Caprelsa (vandetanib)

P2, N=164, Completed, Genzyme, a Sanofi Company | Active, not recruiting --> Completed

Sorafenib, lenvatinib, and cabozantinib are multikinase inhibitors approved for patients with metastatic RAI-refractory DTC, whereas vandetanib and cabozantinib are approved for patients with MTC. Management of thyroid carcinomas has evolved such that targeted therapies have become therapeutic options for patients with BRAF, RET, NTRK, ALK, and ROS1 alterations and even have reported efficacy in anaplastic thyroid carcinomas. In this article, we review the advances made over the years in the treatment of metastatic thyroid carcinoma and focus on the systemic therapies that have recently transformed the treatment landscape of advanced disease.

Lastly, we identified RTN1 as a potential biomarker, exhibiting lower expression in sensitive rare-tumor PDX models prior to Axitinib and Vandetanib treatment.ConclusionsWith the multi-omics datasets comprising proteomics/phospho-proteomics, RNA-Seq and WES datasets from the NCI Patient Derived Models Repository cohort, we were able to query some important cancer biological processes at a higher resolution. In addition, we revealed gene- and pathway-level regulatory differences from various histologies. Overall, the multi-omics data from PDX models showed promising recapitulation of original tumor activity and should continue to serve as an amenable and scalable drug screening platform for pre-clinical trials.

We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells...The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.

P2, N=1460, Active, not recruiting, UNICANCER | Trial completion date: Dec 2023 --> Dec 2024

P2, N=999, Completed, UNICANCER | Active, not recruiting --> Completed

Patients with aMTC report substantial disease/treatment burden. Outcomes could be improved by identifying patients eligible for treatment with selective RET inhibitors through more optimal RET mutation testing.

P3, N=0, Withdrawn, Hoffmann-La Roche | N=198 --> 0 | Recruiting --> Withdrawn

Exosomal ANGPTL1 suppressed GBM angiogenesis by inhibiting the VEGFA/VEGFR2/Akt/eNOS axis.

In this updated analysis of the ARROW study, pralsetinib continued to show deep and durable clinical activity and a manageable safety profile in patients with advanced/metastatic RET-altered thyroid cancer.

Multi tyrosine kinase inhibitors (mTKIs) cabozantinib and vandetanib are good first line options, even vandetanib prescription is currently limited to RET mutated patients. Selective RET inhibitors such as pralsetinib could be a preferred upfront treatment in case of RET mutated MTC presenting common or gatekeeper RET mutations (e.g. M918T; V804L/M). Selpercatinib, otherwise, can be prescribed as the second line after disease progression to mTKIs. The best option for subsequent lines is to consider inclusion in clinical trials or alternatively other mTKIs such as sunitinib, sorafenib, lenvatinib, or pazopanib could be evaluated. New perspectives include next-generation RET inhibitors able to overcome resistance mechanisms responsible for disease progression to standard mTKIs and RET inhibitors, and immunotherapy for MTC presenting with high tumor mutational burden.

Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

P3, N=291, Active, not recruiting, Loxo Oncology, Inc. | Completed --> Active, not recruiting | Trial completion date: May 2023 --> Feb 2026

P3, N=291, Completed, Loxo Oncology, Inc. | Active, not recruiting --> Completed | Trial completion date: Nov 2026 --> May 2023

The combination of vandetanib and everolimus showed early activity and tolerable toxicity profile in pediatric patients with advanced cancers.

P3, N=437, Active, not recruiting, Genzyme, a Sanofi Company | Trial completion date: Dec 2023 --> Jun 2024

This study highlights the importance of selectivity in targeting RET-mutant MTC. Selpercatinib should be considered the preferred first-line standard of care for patients with advanced RET-mutant MTC.

The concurrent treatment (PI3K, inhibitor+ 1, 5 µM vandetanib) also considerably reduced epithelial-mesenchymal transition (EMT) markers such as VE-cadherin (P<0.05). Vandetanib suppressed vasculogenic mimicry (VM) networking through blunting stemness properties, coincided with suppression of VE-cadherin in CSCs.

He began treatment with vandetanib, a multityrosine kinase inhibitor, which resulted in decreased tumor burden as well as clinical and biochemical resolution of ECS. Due to progressive structural disease 10 months later, he was switched to the selective RET inhibitor selpercatinib, which was followed by a rapid reduction of cortisol nearing the threshold of adrenal insufficiency...Selective RET inhibitors may emerge as preferred targeted treatment options due to better efficacy and toxicity profiles compared to multikinase inhibitors. Clinicians should monitor for adrenal insufficiency following treatment of paraneoplastic ECS with selective RET inhibitors.

P3, N=400, Active, not recruiting, Loxo Oncology, Inc. | Recruiting --> Active, not recruiting | Trial primary completion date: May 2024 --> May 2023

As of now, the U.S. FDA has approved eleven small chemical inhibitors of VEGFR-2 for various types of malignancies, with a prime example being vandetanib, a quinazoline derivative, which is a multi targeted kinase inhibitor used for the treatment of late-stage medullary thyroid cancer...Through the gathering of this review, we have strived to broaden the extent of our view over the entire scope of quinazoline-based VEGFR-2 inhibitors. Herein, we give an overview of the importance and advancement status of reported structures, highlighting the SAR, biological evaluations and their binding modes.

D898_E901 RET deletion is a gain-of-function mutation and responds to tyrosine kinase inhibitors in MTC. RET Δ898-901 mutant is sensitive to selpercatinib and vandetanib, and acquired resistance to selpercatinib may develop via RET-independent mechanisms.

Several tyrosine kinase inhibitors are approved in the treatment of advanced MTC, including vandetanib and cabozantinib...Newer RET-specific TKIs are expected to overcome previous limitations and improve patient outcomes. Herein, we aim to review MTC signaling pathways, the most recent options for treatment and the applications for personalized medicine.

The approval of cabozantinib as salvage therapy for progressive radioactive iodine-refractory differentiated thyroid cancer following failure with sorafenib or lenvatinib adds to the available armamentarium of active agents. Vandetanib and cabozantinib have become mainstay treatments for metastatic medullary thyroid cancer regardless of RET mutation status. Selpercatinib and pralsetinib, potent and selective receptor kinase inhibitors with activity against RET, have revolutionized the treatment paradigm for medullary thyroid cancers and other cancers with driver mutations in RET. Dabrafenib plus trametinib for BRAF mutated anaplastic thyroid cancer provides an effective treatment option for this aggressive cancer with a dismal prognosis. In order to design the next generation of agents for thyroid cancer, future efforts will need to focus on developing a better understanding of the mechanisms of resistance to kinase inhibition including bypass signaling and escape mutations.

No abstract available

When combined with cabozantinib and vandetanib, miR-21 silencing did not affect cell cycle or migration but was able to enhance apoptosis. Silencing miR-21, although not showing synergistic activity with TKIs (tyrosine kinase inhibitors), represents a potential alternative worth exploring as a therapeutic target for MTC.

We identified patients with thyroid cancer who had prescription claims for at least one of the 15 SMKIs of interest (axitinib, cabozantinib, dabrafenib, entrectinib, everolimus, larotrectinib, lenvatinib, pazopanib, pralsetinib, selpercatinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib)...Since 2015 when lenvatinib was approved by the FDA for treatment of advanced differentiated thyroid cancer, it has become the most commonly prescribed SMKI for treatment of advanced thyroid cancer. However, variation exists in which SMKIs are used to treat patients with advanced thyroid cancer, with almost one-quarter of patients initiated on commercially available SMKIs.

Patient hPitNETsorg were pretreated with either Vandetanib (Vand), Rapamycin (Rapa, mTOR inhibitor), Erastin (xCT inhibitor), Mifepristone (Mife, glucocorticoid inhibitor) or Cabergoline (Caber, D2 receptor inhibitor) prior to 0, 4, 8 and 16Gy radiation doses. The EGF-TBX19-EGFR positive feedback loop regulates CD44v9/xCT resistance to radiation therapy. Therefore, pretreatment of CD patients with drugs targeting the CD44v9/xCT antioxidant system may increase the efficacy, shorten latency time to remission, and decrease toxicity of stereotactic radiosurgery for the treatment of residual or recurrent functional corticotroph PitNETs.

We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.

Despite some inherent limitations, our analysis may cast light upon some of the MKIs metabolic disorders that can impact on patients' health, especially when long-term survival is expected. Future clinical trials should consider routine assessment of glucose and lipid levels, because underdetection and underreporting of alterations can lead to the overlooking of important adverse events.

Oncostatin M secreted by stromal cells derived from the pancreas activates the IRS1-ERK axis, causing resistance to vandetanib.

Src inhibitors (bosutinib, ponatinib, dasatinib, and vandetanib) have been put into clinical use. Many natural compounds and TCM extracts have the potential for anti-Src treatment. This article describes the natural compounds and extracts from TCM.

Vandetanib and octreotide were previously trialed but discontinued due to financial constraints... Severe hypokalemia causes autophagic degradation of aquaporin-2 channels in the renal tubules and is an under-recognized cause of NDI. Profound hypercortisolism in ectopic-CS may result in cortisol-mediated overactivation of mineralocorticoid receptors that can cause renal potassium loss leading to NDI. Only 0.6% of MTCs are associated with ectopic-CS (PMID: 16029131).

We identified patients with thyroid cancer who had prescription claims for at least one of the 15 SMKIs of interest (axitinib, cabozantinib, dabrafenib, entrectinib, everolimus, larotrectinib, lenvatinib, pazopanib, pralsetinib, selpercatinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib)...Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*

Background: Vepafestinib (TAS0953/HM06, Vepa) is a 2nd generation RET-selective inhibitor that effectively penetrates the brain, and inhibits the wildtype RET kinase domain (KD) and RET KD mutants (G810, V804, Y806, L730) (presented at AACR-NCI-EROTC 2021 meeting)...Vepa was more effective than vandetanib and similar to the FDA-approved RET inhibitors, selpercatinib (Selp) and pralsetinib (Pral), in all in vitro assays... Our preclinical results suggest that vepafestinib has the potential to more effectively manage CNS metastasis compared to selpercatinib, representing a promising new therapeutic option for patients with RET-driven sarcomas. Vepafestinib is currently in a phase 1/2 trial for adult patients with advanced solid tumors harboring RET alterations (margaRET, NCT04683250).

P3, N=198, Recruiting, Hoffmann-La Roche | Not yet recruiting --> Recruiting

P2, N=1460, Active, not recruiting, UNICANCER | Trial completion date: Dec 2022 --> Dec 2023

Meta-MTCs treatment results in disease stabilization in 42.6% during a median 10.5 year follow-up. Combination of locoregional and systemic therapies may result in more favorable PFS. Family history, younger age, SAEs may predict better response; biochemical escape under TKI needs to be followed-up closely as it may indicate disease progression.

The RET proto-oncogene is located on the long arm of chromosome 10 with a length of 60,000 bp, and the expression of RET gene affects cell survival, proliferation, growth and differentiation. This review will describe the basic characteristics and common fusion methods of RET genes; analyze the advantages and disadvantages of different RET fusion detection methods; summarize and discuss the recent application of non-selective and selective RET fusion-positive inhibitors, such as Vandetanib, Selpercatinib, Pralsetinib and Alectinib; discuss the mechanism and coping strategies of resistance to RET fusion-positive inhibitors.

The integrated analysis set (IAS, n=143) includes efficacy evaluable MTC pts previously treated with cabozantinib and/or vandetanib (cabo/vande)... A global, randomized, phase 3 trial (LIBRETTO-531) eval- uating selpercatinib vs cabo/vande in kinase inhibitor-naïve MTC pts is ongoing.

Six inhibitors have been approved for the treatment of RET-driven cancers: vandetanib, cabozantinib, lenvatinib, sorafenib, selpercatinib, and pralsetinib...It is imperative that the next iteration of RET inhibitors are developed to block common treatment resistant mutations. To accomplish this, RET inhibitors should be developed in concert with genomic profiling to ensure the most relevant clinical mutations are targeted.