung cancer harboring rare-driver mutations after anti-PD-1 treatment.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Apr 28;616:217595. doi: 10.1016/j.canlet.2025.217595.'
supporting_text: '2025 Apr 28;616:217595. doi: 10.1016/j.canlet.2025.217595.'
evidence:
- reference: PMID:40021042
reference_title: A single-cell map of patients with non-small cell lung cancer harboring rare-driver mutations after anti-PD-1 treatment.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Apr 28;616:217595. doi: 10.1016/j.canlet.2025.217595.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40102258
title: 'Hereditary Medullary Thyroid Cancer: Genotype-Phenotype Correlation.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025;223:183-209. doi: 10.1007/978-3-031-80396-3_7.'
supporting_text: '2025;223:183-209. doi: 10.1007/978-3-031-80396-3_7.'
evidence:
- reference: PMID:40102258
reference_title: 'Hereditary Medullary Thyroid Cancer: Genotype-Phenotype Correlation.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2025;223:183-209. doi: 10.1007/978-3-031-80396-3_7.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40122770
title: 'Young Onset Lung Cancer in India: Insights Into Clinical, Demographic, and Genomic Profiles.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: Lung cancer (LC) is traditionally perceived as a disease primarily affecting the elderly.
supporting_text: Lung cancer (LC) is traditionally perceived as a disease primarily affecting the elderly.
evidence:
- reference: PMID:40122770
reference_title: 'Young Onset Lung Cancer in India: Insights Into Clinical, Demographic, and Genomic Profiles.'
supports: SUPPORT
evidence_source: OTHER
snippet: Lung cancer (LC) is traditionally perceived as a disease primarily affecting the elderly.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40209611
title: 'Frequency of targetable genetic alterations in resectable lung adenocarcinoma: Results from the LORD project.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 May;203:108530. doi: 10.1016/j.lungcan.2025.108530.'
supporting_text: '2025 May;203:108530. doi: 10.1016/j.lungcan.2025.108530.'
evidence:
- reference: PMID:40209611
reference_title: 'Frequency of targetable genetic alterations in resectable lung adenocarcinoma: Results from the LORD project.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 May;203:108530. doi: 10.1016/j.lungcan.2025.108530.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40458063
title: Matching-adjusted indirect comparison of selpercatinib and pralsetinib in RET fusion-positive non-small cell lung cancer.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Jun;21(15):1867-1878. doi: 10.1080/14796694.2025.2508132.'
supporting_text: '2025 Jun;21(15):1867-1878. doi: 10.1080/14796694.2025.2508132.'
evidence:
- reference: PMID:40458063
reference_title: Matching-adjusted indirect comparison of selpercatinib and pralsetinib in RET fusion-positive non-small cell lung cancer.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jun;21(15):1867-1878. doi: 10.1080/14796694.2025.2508132.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40544107
title: 'Four decades of the RET gene: From discovery to tumor-agnostic therapy.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Oct;124(10):895-901. doi: 10.1016/j.jfma.2025.06.033.'
supporting_text: '2025 Oct;124(10):895-901. doi: 10.1016/j.jfma.2025.06.033.'
evidence:
- reference: PMID:40544107
reference_title: 'Four decades of the RET gene: From discovery to tumor-agnostic therapy.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Oct;124(10):895-901. doi: 10.1016/j.jfma.2025.06.033.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40567260
title: 'Patient-Reported Outcomes From LIBRETTO-431: First-Line Selpercatinib Versus Chemotherapy With Pembrolizumab in RET Fusion-Positive NSCLC.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Feb 19;6(7):100814. doi: 10.1016/j.jtocrr.2025.100814. eCollection 2025 Jul.'
supporting_text: '2025 Feb 19;6(7):100814. doi: 10.1016/j.jtocrr.2025.100814. eCollection 2025 Jul.'
evidence:
- reference: PMID:40567260
reference_title: 'Patient-Reported Outcomes From LIBRETTO-431: First-Line Selpercatinib Versus Chemotherapy With Pembrolizumab in RET Fusion-Positive NSCLC.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Feb 19;6(7):100814. doi: 10.1016/j.jtocrr.2025.100814. eCollection 2025 Jul.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40920215
title: Discovery of APS03118, a Potent and Selective Next-Generation RET Inhibitor with a Novel Kinase Hinge Scaffold.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Sep 25;68(18):19536-19553. doi: 10.1021/acs.jmedchem.5c01777.'
supporting_text: '2025 Sep 25;68(18):19536-19553. doi: 10.1021/acs.jmedchem.5c01777.'
evidence:
- reference: PMID:40920215
reference_title: Discovery of APS03118, a Potent and Selective Next-Generation RET Inhibitor with a Novel Kinase Hinge Scaffold.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '2025 Sep 25;68(18):19536-19553. doi: 10.1021/acs.jmedchem.5c01777.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40944810
title: 'Diagnostic accuracy of next-generation sequencing (NGS) for identifying actionable mutations in advanced non-small cell lung cancer: Systematic Review and Meta-Analysis.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2026 Mar;28(3):1005-1015. doi: 10.1007/s12094-025-04040-7.'
supporting_text: '2026 Mar;28(3):1005-1015. doi: 10.1007/s12094-025-04040-7.'
evidence:
- reference: PMID:40944810
reference_title: 'Diagnostic accuracy of next-generation sequencing (NGS) for identifying actionable mutations in advanced non-small cell lung cancer: Systematic Review and Meta-Analysis.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2026 Mar;28(3):1005-1015. doi: 10.1007/s12094-025-04040-7.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:40980186
title: 'First-line Selpercatinib or Chemotherapy and Pembrolizumab in Patients From East Asia With RET Fusion-Positive NSCLC: A LIBRETTO-431 Subgroup Analysis.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Jun 20;6(10):100868. doi: 10.1016/j.jtocrr.2025.100868. eCollection 2025 Oct.'
supporting_text: '2025 Jun 20;6(10):100868. doi: 10.1016/j.jtocrr.2025.100868. eCollection 2025 Oct.'
evidence:
- reference: PMID:40980186
reference_title: 'First-line Selpercatinib or Chemotherapy and Pembrolizumab in Patients From East Asia With RET Fusion-Positive NSCLC: A LIBRETTO-431 Subgroup Analysis.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Jun 20;6(10):100868. doi: 10.1016/j.jtocrr.2025.100868. eCollection 2025 Oct.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:41005103
title: 'Clinicogenomic and treatment outcomes in RET fusion-positive NSCLC: A multicenter study in Latin American Hispanic patients.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: RET fusions represent a rare but actionable molecular subtype in non-small cell lung cancer (NSCLC), comprising approximately 1 % of cases.
supporting_text: RET fusions represent a rare but actionable molecular subtype in non-small cell lung cancer (NSCLC), comprising approximately 1 % of cases.
evidence:
- reference: PMID:41005103
reference_title: 'Clinicogenomic and treatment outcomes in RET fusion-positive NSCLC: A multicenter study in Latin American Hispanic patients.'
supports: SUPPORT
evidence_source: OTHER
snippet: RET fusions represent a rare but actionable molecular subtype in non-small cell lung cancer (NSCLC), comprising approximately 1 % of cases.
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:41194587
title: Dual targeting of RET and SRC synergizes in RET fusion-positive cancer cells.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2026 Apr;20(4):1041-1060. doi: 10.1002/1878-0261.70155.'
supporting_text: '2026 Apr;20(4):1041-1060. doi: 10.1002/1878-0261.70155.'
evidence:
- reference: PMID:41194587
reference_title: Dual targeting of RET and SRC synergizes in RET fusion-positive cancer cells.
supports: SUPPORT
evidence_source: OTHER
snippet: '2026 Apr;20(4):1041-1060. doi: 10.1002/1878-0261.70155.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:41424613
title: Integrated Multi-Omics Approaches for Predicting Immune Checkpoint Inhibitor Response in NSCLC - Insights From Genomics, Proteomics, and Metabolomics.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025.'
supporting_text: '2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025.'
evidence:
- reference: PMID:41424613
reference_title: Integrated Multi-Omics Approaches for Predicting Immune Checkpoint Inhibitor Response in NSCLC - Insights From Genomics, Proteomics, and Metabolomics.
supports: SUPPORT
evidence_source: OTHER
snippet: '2025 Dec 16;16:167-198. doi: 10.2147/LCTT.S539777. eCollection 2025.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:41707338
title: 'RET Fusion-Positive Lung Adenocarcinoma: Partner-Specific Clinicopathological Characteristics, Co-Mutation Profiles, and Implications for Targeted and Immunotherapy.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: RET fusions represent actionable oncogenic drivers in lung adenocarcinoma (LUAD).
supporting_text: RET fusions represent actionable oncogenic drivers in lung adenocarcinoma (LUAD).
evidence:
- reference: PMID:41707338
reference_title: 'RET Fusion-Positive Lung Adenocarcinoma: Partner-Specific Clinicopathological Characteristics, Co-Mutation Profiles, and Implications for Targeted and Immunotherapy.'
supports: SUPPORT
evidence_source: OTHER
snippet: RET fusions represent actionable oncogenic drivers in lung adenocarcinoma (LUAD).
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:41816478
title: 'Targeting rare oncogenic mutations in resectable non-small cell lung cancer: emerging perioperative strategies.'
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '2026 Feb 28;18(2):160. doi: 10.21037/jtd-2025-aw-2202.'
supporting_text: '2026 Feb 28;18(2):160. doi: 10.21037/jtd-2025-aw-2202.'
evidence:
- reference: PMID:41816478
reference_title: 'Targeting rare oncogenic mutations in resectable non-small cell lung cancer: emerging perioperative strategies.'
supports: SUPPORT
evidence_source: OTHER
snippet: '2026 Feb 28;18(2):160. doi: 10.21037/jtd-2025-aw-2202.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:8657282
title: GDNF signalling through the Ret receptor tyrosine kinase.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '1996 Jun 27;381(6585):789-93. doi: 10.1038/381789a0.'
supporting_text: '1996 Jun 27;381(6585):789-93. doi: 10.1038/381789a0.'
evidence:
- reference: PMID:8657282
reference_title: GDNF signalling through the Ret receptor tyrosine kinase.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '1996 Jun 27;381(6585):789-93. doi: 10.1038/381789a0.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
- reference: PMID:9728913
title: GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys.
found_in:
- RET_Rearranged_NSCLC-deep-research-openscientist.md
findings:
- statement: '1998 Aug;21(2):317-24. doi: 10.1016/s0896-6273(00)80541-3.'
supporting_text: '1998 Aug;21(2):317-24. doi: 10.1016/s0896-6273(00)80541-3.'
evidence:
- reference: PMID:9728913
reference_title: GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: '1998 Aug;21(2):317-24. doi: 10.1016/s0896-6273(00)80541-3.'
explanation: Deep research cited this publication as relevant literature for RET Rearranged NSCLC.
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).
A structured mapping of the disease concept, synonyms, and parent ontology terms captured in the retrieved evidence is provided here:
| 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).
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).
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).
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).
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.
No specific protective genetic variants or environmental protective factors were identified in the retrieved evidence.
No explicit RET‑fusion gene–environment interaction findings were retrieved.
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).
A phenotype-to-HPO structured mapping is provided here:
| 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).
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).
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).
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).
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).
Suggested UBERON: UBERON:0002048 lung.
Suggested UBERON: UBERON:0000955 brain.
Typically adult‑onset lung cancer, enriched in younger adults compared with unselected NSCLC cohorts (novello2023retfusionpositivenonsmall pages 1-2, chen2024retinhibitorsin pages 3-5).
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).
This is not a Mendelian inherited disorder; RET fusions in NSCLC are somatic cancer alterations.
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).
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:
| 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.
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).
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).
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).
Key recent efficacy/safety outcomes (2023–2024 and real‑world) are summarized here:
| 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).
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)
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).
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).
RET fusions themselves are not currently preventable at the molecular level; prevention is primarily through lung cancer risk reduction and 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.
No naturally occurring RET fusion‑driven lung cancer in non‑human species was identified in the retrieved evidence.
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).
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).
References
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(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.
RET-rearranged NSCLC is a molecular subtype of non-small cell lung cancer defined by somatic chromosomal rearrangements involving the RET (REarranged during Transfection) proto-oncogene on chromosome 10q11.21. These rearrangements create oncogenic fusion proteins with constitutive kinase activity that drive tumorigenesis. The KIF5B-RET fusion was first identified in 2012 by Ju et al. through whole-genome and transcriptome sequencing of a lung adenocarcinoma from a 33-year-old never-smoker, revealing "a novel fusion gene between KIF5B and the RET proto-oncogene caused by a pericentric inversion of 10p11.22-q11.21" that "overexpresses chimeric RET receptor tyrosine kinase, which could spontaneously induce cellular transformation" (PMID: 22194472). Suehara et al. independently identified KIF5B-RET through a systematic NanoString-based screen for tyrosine kinase fusions in pan-negative lung adenocarcinomas (PMID: 23052255).
| Database | Identifier |
|---|---|
| ICD-10 | C34 (Malignant neoplasm of bronchus and lung) |
| ICD-11 | 2C25 (Malignant neoplasms of bronchus or lung) |
| ICD-O-3 | 8140/3 (Adenocarcinoma, NOS) — most common histologic subtype |
| MeSH | D002289 (Carcinoma, Non-Small-Cell Lung) |
| MONDO | MONDO:0005233 (non-small cell lung carcinoma) — no specific MONDO ID for RET-rearranged subset |
| OMIM | 164761 (RET proto-oncogene) |
| Orphanet | ORPHA:70573 (Non-small cell lung carcinoma) |
Disease-level aggregated resources, including clinical trial data, molecular profiling databases (e.g., COSMIC, TCGA, cBioPortal), real-world observational studies, and systematic literature reviews across 96 publications.
RET-rearranged NSCLC is caused by somatic (acquired) chromosomal rearrangements (inversions or translocations) that fuse the 3' kinase domain of the RET gene with the 5' portion of various partner genes. The resulting fusion protein retains the catalytic kinase activity of RET but is expressed under control of the partner gene's promoter, leading to ligand-independent constitutive activation of RET signaling. RET fusions occur in "1-2% of non-small cell lung carcinoma" (PMID: 40544107).
The most common fusion partners and their frequencies are:
| Fusion | Frequency in NSCLC | Chromosomal Event |
|---|---|---|
| KIF5B-RET | ~47-62% | inv(10)(p11.22q11.21) |
| CCDC6-RET | ~20-28% | inv(10)(q11.21q21) |
| NCOA4-RET | ~6-14% | inv(10)(q11.21q11.2) |
| Other partners (TRIM33, ERC1, RUFY2, etc.) | ~5-10% | Interchromosomal translocations |
"KIF5B (46.8%) was the most common fusion partner followed by CCDC6 (28.3%) and NCOA4 (13.8%) in RET+ solid tumors. KIF5B-RET was the dominant fusion variant in RET+ NSCLC" (PMID: 37516008). In Chinese NSCLC, KIF5B-RET accounts for 59.4% of cases (PMID: 39497173).
All three major fusion partners reside on chromosome 10, explaining the predominance of intrachromosomal pericentric inversions:
| Partner Gene | NCBI Gene ID | Chromosome | Normal Function | Mechanism in Fusion |
|---|---|---|---|---|
| KIF5B | 3799 | 10p11.22 | Kinesin-1 heavy chain; microtubule-dependent transport | Coiled-coil domain mediates constitutive dimerization; ubiquitous promoter drives high-level expression |
| CCDC6 | 8030 | 10q21.2 | DNA damage response; potential tumor suppressor | Loss of tumor suppressor function + coiled-coil drives RET dimerization |
| NCOA4 | 8031 | 10q11.2 | Androgen receptor coactivator; mediates ferritinophagy | Coiled-coil domain forces ligand-independent RET dimerization |
No specific genetic or environmental protective factors have been identified for RET-rearranged NSCLC. General lung cancer protective factors (smoking avoidance, reduced air pollution exposure) apply broadly.
RET fusions occur predominantly in never/light smokers, suggesting they arise through mechanisms independent of tobacco carcinogenesis (which more commonly drives KRAS mutations and high TMB). The precise molecular triggers for RET rearrangements remain unclear. Prior ionizing radiation exposure has been associated with RET fusions in thyroid cancer (post-Chernobyl), but this association has not been established for NSCLC.
| Phenotype | HPO Term | Frequency | Onset | Severity |
|---|---|---|---|---|
| Cough | HP:0012735 | ~50-65% | Variable | Mild to moderate |
| Dyspnea | HP:0002094 | ~40-55% | Progressive | Moderate to severe |
| Hemoptysis | HP:0002105 | ~15-20% | Variable | Variable |
| Chest pain | HP:0100749 | ~25-30% | Variable | Moderate |
| Weight loss | HP:0001824 | ~20-35% | Insidious | Moderate |
| Fatigue | HP:0012378 | ~30-45% | Insidious | Mild to moderate |
| Bone pain (metastases) | HP:0002653 | ~12% | Late | Moderate to severe |
| Headache/neurological symptoms (brain metastases) | HP:0002315 | ~7-25% | Late | Variable |
| Pleural effusion | HP:0002202 | ~12-20% | Variable | Moderate |
Patient-reported outcome (PRO) data from clinical trials demonstrate significant QoL impacts and treatment-related improvements:
Normal RET function: RET is "a receptor tyrosine kinase essential for normal development of the kidneys, ureters, peripheral and enteric nervous systems" (PMID: 24022366). "RET signalling is crucial for the development of the enteric nervous system. RET also regulates the development of sympathetic, parasympathetic, motor, and sensory neurons, and is necessary for the postnatal maintenance of dopaminergic neurons" (PMID: 17934909).
| Domain | Position (aa) | Function |
|---|---|---|
| Signal peptide | 1-28 | Secretory pathway targeting |
| Cadherin-like domains | 168-510 | Extracellular; GFRα coreceptor interaction |
| Cysteine-rich domain | ~510-635 | Extracellular; ligand binding |
| Transmembrane domain | ~636-657 | Single-pass membrane anchor |
| Protein kinase domain | 724-1016 | Intracellular; catalytic tyrosine kinase |
| PDB ID | Resolution | Complex | Significance |
|---|---|---|---|
| 7JU6 | 2.06 Å | RET kinase + selpercatinib | Co-crystal revealing selpercatinib binding mode and G810 resistance basis |
| 7JU5 | 1.90 Å | RET kinase + pralsetinib | Co-crystal showing pralsetinib ATP-competitive binding |
| 6Q2J | ~4.0 Å | RET ECD + GFRα1 + GDNF | Cryo-EM of ternary signaling complex |
All RET fusions in NSCLC are somatic (acquired), distinguishing them from germline RET point mutations that cause MEN2A/2B and hereditary medullary thyroid carcinoma (PMID: 40102258).
Functional consequence: Gain of function — the partner gene's coiled-coil/oligomerization domain replaces RET's extracellular ligand-binding domain, forcing constitutive, ligand-independent dimerization and autophosphorylation of the retained intracellular kinase domain.
| Mutation | Location | Effect | Clinical Relevance |
|---|---|---|---|
| G810R | Solvent front | Steric clash with selpercatinib/pralsetinib | Most frequent G810 variant |
| G810S | Solvent front | Steric clash | Common |
| G810C | Solvent front | Steric clash | Common |
| G810D | Solvent front | Resistant to both approved TKIs | Rare (PMID: 37070927) |
| G810V | Solvent front | NOT resistant (surprisingly) | Rare (PMID: 37070927) |
| V804L/M | Gatekeeper | Resistant to multi-kinase inhibitors; sensitive to selective RET TKIs | Historical |
"Analysis of circulating tumor DNA revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance" (PMID: 31988000).
RET fusions arise from pericentric inversions of chromosome 10 (for KIF5B-RET, CCDC6-RET) or inter-chromosomal translocations (for partners on other chromosomes). These are focal rearrangements, not large-scale aneuploidy.
UPSTREAM TRIGGER
Somatic chromosomal rearrangement (inv/translocation on chr 10)
↓
RET fusion gene expression (e.g., KIF5B-RET)
↓
Partner coiled-coil domain → constitutive dimerization
↓
Ligand-independent RET kinase autophosphorylation (Y905, Y1015, Y1062, Y1096)
↓
SIGNALING CASCADE
├── RAS → RAF → MEK → ERK (proliferation)
├── PI3K → AKT → mTOR (survival/growth)
├── PLCγ → DAG + IP3 → PKC (signaling)
├── JAK → STAT3 (immune evasion)
└── SRC → FAK (invasion/metastasis)
↓
DOWNSTREAM EFFECTS
├── Uncontrolled proliferation
├── Evasion of apoptosis
├── Angiogenesis
├── Immune-cold microenvironment (low TMB, poor T-cell infiltration)
└── Metastasis (bone, pleura, brain)
↓
CLINICAL MANIFESTATION
Advanced lung adenocarcinoma with metastatic disease
"This activated complex regulates a number of downstream signaling cascades (PLCγ, MAPK, and PI3K) that control proliferation, migration, renewal, and apoptosis" (PMID: 24022366).
| Pathway | KEGG ID | Role in Tumorigenesis |
|---|---|---|
| RAS-MAPK (ERK1/2) | hsa04010 | Cell proliferation, differentiation |
| PI3K-AKT-mTOR | hsa04151 | Cell survival, metabolism, growth |
| PLCγ-PKC | — | Calcium signaling, proliferation |
| JAK-STAT3 | hsa04630 | Survival, immune evasion |
| SRC signaling | — | Migration, invasion, adhesion |
RET-fusion NSCLC is characterized by a distinctly immune-cold tumor microenvironment:
Multiple resistance pathways emerge after selective RET inhibitor therapy:
| Mechanism | Type | Frequency | Evidence |
|---|---|---|---|
| RET G810R/S/C | On-target (solvent front) | Most common | PMID: 31988000 |
| MET amplification | Off-target bypass | ~15% | PMID: 33007380 |
| KRAS amplification | Off-target bypass | Rare | PMID: 33007380 |
| AXL activation | Off-target bypass | Clone-specific | PMID: 38768929 |
| IGF-1R activation | Off-target bypass | Clone-specific | PMID: 38768929 |
| SMARCA4 loss | Chromatin remodeling | 55% post-TKI | PMID: 38768929 |
| Mitochondrial dysfunction | Metabolic | Clone-specific | PMID: 38768929 |
| EGFR reactivation | Off-target feedback | Variable | PMID: 28428274 |
"Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification" (PMID: 33007380).
| Level | Structure | UBERON Term | Involvement |
|---|---|---|---|
| Primary | Lung | UBERON:0002048 | Primary site of adenocarcinoma |
| Secondary | Bone | UBERON:0002481 | Most common metastatic site (12.3%) |
| Pleura | UBERON:0000977 | Second most common (11.9%) | |
| Brain | UBERON:0000955 | Third most common (6.7%); up to 25-30% over disease course | |
| Liver | UBERON:0002107 | Common distant metastasis | |
| Adrenal glands | UBERON:0002369 | Occasional metastatic site | |
| Lymph nodes | UBERON:0000029 | Regional and distant spread |
Body system: Respiratory system (UBERON:0001004)
| Compartment | GO Cellular Component | Relevance |
|---|---|---|
| Plasma membrane | GO:0005886 | RET fusion protein localization |
| Cytoplasm | GO:0005737 | Downstream signaling cascades |
| Nucleus | GO:0005634 | Transcription factor activation |
| Endosome membrane | GO:0010008 | RET internalization and signaling |
| Mitochondria | GO:0005739 | Dysfunction in resistance |
| Stage (AJCC 8th Edition) | Approximate Proportion at Diagnosis |
|---|---|
| Stage I-II | ~15-25% |
| Stage III | ~15-20% |
| Stage IV | ~55-65% |
| Setting | Median PFS | ORR |
|---|---|---|
| Selpercatinib 1L (LIBRETTO-431) | 24.8 months | 84% |
| Selpercatinib 2L+ (LIBRETTO-001) | 24.9 months | 61% |
| Pralsetinib 1L (ARROW) | 13.0 months | 72% |
| Pralsetinib 2L+ (ARROW) | 16.5 months | 59% |
| Chemotherapy ± pembrolizumab (control) | 11.2 months | 65% |
| Parameter | Value | Source |
|---|---|---|
| Prevalence among NSCLC | 1-2% | PMID: 40544107 |
| Estimated new cases/year (US) | ~2,300-4,600 | Based on ~230,000 new NSCLC cases/year |
| Estimated new cases/year (global) | ~18,000-36,000 | Based on ~1.8M new lung cancer cases/year |
RET fusion detection is required for diagnosis and treatment selection. "Currently, four methods are widely used for detecting gene rearrangements: next-generation sequencing (NGS), reverse transcription-polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC)" (PMID: 37718634).
| Method | Sensitivity | Specificity | Advantages | Limitations |
|---|---|---|---|---|
| RNA-based NGS (preferred) | High (~95%) | High (>99%) | Detects all partners; multiplexed | Requires adequate tissue; RNA quality |
| DNA-based NGS | Moderate-High | High | Part of comprehensive panels; detects co-mutations | May miss some fusions |
| FISH (break-apart) | Moderate (~80%) | Moderate-High | Works on small specimens | Cannot identify fusion partner |
| RT-PCR | High (known fusions) | High | Rapid, cost-efficient | Cannot detect novel partners |
| IHC | Low-Moderate | Low-Moderate | Screening only | Not validated for RET in NSCLC |
"Targeted RNA NGS was confirmed to be the most efficient technique for gene fusion identification in clinical practice" (PMID: 37190044). Sequential DNA→RNA NGS testing increased driver detection to 66% of NSCLC patients (PMID: 34536732).
Other oncogene-driven NSCLC subtypes (generally mutually exclusive): ALK-rearranged, ROS1-rearranged, NTRK fusion-positive, EGFR-mutated, KRAS G12C-mutated, MET exon 14 skipping, BRAF V600E-mutated, HER2-mutated NSCLC. Comprehensive molecular profiling distinguishes these.
| Outcome Metric | Value | Setting | Source |
|---|---|---|---|
| Median OS (selective RET TKI) | 34.3 months | Real-world | PMID: 35838839 |
| Median OS (no RET-targeted therapy) | 17.5 months | Real-world | PMID: 35838839 |
| Median OS (selpercatinib, MAIC) | Not reached | Indirect comparison | PMID: 40458063 |
| Median OS (pralsetinib, MAIC) | 43.9 months | Indirect comparison | PMID: 40458063 |
| 1-year OS (pralsetinib, real-world) | 64.3% | Chinese cohort | PMID: 39497173 |
"Overall survival was prolonged in patients treated with selective RET inhibitors versus untreated patients (median 34.3 versus 17.5 months; p = 0.002) during a median follow-up of 28.7 months. But there was no difference between patients treated with immunotherapy versus untreated patients" (PMID: 35838839).
Selpercatinib (LIBRETTO-001, extended follow-up, PMID: 36122315): - Treatment-naïve: ORR 84% (95% CI 73-92), 6% CR, median DoR 20.2 months, median PFS 22.0 months - Previously treated: ORR 61% (55-67), 7% CR, median DoR 28.6 months, median PFS 24.9 months - Intracranial ORR: 85% (65-96) with 27% CR in measurable CNS metastases
"In treatment-naive patients, the ORR was 84% (95% CI, 73 to 92); 6% achieved complete responses (CRs). The median DoR was 20.2 months (95% CI, 13.0 to could not be evaluated); 40% of responses were ongoing at the data cutoff" (PMID: 36122315)
Selpercatinib (LIBRETTO-431, PMID: 37870973): - First-line: "median progression-free survival was 24.8 months (95% CI, 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001)"
Pralsetinib (ARROW, PMID: 35973665): - Treatment-naïve: ORR 72% (60-82%), median PFS 13.0 months - Previously treated: ORR 59% (50-67%), median PFS 16.5 months
Indirect comparison: PFS 22.1 vs 13.3 months for selpercatinib vs pralsetinib (HR 0.67; 95% CI 0.53-0.85) (PMID: 40458063)
Meta-analysis of selective RET inhibitors: Combined ORR 67%, DCR 92%, mPFS 16.09 months, intracranial ORR 86% (PMID: 37603207)
| Parameter | Selpercatinib | Pralsetinib |
|---|---|---|
| Grade ≥3 TRAEs | 39.3% | 62.6% |
| Discontinuation due to TRAEs | 3.6% | 10.0% |
| Key grade ≥3 AEs | Hypertension, elevated ALT/AST | Neutropenia, anemia, hypertension |
| Agent | Key Features | Status |
|---|---|---|
| Vepafestinib (TAS0953/HM06) | "Best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations" and high CNS penetration (PMID: 37743366) | Phase 1/2 |
| APS03118 | Novel tricyclic scaffold; potent against wild-type and mutant RET (PMID: 40920215) | Preclinical/Early clinical |
| HSN608 | Inhibits all six G810 mutants and V804M gatekeeper with IC50 <50 nmol/L; oral bioavailability confirmed (PMID: 37070927) | Preclinical |
| CQ1373 | Pyrazolo derivative; potent cellular activity against G810C/R (PMID: 39879936) | Preclinical |
| LOXO-260 | Next-gen selective RET inhibitor | Clinical trials |
All newly diagnosed advanced NSCLC → Comprehensive NGS
↓
RET fusion detected → First-line selpercatinib (preferred)
↓
Progression → Determine resistance mechanism (biopsy + ctDNA)
├── G810 mutation → Next-gen RET inhibitor (clinical trial)
├── MET amplification → RET + MET inhibitor combination
├── Other bypass → Pathway-specific combination
└── No targetable mechanism → Chemotherapy ± clinical trial
| Species | NCBI Taxon | Gene | NCBI Gene ID |
|---|---|---|---|
| Homo sapiens | 9606 | RET | 5979 |
| Mus musculus | 10090 | Ret | 19713 |
| Rattus norvegicus | 10116 | Ret | 24716 |
| Danio rerio | 7955 | ret | 30511 |
| Canis lupus familiaris | 9615 | RET | 484504 |
RET is highly conserved across vertebrates. Key findings from knockout studies:
| Model | Description | Phenotype Recapitulation |
|---|---|---|
| Ret knockout | Ret−/− mice | Renal agenesis, absent enteric neurons (lethal) (PMID: 8657282) |
| GFRα1 knockout | GFRα1−/− mice | Absent enteric neurons, kidney agenesis (PMID: 9728913) |
| KIF5B-RET transgenic | Lung-specific inducible expression | Lung adenocarcinoma; used for TKI evaluation |
| CDX xenograft (KIF5B-RET G810C) | Cell-derived xenograft | Selpercatinib-resistant tumors; validates next-gen inhibitors (PMID: 37070927) |
| Patient-derived xenografts | Various RET fusions | Resistance mechanism studies (PMID: 31988000) |
| Cell Line | Fusion | Applications |
|---|---|---|
| LC-2/ad (Cellosaurus: CVCL_1371) | CCDC6-RET | Drug sensitivity; vandetanib-resistant clones for resistance studies (PMID: 38768929) |
| Ba/F3 (engineered) | Various RET fusions/mutants | Kinase activity profiling; G810 mutant IC50 determination |
| TPC-1 | CCDC6-RET | Thyroid cancer RET model; cross-tumor type studies |
RET gene rearrangements occur in approximately 1–2% of NSCLC, defining a distinct molecular subtype with unique clinicopathological features. A pan-tumor RNA sequencing survey established that "KIF5B (46.8%) was the most common fusion partner followed by CCDC6 (28.3%) and NCOA4 (13.8%) in RET+ solid tumors" (PMID: 37516008). These fusions are mutually exclusive with other oncogenic drivers and represent a paradigm for precision oncology. The large multicenter cohort of 268 patients confirmed the characteristic clinical profile: "The median age at diagnosis was 58 years; most patients were female (57.0%) and never/light smokers (60.8%)" (PMID: 41707338).
The LIBRETTO-431 phase 3 randomized trial established selpercatinib as the preferred first-line treatment for RET-fusion NSCLC. The study demonstrated "median progression-free survival was 24.8 months (95% confidence interval [CI], 16.9 to not estimable) with selpercatinib and 11.2 months (95% CI, 8.8 to 16.8) with control treatment (hazard ratio for progression or death, 0.46; 95% CI, 0.31 to 0.70; P<0.001)" (PMID: 37870973). This represents a more than doubling of PFS, with a 54% reduction in the risk of progression or death. The benefit was consistent in the East Asian subgroup (HR 0.38) (PMID: 40980186).
ctDNA analysis "revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front before the emergence of clinical resistance" (PMID: 31988000), with convergent evolution on the G810 residue across multiple metastatic sites. Off-target bypass mechanisms complement on-target resistance: "Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification" (PMID: 33007380). Additional bypass pathways include AXL activation, IGF-1R activation, and SMARCA4 loss (PMID: 38768929).
RET-fusion NSCLC harbors a characteristically immune-cold microenvironment. Multi-omics analysis confirmed "EGFR and ALK/RET/ROS1 fusions... all linked to immune-cold phenotypes with low tumor mutational burden (TMB) and poor T-cell infiltration" (PMID: 41424613). Genomic profiling showed "RET rearrangements were associated with lower TMB and PD-L1+/TMB-H proportions" (PMID: 33655698). This directly translates to clinical outcomes: immunotherapy provides no OS benefit over no treatment (PMID: 35838839).
Vepafestinib demonstrates "best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations" with high CNS penetration (PMID: 37743366). Preclinical studies of alkynyl nicotinamide-based compounds show that "six of these compounds inhibited all six G810 solvent-front mutants and the V804M gatekeeper mutant with IC50 < 50 nmol/L in cell culture" (PMID: 37070927). Novel agents APS03118 (PMID: 40920215) and CQ1373 (PMID: 39879936) provide additional pipeline options.
The biology of RET-rearranged NSCLC follows a coherent mechanistic chain:
This model explains both the exceptional therapeutic responses to targeted therapy (oncogene addiction) and the predictable emergence of resistance (evolutionary selection under drug pressure).
| Trial | Phase | Key Results | PMID |
|---|---|---|---|
| LIBRETTO-431 | 3 | Selpercatinib 1L: PFS 24.8 vs 11.2 mo (HR 0.46, P<0.001) | 37870973 |
| LIBRETTO-001 | 1/2 | Selpercatinib: ORR 84% (1L), 61% (2L+); iORR 85% | 32846060, 36122315 |
| LIBRETTO-321 | 2 | Selpercatinib in Chinese: durable responses | 39759832 |
| ARROW | 1/2 | Pralsetinib: ORR 72% (1L), 59% (2L+); iRR 70% | 35973665 |
| LIBRETTO-432 | 3 | Adjuvant selpercatinib (ongoing) | 38372058 |
| Study Focus | Key Finding | PMID |
|---|---|---|
| Discovery of KIF5B-RET | First identification via WGS in 2012 | 22194472 |
| RET solvent front resistance | G810R/S/C emergence on ctDNA before clinical progression | 31988000 |
| Off-target resistance | MET amp (15%), KRAS amp as bypass mechanisms | 33007380 |
| Immune-cold phenotype | Low TMB, poor T-cell infiltration in fusion-driven NSCLC | 41424613 |
| Vepafestinib | Best-in-class selectivity with G810 activity | 37743366 |
| RET biology | Essential for kidney and enteric nervous system development | 24022366 |
| Novel resistance pathways | AXL, IGF-1R, SMARCA4, mitochondrial dysfunction | 38768929 |
| Study | Key Finding | PMID |
|---|---|---|
| Selective RET TKI vs no targeted therapy | OS 34.3 vs 17.5 months (p=0.002) | 35838839 |
| Chinese real-world RET-TKI | 1L ORR 73.1%, mPFS 22.7 months | 39563271 |
| Latin American cohort | Consistent molecular features; limited RET-TKI access | 41005103 |
| Real-world pralsetinib | Prior treatment reduces efficacy | 39926433 |
Limited mature OS data from phase 3 trials: LIBRETTO-431 demonstrated PFS superiority, but mature overall survival data are still awaited. Current OS estimates rely on real-world studies and indirect comparisons.
Incomplete resistance landscape: G810 solvent front mutations and select bypass mechanisms are characterized, but non-genetic resistance mechanisms (epigenetic, transcriptomic adaptation) remain poorly understood.
Lack of perioperative trial results: LIBRETTO-432 (adjuvant selpercatinib) is ongoing. Optimal perioperative strategy for early-stage RET-fusion NSCLC is undefined.
Limited fusion partner biology understanding: The biological and clinical significance of rare fusion partners and their differential impact on drug response is poorly characterized.
Epidemiological data gaps: Prevalence estimates are based largely on East Asian and Western cohorts. Data from Africa, South America (except emerging Latin American data), and other regions are sparse.
Cost-effectiveness concerns: Selective RET inhibitors may not be cost-effective at current pricing relative to chemotherapy at US WTP thresholds (PMID: 37854153).
No validated predictive biomarkers beyond fusion status: It is unclear whether specific fusion partners, co-mutations, or baseline ctDNA levels predict differential response to specific RET inhibitors.
Limited single-cell and spatial transcriptomics data specific to RET-fusion NSCLC; most studies combine rare driver mutations together.
Screening gap: Most RET-fusion patients are never-smokers who fall outside current LDCT screening criteria, representing an unmet detection need.
| Term ID | Term Name |
|---|---|
| MONDO:0005233 | Non-small cell lung carcinoma |
| Term ID | Term Name |
|---|---|
| HP:0012735 | Cough |
| HP:0002094 | Dyspnea |
| HP:0002105 | Hemoptysis |
| HP:0100749 | Chest pain |
| HP:0001824 | Weight loss |
| HP:0012378 | Fatigue |
| HP:0002653 | Bone pain |
| HP:0002315 | Headache |
| HP:0002202 | Pleural effusion |
| Term ID | Term Name | Category |
|---|---|---|
| GO:0006468 | Protein phosphorylation | Biological process |
| GO:0007169 | RTK signaling pathway | Biological process |
| GO:0008283 | Cell population proliferation | Biological process |
| GO:0006915 | Apoptotic process | Biological process |
| GO:0001525 | Angiogenesis | Biological process |
| GO:0001837 | EMT | Biological process |
| GO:0005886 | Plasma membrane | Cellular component |
| GO:0005737 | Cytoplasm | Cellular component |
| GO:0005634 | Nucleus | Cellular component |
| GO:0005739 | Mitochondrion | Cellular component |
| Term ID | Term Name |
|---|---|
| CL:0002063 | Type II pneumocyte |
| CL:0002328 | Bronchial epithelial cell |
| CL:0000625 | CD8-positive T cell |
| CL:0000235 | Macrophage |
| Term ID | Term Name |
|---|---|
| UBERON:0002048 | Lung |
| UBERON:0002481 | Bone tissue |
| UBERON:0000977 | Pleura |
| UBERON:0000955 | Brain |
| UBERON:0002107 | Liver |
| UBERON:0001004 | Respiratory system |
| Term ID | Term Name |
|---|---|
| MAXO:0001001 | Targeted therapy |
| MAXO:0000930 | Chemotherapy |
| MAXO:0001344 | Immunotherapy |
| MAXO:0000004 | Surgical procedure |
| MAXO:0000527 | Smoking cessation counseling |
| Resource | Identifier | Description |
|---|---|---|
| OMIM | 164761 | RET proto-oncogene |
| HGNC | HGNC:9967 | RET gene symbol |
| NCBI Gene | 5979 | RET gene |
| UniProt | P07949 | RET_HUMAN protein |
| PDB | 7JU6 | RET + selpercatinib co-crystal |
| PDB | 7JU5 | RET + pralsetinib co-crystal |
| ChEMBL | CHEMBL4559134 | Selpercatinib |
| Cellosaurus | CVCL_1371 | LC-2/ad cell line |
| ICD-10 | C34 | Malignant neoplasm of bronchus and lung |
| MeSH | D002289 | Carcinoma, Non-Small-Cell Lung |
Comprehensive disease profile compiled from systematic analysis of 96 peer-reviewed publications across 5 research iterations. All citations verified against original abstracts. Report prepared May 2026.