^
10d
Evolution of treatment strategies for solid tumors with RET rearrangement in China and real-world treatment status of Non-small Cell Lung Cancer (NSCLC). (PubMed, BMC Pulm Med)
This study encapsulates the research endeavors and treatment advancements of RET rearrangement solid tumors within the Chinese healthcare landscape, specifically highlighting the diverse real-world therapeutic approaches and their effectiveness in managing advanced RET rearrangement NSCLC among Chinese patients. Notably, targeted RET inhibitors like Pralsetinib have emerged as potent therapeutic agents, exhibiting remarkable efficacy and a manageable safety profile in this patient cohort. These findings underscore the potential of Pralsetinib and similar targeted therapies as novel treatment options for individuals with RET fusion-positive NSCLC.
Journal • HEOR • Real-world evidence • Real-world
|
RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B)
|
RET fusion • RET rearrangement • RET positive
|
Gavreto (pralsetinib)
10d
YAP regulates HER3 signaling-driven adaptive resistance to RET inhibitors in RET-aberrant cancer. (PubMed, Clin Cancer Res)
The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment.
Journal
|
RET (Ret Proto-Oncogene) • ERBB3 (V-erb-b2 avian erythroblastic leukemia viral oncogene homolog 3)
|
RET fusion • ERBB3 expression • RET expression • RET positive
|
Gilotrif (afatinib) • Retevmo (selpercatinib) • Gavreto (pralsetinib) • Visudyne (verteporfin)
1m
A case of neoadjuvant targeted therapy with pralsetinib for locally advanced lung adenocarcinoma with RET fusion mutation. (PubMed, J Cardiothorac Surg)
The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.
Journal • Metastases
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation
|
Gavreto (pralsetinib)
2ms
Molecular genetics, therapeutics and RET inhibitor resistance for medullary thyroid carcinoma and future perspectives. (PubMed, Cell Commun Signal)
Two multi-kinase inhibitors (MKIs) including Cabozantinib and Vandetanib have been shown to increase progression-free survival (PFS) for patients with metastatic MTC and have been approved as choices of first-line treatment...Recently, new generation TKIs, including Selpercatinib and Pralsetinib, have demonstrated highly selective efficacy against RET and more favorable side effect profiles, and gained approval as second-line treatment options...Besides, new promising therapeutic approaches, such as novel drug combinations and next generation RET inhibitors are under development. Herein, we overview the pathogenesis, molecular genetics and current management approaches of MTC, and focus on the recent advances of RET inhibitors, summarize the current situation and unmet needs of these RET inhibitors in MTC, and provide an overview of novel strategies for optimizing therapeutic effects.
Review • Journal
|
RET (Ret Proto-Oncogene)
|
RET mutation • RET rearrangement
|
Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Gavreto (pralsetinib) • Caprelsa (vandetanib)
2ms
Pralsetinib as neoadjuvant therapy for RET-Altered differentiated thyroid cancer: Two case reports. (PubMed, Oral Oncol)
There is a potential for pralsetinib as a neoadjuvant treatment in PTC with RET-fusion.
Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Gavreto (pralsetinib)
2ms
Assessing the Effectiveness of Selective RET Inhibitors in RET-Positive Cancers through Fluorodeoxyglucose Uptake Analysis. (PubMed, Diagnostics (Basel))
Selective RET inhibitors, such as selpercatinib and pralsetinib, have revolutionized the treatment of cancers with RET gene alterations. The findings suggest that FDG-PET has the potential to serve as a non-invasive biomarker for monitoring treatment response in patients with RET-positive cancers. However, further research is required to establish standardized criteria for interpreting FDG-PET scans in the context of selective RET inhibitors and to uncover the broader applications of FDG-PET in precision oncology.
Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
2ms
Efficacy and safety of pralsetinib in patients with RET fusion positive non-small cell lung cancer: An observational real world study. (PubMed, Lung Cancer)
Pralsetinib demonstrated promising activity in patients with advanced NSCLC harboring RET fusion with a favorable safety profile.
Journal • Real-world evidence • Real-world
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Gavreto (pralsetinib)
2ms
Development and validation of a novel high-performance liquid chromatography (HPLC) method for the detection of related substances of pralsetinib, a new anti-lung cancer drug. (PubMed, Front Chem)
Overall, the chromatographic technique established in this study can effectively separate pralsetinib and its impurities, providing reliable assurance for the accurate detection and quantification of impurities. The chromatographic method developed in this study can be utilized for the detection of pralsetinib and its impurities, offering a crucial reference for research on the quality of pralsetinib.
Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Gavreto (pralsetinib)
2ms
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". (PubMed, Cancers (Basel))
New potent and selective RET inhibitors (RET-Is) (pralsetinib and selpercatinib) have achieved a higher efficacy minimizing the known toxicities of the multitargeted agents. We will further proceed to deal with the new drugs and strategies proposed to overcome the resistance to RET-Is. In the last section, we will also focus on the safety profile of RET-Is, dealing with the main toxicities as well as the rare but severe adverse events.
Review • Journal
|
RET (Ret Proto-Oncogene)
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
3ms
Lazarus Response to Selpercatinib for Bleeding Colic Metastasis in a Patient With RET Fusion-Positive Pulmonary Sarcomatoid Carcinoma: A Case Report. (PubMed, Cureus)
RET inhibitors, like selpercatinib and pralsetinib, for RET rearrangements in lung cancer showed high efficacy and clinical benefit. Indeed, pulmonary sarcomatoid carcinoma (PSC) remains a rare form of NSCLC, unresponsive to standard chemotherapy, and associated with extremely poor prognosis. We report the first case of a patient affected by RET fusion-positive PSC with a bleeding colic metastasis and a consequent poor performance status who achieved a dramatic response to selpercatinib and a remarkable clinico-radiological benefit.
Journal
|
RET (Ret Proto-Oncogene)
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
3ms
New P2 trial
|
Mekinist (trametinib) • Xalkori (crizotinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • Irene (pyrotinib) • Gavreto (pralsetinib) • Ensacove (ensartinib) • Orpathys (savolitinib) • glecirasib (JAB-21822) • sunvozertinib (DZD9008)
3ms
A double-edged sword: unusual multiple severe infections with pralsetinib: a case report and literature review. (PubMed, Front Med (Lausanne))
Of particular note, during pralsetinib therapy, the clinical course was complicated by five severe infectious events, namely, two oxygen-requiring pneumonias, two distinct spondylodiscitis, and one pneumocystis. Our study highlights the increased risk of any type of opportunistic infectious event with pralsetinib, but not selpercatinib, which is probably caused by off-target JAK1/2 inhibition.
Review • Journal
|
RET (Ret Proto-Oncogene) • CCDC6 (Coiled-Coil Domain Containing 6) • JAK1 (Janus Kinase 1)
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
3ms
Cardiovascular toxicities of selective ret-specific tyrosine kinase inhibitors: a pharmacovigilance study based on the united states food and drug administration adverse event reporting system database. (PubMed, Expert Opin Drug Saf)
Selective RET-TKIs are related to multiple cardiovascular toxicities. Pralsetinib was linked to ischemic heart disease, and selpercatinib to torsade de pointes/QT prolongation and thrombotic events.
Journal • Adverse events
|
RET (Ret Proto-Oncogene)
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
3ms
KOSMOS-II: KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II (clinicaltrials.gov)
P=N/A, N=1000, Recruiting, Seoul National University Bundang Hospital | Trial completion date: Sep 2025 --> Mar 2027 | Trial primary completion date: Sep 2025 --> Sep 2026
Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases
|
Avastin (bevacizumab) • Herceptin (trastuzumab) • Tecentriq (atezolizumab) • erlotinib • Zelboraf (vemurafenib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Perjeta (pertuzumab) • Kadcyla (ado-trastuzumab emtansine) • Gavreto (pralsetinib)
4ms
A Locally Advanced NSCLC Patient Harboring a Rare KIF13A-RET Fusion Benefited from Pralsetinib: A Case Report. (PubMed, Curr Oncol)
The addition of bevacizumab to the original regimen upon recurrence continued to be beneficial. Pralsetinib demonstrated promising efficacy as adjuvant therapy, while ctDNA analysis offered a valuable tool for early detection of tumor recurrence. By leveraging targeted therapies and innovative monitoring techniques, we aim to improve outcomes and quality of life for NSCLC patients in the future.
Journal • Metastases
|
RET (Ret Proto-Oncogene) • KIF13A (Kinesin Family Member 13A)
|
Avastin (bevacizumab) • Gavreto (pralsetinib)
4ms
RET Inhibitors in RET Fusion-Positive Lung Cancers: Past, Present, and Future. (PubMed, Drugs)
This led to lung and thyroid cancer, and later tumor-agnostic regulatory approvals. While next-generation RET TKIs were designed to abrogate uncommon on-target (e.g., solvent front mutation) resistance to selpercatinib and pralsetinib, many of these drugs lacked the selectivity of the first-generation TKIs, raising the question of what the future holds for drug development in RET-dependent cancers.
Review • Journal
|
RET (Ret Proto-Oncogene)
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
5ms
New P2 trial • Metastases
|
Mekinist (trametinib) • Tafinlar (dabrafenib) • Vitrakvi (larotrectinib) • sorafenib • Rozlytrek (entrectinib) • Focus V (anlotinib) • everolimus • Lenvima (lenvatinib) • AiTan (rivoceranib) • Cabometyx (cabozantinib tablet) • Gavreto (pralsetinib) • Caprelsa (vandetanib) • Zepsun (donafenib)
5ms
PIKACHU: Treatment Strategies and Survival Outcome for Non-small Cell Lung Cancer With Oncogenic Mutation (clinicaltrials.gov)
P2, N=6000, Recruiting, Hunan Province Tumor Hospital | Phase classification: P --> P2 | N=100 --> 6000 | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2024 --> Dec 2026
Phase classification • Enrollment change • Trial completion date • Trial primary completion date
|
EGFR (Epidermal growth factor receptor) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
|
cisplatin • Xalkori (crizotinib) • Tagrisso (osimertinib) • erlotinib • gefitinib • Rozlytrek (entrectinib) • Alecensa (alectinib) • Lorbrena (lorlatinib) • Zykadia (ceritinib) • pemetrexed • Alunbrig (brigatinib) • Gavreto (pralsetinib) • Ameile (aumolertinib) • Orpathys (savolitinib) • Ivesa (firmonertinib)
6ms
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. (PubMed, Lung Cancer (Auckl))
The addition of pembrolizumab to platinum/pemetrexed chemotherapy resulted in numerically identical PFS (11.2 months). These results point to selpercatinib's superiority to traditional chemotherapy regimens in the treatment of NSCLC harboring RET fusions and add to literature on the salience of targeted precision oncology and lack of efficacy of immune checkpoint inhibitor in NSCLC patients with never-smoker predominant actionable driver mutations. RET+ NSCLC should be added to the list of molecular subtypes (EGFR+, ALK+, ROS1+) of NSCLC to be excluded in chemoimmunotherapy trial.
Journal • Checkpoint inhibition • Head-to-Head • PD(L)-1 Biomarker • IO biomarker • Metastases
|
EGFR (Epidermal growth factor receptor) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • KIF5B (Kinesin Family Member 5B)
|
Keytruda (pembrolizumab) • Retevmo (selpercatinib) • pemetrexed • Gavreto (pralsetinib)
6ms
Chemotherapy-free treatment targeting fusions and driver mutations in KRAS wild-type pancreatic ductal adenocarcinoma, a case series. (PubMed, Ther Adv Med Oncol)
Five patients were treated with matched targeted therapy, with three having durable benefit: (i) erlotinib for EGFR-altered tumor, followed by osimertinib/capmatinib when MET amplification emerged (first-line therapy); (ii) pralsetinib for RET fusion (fifth line); and (iii) dabrafenib/trametinib for BRAF N486_P490del (third line). Sustained therapeutic benefit can be achieved in a real-world setting in a subset of patients with advanced/metastatic KRAS-WT PDAC treated with chemotherapy-free matched targeted agents. Prospective studies are warranted.
Journal
|
EGFR (Epidermal growth factor receptor) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • MET (MET proto-oncogene, receptor tyrosine kinase) • RET (Ret Proto-Oncogene) • FGFR2 (Fibroblast growth factor receptor 2) • STK11 (Serine/threonine kinase 11) • MUTYH (MutY homolog) • PCM1 (Pericentriolar Material 1) • POC1B (POC1 Centriolar Protein B)
|
KRAS mutation • MET amplification • RET fusion • KRAS wild-type • FGFR2 fusion • RAS wild-type • EGFR E746
|
Mekinist (trametinib) • Tagrisso (osimertinib) • erlotinib • Tafinlar (dabrafenib) • Gavreto (pralsetinib) • Tabrecta (capmatinib)
6ms
Discovery of 9H-pyrimido[4,5-b]indole derivatives as dual RET/TRKA inhibitors. (PubMed, Bioorg Med Chem)
Recent approvals of selective RET inhibitors, pralsetinib and selpercatinib, has shifted the focus of RET kinase drug discovery programs towards the development of selective inhibitors. This selective dual RET/TRK inhibitor can be utilized in tumors with both RET and TRK genetic backgrounds and can also provide blockade of NTRK-fusions that are selected for from RET inhibitor treatments. Efforts towards developing dual RET/TRK inhibitors can be beneficial in terms of encompassing more diverse patient classes while also achieving blockade against emerging resistance mechanisms.
Journal
|
NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK fusion
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
6ms
AcceleRET Lung: A Study of Pralsetinib Versus Standard of Care for First-Line Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC) (clinicaltrials.gov)
P3, N=223, Active, not recruiting, Hoffmann-La Roche | Trial completion date: Jun 2026 --> Jun 2025 | Trial primary completion date: Nov 2024 --> Jun 2025
Trial completion date • Trial primary completion date • Metastases
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Keytruda (pembrolizumab) • cisplatin • carboplatin • gemcitabine • albumin-bound paclitaxel • pemetrexed • Gavreto (pralsetinib)
7ms
Patient with mediastinal carcinoma of unknown primary with RET fusion achieves durable response with RET inhibition. (PubMed, Anticancer Drugs)
The patient was initiated on selpercatinib, which was held after 3 weeks due to thrombocytopenia and hypertension. Pralsetinib was held during adjuvant chemoradiation for the GBM, and again for 4 weeks due to pneumonitis that resolved with steroids, and pralsetinib was restarted at a reduced dose. The patient has since demonstrated a stable reduction of the mediastinal mass for >15 months with RET inhibition therapy, despite several treatment interruptions.
Journal • PD(L)-1 Biomarker • IO biomarker
|
TP53 (Tumor protein P53) • RET (Ret Proto-Oncogene) • FGFR3 (Fibroblast growth factor receptor 3) • TERT (Telomerase Reverse Transcriptase) • TACC3 (Transforming acidic coiled-coil containing protein 3) • CCDC6 (Coiled-Coil Domain Containing 6)
|
TP53 mutation • RET fusion • FGFR3-TACC3 fusion • FGFR3 mutation • CCDC6-RET fusion • FGFR3 fusion • TERT mutation • TERT 124C>T
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
7ms
Management of Advanced Medullary Thyroid Carcinoma: Current Systemic Therapy Options. (PubMed, Crit Rev Oncog)
Multikinase inhibitors (MKIs) with nonselective RET inhibition like Vandetanib and Cabozantinib were approved for the treatment of MTC, although the efficacy is limited due to the lack of specificity resulting in a higher rate of drug-related adverse events, leading to subsequent dose reductions, or discontinuation, and the development of a resistance mechanism like seen on the RET Val804 gatekeeper mutations. MTC is associated with mutations in the RET protooncogene, and new highly selective RET inhibitors have been developed including Selpercatinib and Pralsetinib, drugs that have demonstrate excellent results in clinical trials, and efficacy even in the presence of gatekeeper mutations. However, despite their efficacy and great tolerability, mechanisms of resistance have been described, such as the RET solvent front mutations. Due to this, the need of constant evolution and drug research is necessary to overcome the emergence of resistance mechanisms.
Review • Journal • Metastases
|
RET (Ret Proto-Oncogene)
|
RET mutation
|
Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Gavreto (pralsetinib) • Caprelsa (vandetanib)
7ms
Exploring the Impact of Hepatic Impairment on Pralsetinib Pharmacokinetics. (PubMed, Pharmaceutics)
Results based on the NCI-ODWG classification criteria were comparable; the AUC0-∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.
PK/PD data • Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Gavreto (pralsetinib)
7ms
Determination of Pralsetinib in Human Plasma and Cerebrospinal Fluid for Therapeutic Drug Monitoring by Ultra-performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). (PubMed, Anticancer Agents Med Chem)
We have developed a quick and effective method for concentration detection in both plasma and CSF, and it can be applied for drug monitoring in clinical practice. The method can also provide a reference for further optimization.
Journal
|
RET (Ret Proto-Oncogene)
|
Xalkori (crizotinib) • Tagrisso (osimertinib) • Gilotrif (afatinib) • Gavreto (pralsetinib)
7ms
Trial completion
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation • RET rearrangement
|
Gavreto (pralsetinib)
8ms
Enrollment change
|
PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)
|
PD-L1 expression • KRAS mutation • KRAS G12C • BRAF mutation • BRAF V600 • NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • RET fusion • ALK fusion • RET mutation • ROS1 fusion • KRAS G12 • ALK-ROS1 fusion
|
Tecentriq (atezolizumab) • Zelboraf (vemurafenib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Cotellic (cobimetinib) • Gavreto (pralsetinib) • divarasib (RG6330)
8ms
Targeting RET alterations in non-small cell lung cancer. (PubMed, Curr Probl Cancer)
In recent years, selective RET inhibitors such as selpercatinib and pralsetinib, approved by the Food and Drug Administration (FDA) in 2020, have been part of the revolutionary changes in the treatment landscape for non-small cell lung cancer. This review provides an overview of the biology of RET in NSCLC, methods of RET testing, and a comprehensive analysis of the clinical outcomes associated with multikinase and selective RET inhibitors for NSCLC. Additionally, we will explore future perspectives for RET fusion-positive NSCLC, including ongoing trials and the challenges involved in overcoming resistance to RET inhibitors.
Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation • RET positive
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
8ms
Trial primary completion date
|
PD-L1 (Programmed death ligand 1) • KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • RET (Ret Proto-Oncogene) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2)
|
PD-L1 expression • KRAS mutation • KRAS G12C • BRAF mutation • BRAF V600 • NTRK1 fusion • NTRK3 fusion • NTRK2 fusion • RET fusion • ALK fusion • RET mutation • ROS1 fusion • KRAS G12 • ALK-ROS1 fusion
|
Tecentriq (atezolizumab) • Zelboraf (vemurafenib) • Rozlytrek (entrectinib) • Alecensa (alectinib) • Cotellic (cobimetinib) • Gavreto (pralsetinib) • divarasib (RG6330)
8ms
Understanding CYP3A4 and P-gp mediated drug-drug interactions through PBPK modeling - Case example of pralsetinib. (PubMed, CPT Pharmacometrics Syst Pharmacol)
The verified pralsetinib PBPK model was then applied to predict the effect of other inhibitors and inducers on the PKs of pralsetinib. This work highlights the challenges in understanding DDIs when enzyme-transporter interplay occurs, and demonstrates an important strategy for differentiating enzyme/transporter contributions to enable PBPK predictions for untested scenarios and to inform labeling.
Journal
|
RET (Ret Proto-Oncogene) • CYP3A4 (Cytochrome P450, family 3, subfamily A, polypeptide 4)
|
RET fusion • RET mutation
|
Gavreto (pralsetinib)
8ms
Successful treatment with selpercatinib after pralsetinib-related pneumonitis and intracranial failure in a patient with RET-rearranged nonsmall cell lung cancer. (PubMed, Anticancer Drugs)
In our case report, after pralsetinib dose reduction due to pulmonary toxicity, the therapeutic switch to selpercatinib allowed the patient to receive a full-dose treatment, eventually restoring disease control. Our case report and a few literature data suggest that switching from pralsetinib to selpercatinib may represent a therapeutic opportunity, especially for patients with brain metastases.
Journal
|
RET (Ret Proto-Oncogene)
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
8ms
Trial completion • Tumor mutational burden • Metastases
|
Tecentriq (atezolizumab) • Rozlytrek (entrectinib) • paclitaxel • docetaxel • Alecensa (alectinib) • Perjeta (pertuzumab) • Kadcyla (ado-trastuzumab emtansine) • capecitabine • Gavreto (pralsetinib) • Tukysa (tucatinib) • ipatasertib (RG7440) • Itovebi (inavolisib) • Phesgo (pertuzumab/trastuzumab/hyaluronidase-zzxf) • tiragolumab (RG6058)
8ms
Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer. (PubMed, NPJ Precis Oncol)
Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.
Journal
|
RET (Ret Proto-Oncogene) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • EML4 (EMAP Like 4) • ETV6 (ETS Variant Transcription Factor 6) • NTRK (Neurotrophic receptor tyrosine kinase)
|
NTRK3 fusion • ALK fusion • RET mutation • ETV6-NTRK3 G623R
|
Vitrakvi (larotrectinib) • Rozlytrek (entrectinib) • Retevmo (selpercatinib) • Gavreto (pralsetinib)
9ms
Enrollment closed • Metastases
|
RET (Ret Proto-Oncogene)
|
RET fusion
|
Keytruda (pembrolizumab) • cisplatin • carboplatin • gemcitabine • albumin-bound paclitaxel • pemetrexed • Gavreto (pralsetinib)
9ms
RET Kinase Inhibitors for the Treatment of RET-altered Thyroid Cancers: Current Knowledge and Future Directions. (PubMed, Ann Endocrinol (Paris))
More recently, two potent, highly selective RET inhibitors, selpercatinib and pralsetinib, were shown to have notable efficacy in RET-altered cancers, associated with more tolerable side effect profiles than those of MKIs. This year we celebrate the 30th anniversary of the association of germline mutations of the RET proto-oncogene with the multiple endocrine neoplasia (MEN) type 2 syndromes. In this timely review, we summarize the current state-of-the-art treatment strategies for RET-altered thyroid cancers, their limitations, as well as future therapeutic avenues.
Review • Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET mutation
|
Retevmo (selpercatinib) • Gavreto (pralsetinib)
9ms
Exposure-Response Relationships for Pralsetinib in Patients with RET-Altered Thyroid Cancer or RET Fusion-Positive Nonsmall Cell Lung Cancer. (PubMed, J Clin Pharmacol)
Higher exposure was also associated with an increased risk of grade ≥3 adverse events (AEs); however, the overall incidence of these events was acceptably low (≤20%). This analysis supports the use of a 400 mg starting dose of pralsetinib, allowing for dose reduction in the event of AEs.
Journal
|
RET (Ret Proto-Oncogene)
|
RET fusion • RET positive
|
Gavreto (pralsetinib)
10ms
Real-world outcomes of chemoimmunotherapy and selective RET inhibitors in Chinese patients with RET fusion-positive non-small cell lung cancer. (PubMed, Heliyon)
Of four patients with PD-L1 overexpression (>50%) one received pembrolizumab and the other three patients received pemetrexed, carboplatin, and pembrolizumab or camrelizumab. Fifteen patients received selective RET inhibitors (pralsetinib and selpercatinib), resulting in an ORR of 53.3% (8/15) and median PFS of 10.0 months (95% CI 5.2-14.9). ICIs for PD-L overexpression and treatment naive patients offer comparable benefits for RET fusion-positive NSCLC, warranting further investigation.
Journal • Real-world evidence • PD(L)-1 Biomarker • IO biomarker • Real-world
|
PD-L1 (Programmed death ligand 1) • RET (Ret Proto-Oncogene) • KIF5B (Kinesin Family Member 5B) • CCDC6 (Coiled-Coil Domain Containing 6) • NCOA4 (Nuclear Receptor Coactivator 4)
|
PD-L1 overexpression • RET fusion • KIF5B-RET fusion • CCDC6-RET fusion • NCOA4-RET fusion • RET positive
|
Keytruda (pembrolizumab) • carboplatin • AiRuiKa (camrelizumab) • Retevmo (selpercatinib) • pemetrexed • Gavreto (pralsetinib)
10ms
Efficacy and safety of pralsetinib in Chinese advanced RET-mutant medullary thyroid cancer patients. (PubMed, Endocr Relat Cancer)
No patient discontinued treatment or died from pralsetinib-related adverse events. Pralsetinib demonstrated broad, deep, and durable efficacy, a manageable and acceptable safety profile in Chinese patients with advanced RET-mutant MTC.
Journal • Metastases
|
RET (Ret Proto-Oncogene)
|
RET mutation
|
Gavreto (pralsetinib)
10ms
Tyrosine Kinase Inhibitors for Radioactive Iodine Refractory Differentiated Thyroid Cancer. (PubMed, Life (Basel))
Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway.
Review • Journal • IO biomarker
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BRAF (B-raf proto-oncogene) • RET (Ret Proto-Oncogene) • NTRK (Neurotrophic receptor tyrosine kinase)
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BRAF V600E • BRAF V600 • RET fusion • NTRK fusion
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Mekinist (trametinib) • Tafinlar (dabrafenib) • sorafenib • Rozlytrek (entrectinib) • Lenvima (lenvatinib) • Cabometyx (cabozantinib tablet) • Retevmo (selpercatinib) • Gavreto (pralsetinib)
10ms
Quantitative bias analysis for external control arms using real-world data in clinical trials: a primer for clinical researchers. (PubMed, J Comp Eff Res)
Using a motivating example of a comparison between pralsetinib single-arm trial data versus pembrolizumab alone or combined with chemotherapy real-world data for RET fusion-positive advanced non-small cell lung cancer (aNSCLC) patients (1-2% among all NSCLC), we illustrate how QBA can be applied to external control arms. The robustness of findings is illustrated by showing that no meaningful change to the comparative effect was observed across several 'tipping-point' scenario analyses, and by showing that suspicion of unknown confounding was ruled out by use of E-values. Full R code is also provided.
Review • Journal • Real-world evidence • Real-world
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RET (Ret Proto-Oncogene)
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RET fusion • RET positive
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Keytruda (pembrolizumab) • Gavreto (pralsetinib)
10ms
Selective RET Inhibitors (SRIs) in Cancer: A Journey from Multi-Kinase Inhibitors to the Next Generation of SRIs. (PubMed, Cancers (Basel))
Following the modest success of repurposed RET-active multikinase inhibitors, the first selective RET inhibitors (SRIs), selpercatinib and pralsetinib, received regulatory approval in 2020. The ideal next-generation SRIs will be active against on-target acquired resistance alterations, including those that emerge in the CNS, and will have improved safety and tolerability relative to first-generation SRIs. In this review, we will provide an update on these candidates and their potential to meet the unmet clinical need for patients who progress on first-generation SRIs.
Review • Journal
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RET (Ret Proto-Oncogene)
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RET mutation • RET rearrangement
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Retevmo (selpercatinib) • Gavreto (pralsetinib)