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BIOMARKER:

RET fusion

i
Other names: RET, Ret Proto-Oncogene, Proto-Oncogene Tyrosine-Protein Kinase Receptor Ret, Cadherin-Related Family Member 16, Rearranged During Transfection, RET Receptor Tyrosine Kinase, Cadherin Family Member 12, Proto-Oncogene C-Ret, CDHF12, CDHR16, PTC, Ret Proto-Oncogene (Multiple Endocrine Neoplasia And Medullary Thyroid Carcinoma 1, Hirschsprung Disease), Multiple Endocrine Neoplasia And Medullary Thyroid Carcinoma 1, Hirschsprung Disease 1, RET-ELE1, HSCR1, MEN2A, MEN2B, RET51, MTC1
Entrez ID:
6d
Despite the challenges of the past year brought on by the COVID-19 pandemic, progress continues to be made in neuro-oncology. These include first-of-their-kind FDA approvals and Guidances that are relevant to the management of patients with nervous system tumors.
Review • Journal
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HER-2 (Human epidermal growth factor receptor 2) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene)
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RET fusion • ALK positive • RET positive
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Koselugo (selumetinib) • Alunbrig (brigatinib) • Retevmo (selpercatinib) • Gavreto (pralsetinib) • Tukysa (tucatinib)
17d
Mutations in RAD54L (P=0.018) and MYC (P=0.04) were more common in FP patients; HPD patients showed more frequent RAD54L mutations (P<0.001). We demonstrated different genomic characteristics across different progression patterns following ICI treatment, which might assist clinicians in the prediction of a patient's response, identifying candidates for more effective ICI therapy.
Clinical • Journal • Checkpoint inhibition • Tumor Mutational Burden • IO biomarker
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • RAD54L (DNA Repair And Recombination Protein RAD54) • CDKN1B (Cyclin dependent kinase inhibitor 1B)
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KRAS mutation • EGFR mutation • HER-2 amplification • MET amplification • HER-2 mutation • RET fusion • EGFR amplification • ALK fusion • ALK mutation • MET mutation • ATRX mutation • ALK amplification • RAD54L mutation • NTRK1 mutation
19d
P2, N=86, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Jul 2021 --> Jul 2022 | Trial primary completion date: Jul 2021 --> Jul 2022
Clinical • Trial completion date • Trial primary completion date
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RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • KIF5B (Kinesin Family Member 5B) • AXL (AXL Receptor Tyrosine Kinase) • NTRK (Neurotrophic receptor tyrosine kinase)
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RET fusion • MET overexpression • KIF5B-RET fusion • ROS1 fusion • AXL overexpression • NTRK fusion
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Cabometyx (cabozantinib tablet)
21d
Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC.
Clinical • P1/2 data • Clinical Trial,Phase I • Clinical Trial,Phase II • Journal
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RET (Ret Proto-Oncogene)
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RET fusion • RET positive
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Gavreto (pralsetinib)
25d
In pediatric fusion-oncogene PTC cases with 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric PTC patients.
Clinical • Journal
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ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • CCDC6 (Coiled-Coil Domain Containing 6) • DICER1 (Dicer 1 Ribonuclease III) • NTRK (Neurotrophic receptor tyrosine kinase)
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BRAF V600E • BRAF V600 • NTRK1 fusion • RET fusion • ALK fusion • CCDC6-RET fusion • TPR-NTRK1 fusion
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Vitrakvi (larotrectinib) • Retevmo (selpercatinib)
26d
Selpercatinib (RETEVMO), a targeted inhibitor of RET, was approved by the US Food and Drug Administration for the treatment of RET fusion-positive nonsmall cell lung cancer and nonmedullary thyroid cancer emphasizing the need for rapid and accurate diagnosis of RET fusions...Abbott Molecular break-apart FISH probes can be used to detect RET fusions. Laboratories can optimize cutoffs and/or testing algorithms to maximize sensitivity and specificity to ensure appropriate patients receive effective, timely therapy.
Journal
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RET (Ret Proto-Oncogene)
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RET fusion • RET rearrangement • RET positive
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Retevmo (selpercatinib)
1m
This is one of the largest cohorts of pediatric PTCs. Fusion-driven tumors most frequently show aggressive pathological features; the search for rearrangements, especially in tumors with solid areas, could improve the characterization of pediatric PTCs and offer possible therapeutic options.
Clinical • Journal
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BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • NRAS (Neuroblastoma RAS viral oncogene homolog) • RET (Ret Proto-Oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • PPARG (Peroxisome Proliferator Activated Receptor Gamma)
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NRAS mutation • BRAF mutation • NTRK3 fusion • RET fusion • ALK rearrangement • RET mutation • RET rearrangement
1m
However, injection of the Wnt/β-catenin pathway activator attenuated the effects of Klotho overexpression. Klotho inhibits cell proliferation in RET fusion models of PTC by inhibiting the Wnt/β-catenin pathway, providing a potential target for developing treatment for PTC.
Journal
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RET (Ret Proto-Oncogene) • CCND1 (Cyclin D1) • KL (Klotho)
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RET fusion • CCND1 expression • KL overexpression
1m
Furthermore, TP53 mutations being the most common genomic co-alterations in ALK+ NSCLC also contribute to the heterogeneous response to ALK TKIs. Recognizing ALK+ NSCLC is not one homogeneous disease entity but comprised of different ALK fusion variants with different underlying genomic alterations in particular TP53 mutations that modulate treatment response will provide insight into the further optimization of treatment of ALK+ NSCLC patients potentially leading to improvement in survival.
Review • Journal
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ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • EML4 (EMAP Like 4)
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TP53 mutation • RET fusion • ALK positive • ALK fusion • ROS1 fusion • ALK mutation • ALK G1202R • EML4-ALK G1202R
1m
No new safety concerns were observed, nor where there any treatment-related death. In this real-world setting, the selective RET-inhibitor selpercatinib demonstrated durable systemic and intracranial antitumor activity in RET fusion-positive NSCLC and was well tolerated.
Retrospective data • Journal
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RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
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Retevmo (selpercatinib)
1m
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
1m
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
1m
Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes.
Clinical • Journal • PD(L)-1 Biomarker • IO biomarker
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PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • RET (Ret Proto-Oncogene) • NF1 (Neurofibromin 1) • CCDC6 (Coiled-Coil Domain Containing 6)
|
PD-L1 expression • TP53 mutation • EGFR mutation • PD-L1 overexpression • RET fusion • NF1 mutation • CCDC6-RET fusion • RET mutation
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Keytruda (pembrolizumab)
1m
Recently, two selective and potent RET-inhibitors were approved for the treatment of patients with metastatic RET-fusion-positive lung cancer (RET-NSCLC). Here, we discuss the two RET-inhibitors selpercatinib and pralsetinib, and the management of patients with RET-fusion positive NSCLC.
Review • Journal
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RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
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Retevmo (selpercatinib) • Gavreto (pralsetinib)
1m
Selpercatinib and pralsetinib are RET-selective tyrosine kinase inhibitors (TKIs) with encouraging efficacy, intracranial activity, and tolerability that we recommend as first-line therapy...Alternatively, or in the absence of such findings, platinum doublet chemotherapy or particularly platinum-pemetrexed therapy with or without bevacizumab demonstrates a moderate effect.We would not recommend the routine use of nonselective multi-targeted TKIs such as cabozantinib and vandetanib, which have modest activity but limited tolerability due to predictable off-target effects...While further development of novel RET-selective TKIs may address common RET-specific resistance mutations, they will not have activity against off-target, RET-independent resistance mechanisms. This again highlights the importance of serial biopsy and next-generation sequencing for the rational choice of sequential therapy in RET fusion-positive NSCLC.
Clinical • Review • Journal • IO biomarker
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KRAS (KRAS proto-oncogene GTPase) • RET (Ret Proto-Oncogene)
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RET fusion • RET positive
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Avastin (bevacizumab) • Cabometyx (cabozantinib tablet) • pemetrexed • Retevmo (selpercatinib) • Caprelsa (vandetanib) • Gavreto (pralsetinib)
1m
In the Guardant Health database, progression-free survival was unavailable, and the median overall survival was not reached (n = 29). Outcomes associated with ICI-based treatments in the first-line setting among patients with RET fusion-positive NSCLC are consistent with unselected populations reported in literature.
Clinical • Journal • Checkpoint inhibition
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RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Retevmo (selpercatinib)
1m
Clinical
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ALK (Anaplastic lymphoma kinase)
|
RET fusion • ROS1 fusion
2ms
Recently, new high selective RET inhibitors blu-667 and loxo-292 have made important breakthroughs. This paper will review the review of the fusion mutation of RET gene in NSCLC, the detection methods, clinicopathological characteristics, targeted treatment and the research progress after drug resistance..
Journal
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
RET fusion • RET mutation • ROS1 fusion
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Retevmo (selpercatinib) • Gavreto (pralsetinib)
2ms
Pralsetinib is a new, well-tolerated, potent once-daily oral treatment option for patients with RET-altered thyroid cancer.
Clinical • P1/2 data • Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation • RET positive
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Cabometyx (cabozantinib tablet) • Caprelsa (vandetanib) • Gavreto (pralsetinib)
2ms
Clinical • Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion
2ms
Clinical
|
RET (Ret Proto-Oncogene)
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RET fusion
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Retevmo (selpercatinib)
2ms
Therefore, genetic testing, including at least EGFR mutations and ALK/ROS1 rearrangements, should be performed in all NSCLC patients (in particular with adenocarcinoma) who received a diagnosis of advanced disease. This review focuses on novel druggable oncogenic drivers, such as MET exon 14 mutations/MET amplification, RET fusions, BRAF V600E mutations, KRAS G12C mutations, NTRK rearrangements, and HER2 alterations.
Review • Journal
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
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BRAF V600E • KRAS mutation • EGFR mutation • BRAF V600 • KRAS G12C • MET amplification • RET fusion • ALK rearrangement • MET exon 14 mutation • RET mutation • MET mutation • ROS1 rearrangement • KRAS G12 • BRAF amplification
2ms
Selpercatinib has robust and durable intracranial efficacy in RET fusion-positive NSCLC patients.
Clinical • Journal
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RET (Ret Proto-Oncogene)
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RET fusion • RET positive
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Retevmo (selpercatinib)
2ms
Design, eligibility criteria and key findings from the Phase II VISION trial leading to the recent FDA approval of tepotinib for patients with metastatic NSCLC harboring MET exon 14 skipping alterations Rationale for the design of the ongoing Phase II NAUTIKA1 neoadjuvant and adjuvant study of alectinib, entrectinib, vemurafenib/cobimetinib or pralsetinib for patients with resectable Stage II-III NSCLC harboring ALK, ROS1, NTRK, BRAF V600 or RET molecular alterations Key efficacy and safety outcomes from the Phase II GEOMETRY mono-1 trial supporting the FDA approval of capmatinib for patients with MET exon 14 mutation-positive metastatic NSCLC Practical integration and optimal sequencing of capmatinib and tepotinib into current clinical management of patients with advanced NSCLC harboring MET exon 14 skipping alterations Available safety and efficacy results from the LIBRETTO-001 and ARROW trials leading to the FDA approvals of selpercatinib and pralsetinib for patients with RET fusion-driven NSCLC; optimal integration into clinical practice Design, eligibility and key endpoints of the Phase III LIBRETTO-431 and AcceleRET Lung studies assessing selpercatinib and pralsetinib, respectively, compared to first-line chemotherapy with or without pembrolizumab in patients with treatment-naïve RET fusion-positive advanced NSCLC Frequency and clinical impact of HER2 overexpression or mutations in NSCLC; key efficacy and safety findings from the Phase II DESTINY-Lung01 study evaluating trastuzumab deruxtecan in HER2-overexpressing or mutated NSCLC FDA breakthrough therapy designation and potential nonprotocol role of trastuzumab deruxtecan in patients with HER2-positive metastatic NSCLC Clinical impact of HER3 upregulation as a mechanism of resistance to EGFR tyrosine kinase inhibitors; early efficacy and safety findings with patritumab deruxtecan in a Phase I trial for previously treated patients with EGFR mutation-positive unresectable or metastatic NSCLC Ongoing Phase II HERTHENA-Lung01 trial of patritumab deruxtecan for patients with locally advanced or metastatic EGFR mutation-positive NSCLC who have received prior treatment with osimertinib and at least 1 platinum-based chemotherapy regimen Design, eligibility criteria and key endpoints of the ongoing Phase III GEOMETRY-E trial of capmatinib in combination with osimertinib versus chemotherapy as second-line therapy for patients with locally advanced or metastatic NSCLC harboring non-T790M EGFR activating mutations as well as MET amplification after disease progression on a first/second EGFR tyrosine kinase inhibitor or osimertinib Mechanism of action of sotorasib and available efficacy and safety data from the Phase II CodeBreak 100 trial evaluating sotorasib in patients with previously treated KRAS G12C mutation-positive NSCLC; FDA priority review for sotorasib for KRAS G12C-mutated advanced NSCLC Other ongoing and planned clinical trials investigating novel agents and strategies for patients with advanced NSCLC harboring targetable gene alterations (eg, ECOG-ACRIN LUNG-MAP)
Clinical • PD(L)-1 Biomarker
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • NTRK (Neurotrophic receptor tyrosine kinase)
|
KRAS mutation • HER-2 positive • EGFR mutation • HER-2 overexpression • BRAF V600 • KRAS G12C • MET amplification • EGFR T790M • RET fusion • MET exon 14 mutation • MET mutation • KRAS G12 • RET positive
|
Keytruda (pembrolizumab) • Zelboraf (vemurafenib) • Tagrisso (osimertinib) • Rozlytrek (entrectinib) • Cotellic (cobimetinib) • Alecensa (alectinib) • Enhertu (fam-trastuzumab deruxtecan-nxki) • Lumakras (sotorasib) • Retevmo (selpercatinib) • Gavreto (pralsetinib) • patritumab deruxtecan (U3-1402) • Tepmetko (tepotinib) • Tabrecta (capmatinib)
2ms
We demonstrated translational relevance of PDOs in advanced lung adenocarcinoma. PDOs are an important diagnostic tool which can assist clinical decision making and accelerate development of therapeutic strategies.
Clinical • Journal
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • RET (Ret Proto-Oncogene)
|
EGFR mutation • BRAF mutation • EGFR exon 19 deletion • RET fusion • EGFR L747P • HER-2 exon 20 mutation
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Mekinist (trametinib) • Gilotrif (afatinib) • Tafinlar (dabrafenib) • Gavreto (pralsetinib) • poziotinib (HM 78136B)
2ms
Currently, several approved multikinase inhibitors such as vandetanib and cabozantinib demonstrate clinical activity in patients with RET-rearranged or RET-mutant cancers...Herein, we designed and synthesized a series of RET inhibitors based on the structure of selective RET inhibitor BLU-667 and investigated their biological activities...In mouse xenograft models, compound 9 repressed tumor growth driven by KIF5B-RET-Ba/F3 cells in a dose-dependent manner. Based on its exceptional kinase selectivity, good potency and high exposure in tumor tissues, compound 9 represents a promising lead for the discovery of RET directed therapeutic agents and the study of RET-driven tumor biology.
Journal
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RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B)
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RET fusion • KIF5B-RET fusion • RET M918T • RET mutation • RET V804M • RET V804*
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Cabometyx (cabozantinib tablet) • Caprelsa (vandetanib) • Gavreto (pralsetinib)
2ms
The product label includes warnings and precautions for pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, tumor lysis syndrome, risk of impaired wound healing, and embryo-fetal toxicity. This article summarizes the major considerations during the FDA review leading to the approval of pralsetinib.
FDA event • Review • Journal
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RET (Ret Proto-Oncogene)
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RET fusion • RET mutation • RET positive
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Gavreto (pralsetinib)
2ms
FDA approval has now been given for selpercatinib for RET fusion-positive NSCLC and papillary thyroid cancer, and RET mutation-positive thyroid cancer. This Editorial aims to present a brief overview of the evolution of personalized medicine in oncology and how the 2021 ESMO guidelines have anticipated the need to detect targetable RET-altered tumors using technology currently available in accredited clinical diagnostic laboratories.
Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation • RET rearrangement • RET positive
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Retevmo (selpercatinib)
3ms
This large study demonstrates that almost half of Bethesda III/IV Afirma GSC suspicious and most Bethesda V/VI nodules had at least 1 genomic variant or fusion identified, which may optimize personalized treatment decisions.
Journal
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BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
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BRAF V600E • BRAF V600 • RET fusion • ALK fusion
3ms
IDC of the minor salivary glands is exceedingly rare. We discuss diagnostic problems associated with minor salivary gland lesions, and the "basal-like" phenotype of this case.
Clinical • Journal
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EGFR (Epidermal growth factor receptor) • RET (Ret Proto-Oncogene) • AR (Androgen receptor) • NCOA4 (Nuclear Receptor Coactivator 4) • SOX10 (SRY-Box 10) • KRT19 (Keratin 19) • TP63 (Tumor protein 63)
|
RET fusion • NCOA4-RET fusion
3ms
New P2 trial
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EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
RET fusion • ALK rearrangement • MET exon 14 mutation • ALK fusion • RET rearrangement • ROS1 fusion • ROS1 rearrangement
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carboplatin • gemcitabine • Imfinzi (durvalumab) • Abraxane (albumin-bound paclitaxel) • pemetrexed
3ms
Typically regarded to have ETV6-NTRK3 fusions, secretory carcinomas may alternatively arise with RET fusions as well. Adding our cohort of 6 NCOA4-RET fusion-positive IC compared with 4 cases of secretory carcinoma with ETV6-RET fusions and a single case of fusion-negative IC with salivary duct carcinoma-like genetics, we propose a diagnostic algorithm that integrates histological elements, including atypia and invasiveness, and the likelihood of specific molecular alterations to increase diagnostic accuracy in what can be a very subtle diagnosis with important clinical implications.
Journal
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RET (Ret Proto-Oncogene) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • ETV6 (ETS Variant Transcription Factor 6) • NCOA4 (Nuclear Receptor Coactivator 4) • SOX10 (SRY-Box 10)
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NTRK3 fusion • RET fusion • ETV6-NTRK3 fusion • RET rearrangement • NCOA4-RET fusion • RET positive
3ms
Herein, we outline utility of various diagnostic techniques, provide evidence to guide management of RET-fusion-positive Non-Small Cell Lung Cancer (NSCLC) patients, including specific patient groups, such as EGFR-mutant NSCLC patients who acquired RET fusions after resisting EGFR TKIs, and offer a compendium of mechanisms of acquired resistance to RET targeted therapies. This review further provides a list of ongoing clinical trials and summarizes perspectives to guide future development of drugs and trials for this population.
Review • Journal
|
EGFR (Epidermal growth factor receptor) • RET (Ret Proto-Oncogene)
|
EGFR mutation • RET fusion • RET mutation • RET positive
3ms
The safety profile of lenvatinib in ATC was manageable, and many AEs were attributable to the progression of ATC. The results suggest that lenvatinib monotherapy may not be an effective treatment for ATC; further investigation may be warranted.
Clinical • P2 data • Journal
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BRAF (B-raf proto-oncogene) • RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
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BRAF mutation • RET fusion • RET mutation
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lenvatinib
3ms
In our population, KK-LC-1 expression was higher in adenocarcinoma . Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with higher TMB while lower levels of expression were seen in driver positive cancers including EGFR, ALK, MET, RET and ROS1 . TCR-T therapy directed against KK-LC-1 should be explored in patients whose clinical features reflect these characteristics.
PD(L)-1 Biomarker • IO biomarker
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
PD-L1 expression • KRAS mutation • TMB-H • EGFR mutation • RET fusion • ALK positive • MET exon 14 mutation • ALK fusion • RET mutation • ROS1 fusion • MET mutation
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PD-L1 IHC 22C3 pharmDx • MI Tumor Seek™
3ms
FDA approved systemic therapies for metastatic radioiodine refractory differentiated thyroid cancer (RR-DTC) include multikinase inhibitors (Lenvatinib and sorafenib), NTRK inhibitors (larotrectinib and entrectinib for NTRK fusion+ cancers), and RET inhibitors (selpercatinib and pralsetinib for RET fusion+ cancers) . The trial design includes continuous toxicity monitoring with a Pocock-type stopping boundary . This clinical trial is in progress and 3 patients have been enrolled.
Clinical • PD(L)-1 Biomarker • IO biomarker
|
BRAF (B-raf proto-oncogene) • RET (Ret Proto-Oncogene) • PD-1 (Programmed cell death 1) • NTRK (Neurotrophic receptor tyrosine kinase)
|
PD-L1 expression • BRAF V600E • BRAF mutation • BRAF V600 • RET fusion • RET mutation • NTRK fusion
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Opdivo (nivolumab) • Vitrakvi (larotrectinib) • Nexavar (sorafenib) • Rozlytrek (entrectinib) • lenvatinib • Braftovi (encorafenib) • Mektovi (binimetinib) • Retevmo (selpercatinib) • Gavreto (pralsetinib)
3ms
Pts with RET mutant medullary thyroid cancer (MTC) previously treated with multikinase inhibitors (cabozantinib and/or vandetanib) were enrolled in the global LIBRETTO-001 trial (NCT03157128)... Prior to selpercatinib, response with previous multikinase therapy was rare . By contrast, selpercatinib demonstrated robust efficacy regardless of response to or specific prior therapy in pts with RET mutant MTC.
Clinical
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RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation
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Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Caprelsa (vandetanib)
3ms
LCNEC displays a broad pattern of genomic alterations that overlap in the SCLC-like subset with the classic alterations in SCLC . The distinct genomic alterations and transcriptomic profiles present opportunities for therapeutic targeting and inform a future framework for development of therapeutics for LCNEC.
Tumor Mutational Burden • PD(L)-1 Biomarker • IO biomarker
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EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • PD-L1 (Programmed death ligand 1) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • TMB (Tumor Mutational Burden) • RET (Ret Proto-Oncogene) • PTEN (Phosphatase and tensin homolog) • FGFR1 (Fibroblast growth factor receptor 1) • STK11 (Serine/threonine kinase 11) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • RB1 (RB Transcriptional Corepressor 1) • NF1 (Neurofibromin 1) • CCND1 (Cyclin D1) • KEAP1 (Kelch Like ECH Associated Protein 1) • CCNE1 (Cyclin E1) • FGF19 (Fibroblast growth factor 19) • KMT2D (Lysine Methyltransferase 2D) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • SLFN11 (Schlafen Family Member 11) • FOXA1 (Forkhead Box A1) • NTRK (Neurotrophic receptor tyrosine kinase) • TNFRSF14 (TNF Receptor Superfamily Member 14)
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PD-L1 expression • BRAF V600E • TP53 mutation • KRAS mutation • TMB-H • EGFR mutation • BRAF V600 • KRAS G12C • EGFR L858R • EGFR exon 19 deletion • PTEN mutation • RET fusion • STK11 mutation • KEAP1 mutation • ALK fusion • KRAS G12 • MET expression • FGFR1 fusion • KRAS deletion • NTRK fusion
|
PD-L1 IHC 22C3 pharmDx
3ms
We found one classic EGFR activing mutation (L747_A750delinsP) and one MAP2K1 activating mutation (F53_Q58delinsL), which can be targeted by EGFR-TKIs and MEK inhibitor trametinib, respectively...We also found STK11/TSC2 inactivating mutations and a dominant-negative mutation of PTEN (R130Q) which could be targeted by mTOR inhibitor everolimus and AKT inhibitor capivasertib, respectively... The mutational landscape of our PDAC cohort provided compelling evidence that targetable driver mutations accounted for a significant portion of KRAS wide-type tumors . Our findings demonstrated that genomic profiling of PDAC patients can enable physicians to optimize their clinical management and enroll them into genomically matched clinical trials.
PARP Biomarker • BRCA Biomarker
|
EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • BRCA1 (Breast cancer 1, early onset) • RET (Ret Proto-Oncogene) • PTEN (Phosphatase and tensin homolog) • STK11 (Serine/threonine kinase 11) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3) • PALB2 (Partner and localizer of BRCA2) • TSC2 (TSC complex subunit 2) • NCOA4 (Nuclear Receptor Coactivator 4) • ELF3 (E74 Like ETS Transcription Factor 3)
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BRAF V600E • KRAS mutation • BRCA1 mutation • EGFR mutation • BRAF V600 • MET amplification • PTEN mutation • RET fusion • STK11 mutation • PALB2 mutation • BRAF fusion • TSC2 mutation • ERBB3 mutation • NCOA4-RET fusion • EGFR L747_A750delinsP
|
Onco PanScan™
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Mekinist (trametinib) • everolimus • capivasertib (AZD5363)
3ms
A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab...The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy... It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors . Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors . To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency .
PD(L)-1 Biomarker • Circulating tumor DNA
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RET (Ret Proto-Oncogene)
|
EGFR mutation • EGFR exon 19 deletion • RET fusion • CCDC6-RET fusion
|
Keytruda (pembrolizumab) • Avastin (bevacizumab) • carboplatin • Tagrisso (osimertinib) • Tecentriq (atezolizumab) • paclitaxel • Cabometyx (cabozantinib tablet) • pemetrexed • Retevmo (selpercatinib) • Gavreto (pralsetinib)
3ms
Pralsetinib showed robust, durable antitumor activity in patients with multiple RET fusion‒positive, heavily pre-treated, advanced solid tumors, and was well tolerated . These data highlight the need for broad RET testing to identify candidates who could benefit from treatment with pralsetinib . Enrollment of patients with other RET fusion–positive solid tumors in ARROW is ongoing.
Clinical
|
KRAS (KRAS proto-oncogene GTPase) • RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • CCDC6 (Coiled-Coil Domain Containing 6) • NCOA4 (Nuclear Receptor Coactivator 4) • PIK3CB (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta)
|
KRAS mutation • RET fusion • NCOA4-RET fusion • PIK3CB mutation • RET positive
|
Gavreto (pralsetinib)
3ms
In this updated data set, selpercatinib continued to demonstrate durable antitumor activity in pts with RET-fusion+ NSCLC . Selpercatinib was well-tolerated with a safety profile consistent with previous reports . A global, randomized, phase 3 trial (LIBRETTO-431) evaluating selpercatinib compared with standard frontline therapy is ongoing.
Clinical
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Retevmo (selpercatinib)
3ms
In pts with RET fusion+ NSCLC treated on LIBRETTO-001, systemic therapies administered prior to enrollment achieved less meaningful clinical benefit than selpercatinib . Selpercatinib demonstrated consistent efficacy regardless of the type of prior therapy.
Clinical
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Retevmo (selpercatinib)
3ms
Both the 9-in-1 test and Genexus/OPA had short TATs (3−4 days), high success rates (96−98%) and good concordance (95−98%) compared with another NGS assay (OCA) . These rapid multi-gene assays highly contributed to enabling precision medicine and the development of targeted therapies for advanced NSCLC.
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NRG1 (Neuregulin 1)
|
BRAF V600E • BRAF V600 • NTRK3 fusion • RET fusion • ALK fusion • ROS1 fusion • NRG1 fusion • ALK-ROS1 fusion • NRG1 fusion
|
AmoyDx® Pan Lung Cancer PCR Panel • Oncomine Precision Assay
3ms
Funding: Foundation Medicine Background: The emergence of osimertinib (osi) as standard of care therapy for EGFR-mutant NSCLC has led to investigations into understanding and overcoming drug resistance... Osi resistance in EGFR-mutant NSCLC is a poor prognosis condition . EGFR C797S is a recurring resistance mut which, in a minority of cases, can co-occur with alternate on and off target resistance muts detected with tissue and liquid biopsy.
IO biomarker
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • RET (Ret Proto-Oncogene) • FGFR3 (Fibroblast growth factor receptor 3) • TACC3 (Transforming acidic coiled-coil containing protein 3) • CCDC6 (Coiled-Coil Domain Containing 6) • STRN (Striatin)
|
BRAF V600E • EGFR mutation • HER-2 amplification • BRAF V600 • EGFR L858R • EGFR T790M • EGFR exon 19 deletion • RET fusion • FGFR3-TACC3 fusion • ALK fusion • EGFR C797S • CCDC6-RET fusion • EGFR S768I • BRAF fusion • EGFR G719A • FGFR3 fusion • STRN-ALK fusion • EGFR G724S • EGFR L718Q • EGFR G796S
|
Tagrisso (osimertinib)
3ms
Pralsetinib showed rapid, potent, and durable clinical activity in patients with RET fusion-positive NSCLC (regardless of prior therapies), including poor prognosis patients not eligible for platinum-based therapy . Overall, pralsetinib was well-tolerated . These data highlight the need for RET testing early in the course of disease to identify candidates who may benefit from treatment with pralsetinib.
Clinical
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Gavreto (pralsetinib)
3ms
BOS172738 is a highly potent and selective RET inhibitor with a differentiated safety profile and clinical activity against RET-altered tumors, including patients with brain metastases . BOS172738 continues to be evaluated in patients with NSCLC, MTC, and in patients previously treated with other selective RET inhibitors.
P1 data
|
RET (Ret Proto-Oncogene) • KDR (Kinase insert domain receptor)
|
RET fusion • RET mutation
|
zeteletinib (BOS-172738)
3ms
The lack of pan-TRK immunoreactivity in a subset of SCs is suggestive of atypical exons 4 to 14 or exons 5 to 14 ETV6-NTRK3 fusion or non-NTRK alternative fusion partners such as ETV6-RET. Pan-TRK staining can serve as a strong diagnostic marker to distinguish SC from it mimics and to select patients eligible for TRK inhibitor clinical trials.
Journal
|
RET (Ret Proto-Oncogene) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • ETV6 (ETS Variant Transcription Factor 6) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK3 fusion • RET fusion • ETV6-NTRK3 fusion
3ms
The nodule detection rate was 18.8%, with a 22.5% risk of malignancy among the detected nodules in childhood-onset HT patients, showing increased risk in those with a family history. Additional large-scale studies are required to evaluate the usefulness of K-TIRADS or ACR-TI-RADS risk level for the differentiation of pediatric thyroid nodules.
Clinical • Journal
|
BRAF (B-raf proto-oncogene)
|
RET fusion
3ms
P3, N=170, Not yet recruiting, Loxo Oncology, Inc. | Trial completion date: Apr 2032 --> Nov 2032 | Initiation date: Mar 2021 --> Oct 2021 | Trial primary completion date: Apr 2031 --> Aug 2028
Clinical • Trial completion date • Trial initiation date • Trial primary completion date
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Retevmo (selpercatinib)
4ms
Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.
Journal • Next-generation sequencing
|
RET (Ret Proto-Oncogene) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • NFIB (Nuclear Factor I B) • NR4A3 (Nuclear receptor subfamily 4 group A member 3) • NTRK (Neurotrophic receptor tyrosine kinase) • SS18 (SS18 Subunit Of BAF Chromatin Remodeling Complex) • ZBTB7A (Zinc finger and BTB domain containing 7A) • MAML2 (Mastermind Like Transcriptional Coactivator 2)
|
NTRK2 fusion • RET fusion • MYB-NFIB fusion
4ms
PTC in pediatrics is often metastatic at diagnosis and can be challenging to adequately treat with the current standard of care[MS1] . This case demonstrates the effectiveness of selpercatinib in a 13-year-old patient with RAI-refractory metastatic PTC with a RET-fusion and has been well tolerated. Upfront molecular sequencing of pediatric thyroid cancers with potential use of targeted agents early in treatment should be considered.
Clinical
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET rearrangement • RET positive
|
Retevmo (selpercatinib)
4ms
Comparators in the analysis included pralsetinib, selpercatinib, cabozantinib, pembrolizumab, and combination therapy with pemetrexed/carboplatin... Quantifying the budget impact associated with the adoption of new targeted precision therapies is an important consideration for payers. For metastatic RET+ NSCLC patients, our analysis suggests that adoption of pralsetinib is expected to result in cost savings of $0.0030 PMPM over a 3-year period for US payers.
HEOR
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Keytruda (pembrolizumab) • carboplatin • Cabometyx (cabozantinib tablet) • pemetrexed • Retevmo (selpercatinib) • Gavreto (pralsetinib)
4ms
We demonstrated that the RET inhibitor BLU-667 was effective at inhibiting tumor growth in CUTO42 tumors, but had a much less profound effect in CUTO32 tumors, consistent with our in vitro experiments...Significance Statement We have derived and characterized three novel RET fusion non-small cell lung cancer cell lines and demonstrated that they have differential responses to RET inhibition as well as regulation of downstream signaling; an area that has previously been limited by a lack of diverse cell line modes with endogenous RET fusions. These data offer important insight into regulation of response to RET tyrosine kinase inhibitors and other potential therapeutic targets.
Preclinical • Journal
|
RET (Ret Proto-Oncogene) • EML4 (EMAP Like 4) • KIF5B (Kinesin Family Member 5B) • AURKA (Aurora kinase A) • PLK1 (Polo Like Kinase 1)
|
RET fusion • RET rearrangement • RET expression • RET positive
|
Gavreto (pralsetinib)
4ms
The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.
Review • Journal
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene)
|
MET amplification • RET fusion • KRAS amplification • RET V804L • RET V804*
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
4ms
Somatic interaction analyses implied that young EGFR-positive patients were more likely to also have PIK3CA, MET, TP53 and RB1 mutations than old patients. Lung cancer in young patients, and especially those with adenocarcinoma, exhibited different clinical features and genomic attributes compared to old patients, which should be considered for therapeutic decision-making purposes.
Clinical • Journal • Tumor Mutational Burden
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • MDM2 (E3 ubiquitin protein ligase)
|
TP53 mutation • KRAS mutation • EGFR mutation • PIK3CA mutation • HER-2 mutation • EGFR exon 19 deletion • RET fusion • RB1 mutation • ROS1 fusion • MET mutation • HER-2 exon 20 mutation • EGFR positive
4ms
Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.
Review • Journal • IO biomarker
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
4ms
Direct comparison of different kinase fusions demonstrates that the kinase part and not the fusion partner primarily defines the phosphorylation pattern. The tyrosine phosphorylation patterns differed between ALK, ROS1 and RET fusions, suggesting that oncogenic signaling induced by these kinases involves the modulation of different cellular processes.
Journal
|
ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • EML4 (EMAP Like 4)
|
RET fusion • ALK fusion • ROS1 fusion
4ms
Clinical • New P3 trial
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Retevmo (selpercatinib)
4ms
Two RET inhibitors, selpercatinib and pralsetinib, recently received approval for the treatment of advanced RET fusion-positive lung cancer. Acquired resistance to these inhibitors will be a major challenge. We have shown that resistance can emerge due to recurrent RET kinase domain mutations and, in most cases, due to RET-independent mechanisms.
Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation • RET positive
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
4ms
Loss of the T790M mutation was associated with early resistance to osimertinib, and this was exacerbated by MET amplification. Further work is needed to fully understand the implications of each resistance mechanism.
Clinical • Journal • Next-generation sequencing
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene)
|
KRAS mutation • EGFR mutation • PIK3CA mutation • MET amplification • EGFR T790M • RET fusion • EGFR C797S • RET mutation • MET mutation • EGFR mutation + PIK3CA mutation
|
Tagrisso (osimertinib)
5ms
Furthermore, we describe the genomic sequences in 4 of these cases, 2 of which have previously described KIF5B-RET fusion and 2 of which had a novel LMNA-RET fusion. We believe this report significantly contributes to our current knowledge regarding Spitz neoplasms and describes characteristics features which can help with recognition of the RET subgroup of Spitz.
Journal
|
RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • LMNA (Lamin A/C)
|
RET fusion • KIF5B-RET fusion
5ms
The treatment of advanced differentiated thyroid carcinoma has undergone rapid evolution in the last decade. An emerging treatment era is coming. From now to then, we will need to face the different types of diagnostic tools for molecular characterization, their interpretation and, finally the access to targeted therapies.
Journal
|
RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
|
RET fusion • NTRK fusion
5ms
RNA-based NGS and nCounter show excellent concordance for detection of gene fusions and MET splicing variant in advanced solid tumors.
Clinical
|
EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • EML4 (EMAP Like 4) • FGFR1 (Fibroblast growth factor receptor 1) • NRG1 (Neuregulin 1) • KIF5B (Kinesin Family Member 5B) • ETV6 (ETS Variant Transcription Factor 6) • CCDC6 (Coiled-Coil Domain Containing 6) • HLA-DRB1 (Major Histocompatibility Complex, Class II, DR Beta 1) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK1 fusion • RET fusion • ALK positive • MET exon 14 mutation • ALK fusion • ROS1 fusion • NRG1 fusion • FGFR1 fusion • MET fusion
5ms
Previous researches indicate that NSCLC pts with ERBB2ex20ins are drug-resistant to afatinib, gefitinib and erlotinib. Our results showed that the ERBB2ex20ins mutation tended to occur in younger, female patients. Additionally, ERBB2ex20ins mutated samples exhibited lower levels of TMB compared to wildtype tumors, which may not benefit from anti-PD1 treatment. We also found patients with ERBB2ex20ins mutation have been associated with short PFS and short OS.
Clinical • PD(L)-1 Biomarker • IO biomarker
|
EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ALK (Anaplastic lymphoma kinase) • TP53 (Tumor protein P53) • RET (Ret Proto-Oncogene)
|
HER-2 mutation • RET fusion • HER-2 exon 20 mutation • HER-2 A775
|
erlotinib • Gilotrif (afatinib) • gefitinib
5ms
The tumor agnostic approval of the checkpoint blockade inhibitor, pembrolizumab, in TMB-H solid tumors additionally gave rise to a ~4% increase in Level 1 samples.Analysis of the AACR Project GENIE cohort also revealed significant changes to the OncoKB process, including those reflected in the updated OncoKB Levels of Evidence v2.0...This change was based on clinical data demonstrating that patients with investigational predictive biomarkers for a specific tumor type based on compelling clinical evidence from phase 3 trials (currently Level 3A) are more likely to experience clinical benefit compared to patients with predictive biomarkers that are considered standard care in a different tumor type (previously Level 2B, currently Level 3B), and is consistent with guidelines published by ASCO/AMP/CAP and ESMO.Knowledgebases such as OncoKB have emerged as key informational resources that the clinical oncology and scientific communities have used to rapidly connect sequencing results to clinical actionability. Their utility depends on their ability to stay abreast of clinical data and seamlessly adapt their rules and processes to the evolving field of precision medicine.
Tumor Mutational Burden • PARP Biomarker • PD(L)-1 Biomarker
|
HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • RET (Ret Proto-Oncogene) • FGFR2 (Fibroblast growth factor receptor 2) • NTRK (Neurotrophic receptor tyrosine kinase)
|
BRAF V600E • TMB-H • BRAF V600 • PIK3CA mutation • HER-2 negative • RET fusion • FGFR2 mutation • FGFR2 fusion • NTRK fusion • NTRK positive • RET positive
|
Keytruda (pembrolizumab)
5ms
FDA has approved Retevmo (Selpercatinib) for lung and thyroid cancers with RET gene mutations or fusions... This study revealed the molecular features of RET rearrangement in Chinese cancer pts, which might result in more effective personalized diagnoses and therapies.
Retrospective data • Next-generation sequencing
|
RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • CCDC6 (Coiled-Coil Domain Containing 6) • NCOA4 (Nuclear Receptor Coactivator 4)
|
RET fusion • RET mutation • RET rearrangement • NCOA4-RET fusion • RET positive
|
Retevmo (selpercatinib)
5ms
Very high expression of ALK mRNA in NSCLC is associated with EML4-ALK translocations.In contrast, a significant number of fusion negative patients show high ROS1, RET and NTRK1 mRNAvery high levels. Further research is warranted to determine the clinical relevance of this finding.
Clinical
|
EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • EML4 (EMAP Like 4) • NRG1 (Neuregulin 1) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK1 fusion • RET fusion • ALK positive • EML4-ALK fusion • ALK fusion • ROS1 fusion • ALK translocation • NTRK1 positive • RET expression • NTRK positive
5ms
Patients in the oncogene-driven adenosquamous/squamous group had significantly higher response rates as compared to the historical squamous cell group and no significant difference in response rates as compared to the historical adenocarcinoma comparison group. In summary, contrary to prior studies, this case series does suggest that pemetrexed may be a viable treatment option in patients with squamous cell histology who also have a targetable mutation.
Clinical
|
ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
RET fusion • ROS1 fusion
|
pemetrexed
5ms
Selpercatinib demonstrated promising antitumor activity in RET fusion-positive non-lung/non-thyroid cancers, including multiple treatment-refractory GI malignancies. Broad-based genomic profiling is essential to identify actionable oncogenic drivers, including RET fusions. The safety and efficacy of selpercatinib will continue to be explored in pts with these cancers in the ongoing LIBRETTO-001 study.
Clinical
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Retevmo (selpercatinib)
5ms
Recently, highly potent and selective RET inhibitors, selpercatinib and pralsetinib have been FDA approved for RET fusion+ NSCLC and selpercatinib for RET+ thyroid cancers. RET fusions represent extremely rate events in multiple cancers. RET missense mutations occur in 2% of malignancies. Most RET missense variants are described as variants of unknown significance, limiting the impact of precision oncology for the majority of patients with RET alterations.
Clinical
|
KRAS (KRAS proto-oncogene GTPase) • RET (Ret Proto-Oncogene) • EZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase)
|
RET fusion • RET mutation
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
5ms
Previous studies in pts treated with selpercatinib or pralsetinib have reported the shared emergence of recurrent RET G810 mutations at the solvent front of the ATP pocket, which lead to a steric clash and loss of binding potency for both drugs. These data suggest that LOX-18228, as well as closely related compounds, represent promising next-generation RET inhibitor candidates that could be used to further extend durable disease control for pts with RET-altered cancers following the development of acquired resistance to current agents. An IND is planned for 2021.
Preclinical
|
RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • CCDC6 (Coiled-Coil Domain Containing 6)
|
RET fusion • KIF5B-RET fusion • RET M918T • RET mutation • RET V804M • RET V804* • RET positive
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
5ms
To overcome these issues, new selective RET inhibitors such as pralsetinib (BLU-667) and selpercatinib (LOXO-292) have been developed in clinical trials, with selpercatinib recently approved by the Food and Drug Administration (FDA). The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to review the available methods for the detection of RET gene alterations, their potential applications and strategies for the implementation of a rational approach for the detection of RET fusion genes and mutations in human malignancies. We present here recommendations for the routine clinical detection of targetable RET rearrangements and mutations.
Clinical • Review • Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET rearrangement
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
5ms
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
5ms
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
5ms
Clinical
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Retevmo (selpercatinib)
5ms
Clinical
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
5ms
All true positive cases had exon 3 and exon 15 fusion as the sole abnormality. Cases with MET amplification were also negative on sanger sequencing.Conclusions RNA based exon 13 and exon 15 fusion for detection of exon 14 skipping mutations can have false positive calls by Ion torrent-based sequencing and should be confirmed by alternate Methods
Next-generation sequencing
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • MET (MET proto-oncogene, receptor tyrosine kinase) • KIF5B (Kinesin Family Member 5B) • CTNNB1 (Catenin (cadherin-associated protein), beta 1)
|
MET amplification • RET fusion • EGFR amplification • MET exon 14 mutation • MET mutation • KRAS deletion
|
Oncomine Focus Assay
5ms
Clinical • HEOR
|
RET (Ret Proto-Oncogene)
|
RET fusion
5ms
A multidisciplinary faculty panel, including medical oncologists with expertise in the treatment of lung and thyroid cancer along with a molecular pathologist, will provide guidance on testing for RET alterations, discuss patient cases, and answer questions submitted by participants. Registration: http://www.clinicaloptions.com/NSCLC2021Webinar Joint Accreditation Statement In support of improving patient care, Clinical Care Options, LLC (CCO) is jointly accredited by the Accreditation Council for
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation • RET positive
5ms
Clinical • Journal
|
RET (Ret Proto-Oncogene) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3)
|
NTRK3 fusion • RET fusion • RET positive
|
Retevmo (selpercatinib)
5ms
"In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms."
Journal • Clinical
|
EGFR (Epidermal growth factor receptor) • TMB (Tumor Mutational Burden) • RET (Ret Proto-Oncogene) • CDKN2A (Cyclin-dependent kinase inhibitor 2A) • ARID1A (AT-rich interaction domain 1A) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • MLH1 (MutL homolog 1) • BRCA (Breast cancer early onset)
|
PD-L1 expression • EGFR mutation • RET fusion • ARID1A mutation • CDKN2A mutation • MLH1 mutation • BRCA mutation • EGFR R776H • EGFR fusion
|
OncoDEEP
6ms
However, remarkable progress has been achieved with the identification of novel potent and selective RET kinase inhibitors for the treatment of advanced thyroid cancer. Although expanded clinical validation in future trials is needed, the sustained antitumoural activity and the improved safety profile of these novel compounds is opening a new exciting era in precision oncology for RET-driven cancers.
Review • Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation • RET rearrangement
6ms
All patients with nonsquamous NSCLC should have the results of testing for potentially targetable mutations (alterations) before implementing therapy for advanced lung cancer, regardless of smoking status recommendations, when possible, following other existing high-quality testing guidelines. Most patients should receive targeted therapy for these alterations: Targeted therapies against ROS-1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions should be offered to patients, either as initial or second-line therapy when not given in the first-line setting. New or revised recommendations include the following: Osimertinib is the optimal first-line treatment for patients with activating epidermal growth factor receptor mutations (exon 19 deletion, exon 21 L858R, and exon 20 T790M); alectinib or brigatinib is the optimal first-line treatment for patients with anaplastic lymphoma kinase fusions. For the first time, to our knowledge, the guideline includes recommendations regarding RET, MET, and NTRK alterations. Chemotherapy is still an option at most stages.Additional information is available at www.asco.org/thoracic-cancer-guidelines.
Journal
|
EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)
|
BRAF V600E • EGFR mutation • BRAF V600 • EGFR L858R • EGFR T790M • EGFR exon 19 deletion • RET fusion • MET exon 14 mutation • ALK fusion • RET mutation • ROS1 fusion • MET mutation • NTRK fusion
|
Tagrisso (osimertinib) • Alecensa (alectinib) • Alunbrig (brigatinib)
6ms
FISH is a sensitive but unspecific technique for RET screening, always requiring a confirmation using an orthogonal technique, due to frequently occurring RET rearrangements not resulting in functional fusions in NSCLC.
Journal
|
ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
RET fusion • ALK fusion • RET rearrangement
6ms
Molecular alterations can be effectively identified routinely in formalin-fixed paraffin-embedded ( FFPE) tissue samples. Patients presenting thyroid tumors with targetable alterations could be eligible for specific therapy such as larotrectinib or entrectinib targeting NTRK fusion or selpercatinib and pralsetinib targeting RET fusion. Immunotherapy alone or in combination with other drugs may be a promising treatment for aggressive types of thyroid cancers.
PD(L)-1 Biomarker • IO biomarker
|
BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
|
PD-L1 expression • PD-L1 overexpression • BRAF mutation • RET fusion • ALK fusion • RET mutation • NTRK expression • NTRK fusion
|
VENTANA PD-L1 (SP263) Assay • VENTANA pan-TRK (EPR17341) Assay
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Retevmo (selpercatinib) • Gavreto (pralsetinib)
6ms
A multidisciplinary faculty panel, including medical oncologists with expertise in the treatment of lung and thyroid cancer along with a molecular pathologist, will provide guidance on testing for RET alterations, discuss patient cases, and answer questions submitted by participants. Registration: http://www.clinicaloptions.com/NSCLC2021Webinar
RET (Ret Proto-Oncogene)
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RET fusion • RET mutation • RET positive
6ms
RET (Ret Proto-Oncogene)
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RET fusion • RET mutation • RET positive
6ms
This study indicated increased expression of ALK phosphosite Y1507 in ALK fusion positive NSCLC cases. These results can be extended to a larger cohort in order to determine the potential utility of these novel biomarker used for diagnosis and to evaluate therapeutic efficacy of ALK inhibitors in ALK gene fusion positive lung cancer.
ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • EML4 (EMAP Like 4) • KIF5B (Kinesin Family Member 5B) • KLC1 (Kinesin light chain 1)
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RET fusion • ALK positive • EML4-ALK fusion • ALK fusion • ROS1 fusion • RET expression
6ms
Vail is a member of several professional societies, including the College of American Pathologists, the Association for Molecular Pathology, and the American Society for Clinical Pathology. His work has been published in such journals as JCO Precision Oncology, JAMA Network Open, Clinical Lung Cancer, and JAMA.
RET (Ret Proto-Oncogene)
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RET fusion • RET mutation