scholarly journals Ripretinib: First Approval

Drugs ◽  
2020 ◽  
Vol 80 (11) ◽  
pp. 1133-1138
Author(s):  
Sohita Dhillon
Keyword(s):  
Kinase Inhibitors ◽  
Systemic Mastocytosis ◽  
Drug Application ◽  
Growth Factor Receptor ◽  
Gastrointestinal Stromal Tumour ◽  
Regulatory Review ◽  
The Usa ◽  
Us Fda ◽  
Health Canada ◽  
Advanced Gist

AbstractRipretinib (QINLOCK™) is a novel type II tyrosine switch control inhibitor being developed by Deciphera Pharmaceuticals for the treatment of KIT proto-oncogene receptor tyrosine kinase (KIT)-driven and/or platelet derived growth factor receptor A (PDGFRA)-driven cancers, including gastrointestinal stromal tumour (GIST). Ripretinib inhibits KIT and PDGFRA kinase, including wild-type, primary and secondary mutations, as well as other kinases, such as PDGFRB, TIE2, VEGFR2 and BRAF. In May 2020, oral ripretinib received its first approval in the USA for the treatment of adult patients with advanced GIST who have received prior treatment with ≥ 3 kinase inhibitors, including imatinib. The US FDA, Health Canada and the Australian Therapeutic Goods Administration collaborated on the review of the ripretinib new drug application in this indication as part of Project Orbis; regulatory review in Australia and Canada is ongoing. Clinical development for GIST, solid tumours and systemic mastocytosis is underway in several countries worldwide. This article summarizes the milestones in the development of ripretinib leading to this first approval for the treatment of advanced GIST.

scholarly journals Moving beyond vascular endothelial growth factor-targeted therapy in renal cell cancer: latest evidence and therapeutic implications

2017 ◽  
Vol 9 (4) ◽  
pp. 287-298 ◽  
Author(s):  
Che-Kai Tsao ◽  
Bobby Liaw ◽  
Catherine He ◽  
Matthew D. Galsky ◽  
John Sfakianos ◽  
...  
Keyword(s):  
Growth Factor ◽  
Renal Cell Cancer ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Therapeutic Implications ◽  
Resistance Patterns ◽  
The Usa

Renal cell cancer (RCC) continues to be among the most lethal malignancies in the USA. Introduction of anti-vascular epidermal growth factor receptor tyrosine kinase inhibitors over a decade ago resulted in improvement in disease outcomes, but further development of new therapies largely stagnated for many years. More recently, a better understanding of disease biology and treatment-resistance patterns has led to a second renaissance in drug development, with the anti-programmed cell death protein 1 immune checkpoint inhibitor, nivolumab, paving the way for additional therapies entering clinical trial testing in the treatment of RCC.

scholarly journals Avapritinib: novel hope for patients with metastatic gist with PDGFRA exon 18 mutation

2020 ◽  
Vol 9 (7) ◽  
pp. 1175
Author(s):  
Sachin Maggo ◽  
A. P. Dubey ◽  
Pawan Dhull ◽  
Nilabh Kumar Singh
Keyword(s):  
Kinase Inhibitors ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Oral Formulation ◽  
Current Treatment ◽  
Activating Mutations ◽  
Metastatic Gist ◽  
Fda Approval ◽  
Effective Option ◽  
Us Fda

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms of the gastrointestinal tract associated with high rates of malignant transformation. The activating mutations in platelet-derived growth factor receptor A (PDGFRA) have been linked to the development of GISTs, and up to approximately 10% of GIST cases involve mutations of this gene. Current treatment options for metastatic GIST are minimal, mainly trusting on tyrosine kinase inhibitors (TKIs) such as Imatinib, Sunitinib and Regorafenib. However, eventually, most patients develop resistance to TKIs, usually due to the acquisition of secondary mutations. Moreover, 5-6% of patients with unresectable of metastatic GIST have the primary PDGFRA D842V mutation, which makes it resistant to all approved treatment options. Avapritinib, a potent and selective TKI of KIT and PDGFRA activation loop mutants. The drug demonstrates anti-tumor activity by inhibiting the autophosphorylation of KIT D816V and PDGFRA D842V, thereby terminating the downstream signalling. The drug is available in oral formulation with a recommended dosage of 300 mg once daily. The onset of Avapritinib is fast, shows rapid absorption and linear pharmacokinetics. Most common adverse reactions seen are edema, fatigue, abdominal pain, and neurocognitive defects. Clinical trials for Avapritinib have been positive, and results suggest that the drug may be a new safe and effective option for metastatic GIST treatment. With Blueprint Medicines having already received US FDA approval in January 2020, Avapritinib may soon be an addition to the mounting armoury of drugs against metastatic GIST harbouring PDGFRA exon 18 mutation.

scholarly journals Ripretinib for advanced gastrointestinal stromal tumor: Plain language summary of the INVICTUS study

2021 ◽  
Author(s):  
Marina Symcox ◽  
Neeta Somaiah
Keyword(s):  
Clinical Study ◽  
Side Effects ◽  
Gastrointestinal Stromal Tumor ◽  
Kinase Inhibitors ◽  
Stromal Tumor ◽  
Potential Treatment ◽  
Brand Name ◽  
Plain Language ◽  
The Usa ◽  
Advanced Gist

The purpose of this summary is to help you understand the results of the INVICTUS study originally published in the journal Lancet Oncology. INVICTUS is a clinical study which looked at ripretinib as a potential treatment for advanced gastrointestinal stromal tumor, also known as GIST. GIST is a type of cancer that starts in the digestive tract, also known as the gastrointestinal tract. In the study, all participants had advanced GIST and needed a fourth-line (or greater) treatment following the failures of three previous treatments. The study looked at how well ripretinib worked compared with a nonactive medicine (known as a placebo) and at the side effects. Participants were given ripretinib at a dose of 150 mg once a day or a placebo. The results of the INVICTUS study showed ripretinib increased the length of time participants survived before their cancer got worse. Treatment with ripretinib was associated with side effects that varied in severity. The results of this study led to ripretinib, also known by the brand name Qinlock®, being approved in the USA by regulators as the only medication for adults with advanced GIST who have previously been treated with 3 or more types of treatment called tyrosine kinase inhibitors. ClinicalTrials.gov NCT number: NCT03353753 .

scholarly journals Outstanding Response to Sorafenib in a Patient with Metastatic Gastrointestinal Stromal Tumour

2021 ◽  
pp. 1567-1573
Author(s):  
Charlotte Brinch ◽  
Marie Dehnfeld ◽  
Estrid Hogdall ◽  
Tim Svenstrup Poulsen ◽  
Anders Toxvaerd ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Primary Tumour ◽  
Growth Factor Receptor ◽  
Gastrointestinal Stromal Tumour ◽  
Stromal Tumour ◽  
Correct Treatment ◽  
Imatinib Resistance ◽  
Term Survival ◽  
Mutation Analyses

Gastrointestinal stromal tumour (GIST) is the most common sarcoma and can be seen in any part of the gastrointestinal tract. The effect of tyrosine kinase inhibitors varies with mutation status in receptor tyrosine kinase KIT and in platelet-derived growth factor receptor A (<i>PDGFRA</i>). This case presents a 61-year-old man, diagnosed with an 11-cm GIST located at the stomach with a high risk of recurrence. The patient showed intolerance to imatinib shortly after introduction and subsequently progressed on sunitinib and nilotinib. The patient started fourth-line treatment with sorafenib with an impressive response to a point at which metastases intra-abdominally and in the liver could be resected. After surgery, sorafenib was restarted. Due to toxicity, sorafenib dose was reduced over time. The dose was insufficient to control the disease since a new recurrence was detected. Mutation analyses revealed a GIST harbouring a deletion of codon p.I843_D846del, located at <i>PDGFRA</i> exon 18, right next to the codon D842 where mutations are known leading to imatinib resistance. In this case, the GIST was highly sensitive to sorafenib, and the response was dose related. It is mandatory to perform mutation analyses on primary tumour and at recurrence in the decision-making of the correct treatment for the patient. In March 2021, the patient had been in treatment with sorafenib for 12.5 years and was still without signs of recurrence. A multidisciplinary approach was essential for the long-term survival of the patient in this case.

scholarly journals DRES-13. DUAL KINASE INHIBITION TO COMBAT EGFR-INHIBITOR RESISTANCE IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi74-vi74
Author(s):  
Erin Smithberger ◽  
Abigail Shelton ◽  
Madison Butler ◽  
Alex Flores ◽  
Ryan Bash ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Alternative Pathway ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Genetically Engineered ◽  
Differentially Expressed ◽  
Egfr Inhibitor ◽  
Tumor Resistance ◽  
Pten Deletion ◽  
In Cells

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor with a poor survival rate. One of the most common molecular alterations seen in GBM is amplification and/or mutation of the Epidermal Growth Factor Receptor (EGFR), which has made it an attractive therapeutic target. However, several EGFR tyrosine kinase inhibitors have been tested clinically in GBM with minimal success. One reason for this lack of efficacy could be due to acute, adaptive resistance via alternative pathway activation. To investigate this mechanism of tumor resistance, we used RNA-seq and multiplex inhibitor bead/mass spectrometry (MIB-MS) to analyze the transcriptomes and kinomes of genetically engineered murine astrocytes with common GBM genotypes. We have previously shown that 38% of the expressed kinome varied among a panel of diverse nGEM astrocytes harboring Cdkn2a deletion (C) plus Pten deletion (CP), wild-type human EGFR (CE) or EGFRvIII (CEv3) overexpression or both EGFRvIII overexpression and Pten deletion (CEv3P). Although CE have a similar transcriptional profile to C cells at baseline, when treated with the EGFR inhibitor afatinib, CE respond more similarly to CEv3 cells. When cells containing endogenous murine EGFR (C and CP) are treated with afatinib, fewer than 0.5% of kinases showed differential expression. In cells with EGFR overexpression alone, more than 6% of kinases were differentially expressed upon afatinib treatment, including Ntrk3, Fgfr2 and 3, Lyn, Bmx, Epha2 and 5, Fn3k, a kinase involved in fructosamine processing, and Nrbp2, a kinase involved in regulation of apoptosis. This effect was blunted in cells lacking Pten in addition to having EGFRvIII (CEv3P), resulting in less than 2% of kinases being differentially expressed. The only kinase upregulated in all three EGFR-overexpressing cell types was Coq8a, which is involved in electron transport and response to DNA damage. Given this overlap in response, Coq8a could be a potential dual treatment target for GBM.

scholarly journals Characteristics and Treatment Challenges of Non-Clear Cell Renal Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3807
Author(s):  
Pierangela Sepe ◽  
Arianna Ottini ◽  
Chiara Carlotta Pircher ◽  
Andrea Franza ◽  
Melanie Claps ◽  
...  
Keyword(s):  
Renal Cell ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Case Reports ◽  
Treatment Options ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Mtor Inhibitors ◽  
Cell Renal Cell Carcinoma ◽  
Clear Cell Rcc

Non-clear cell renal cell carcinomas (RCC) comprise several rare and poorly described diseases, often characterized by bad prognosis and with no standard treatments available. The gap in their clinical management is linked to the poor molecular characterization in handling the treatment of non clear-cell RCC with untailored therapies. Due to their rarity, non-clear RCC are in fact under-represented in prospective randomized trials. Thus, treatment choices are based on extrapolating results from clear cell RCC trials, retrospective data, or case reports. Over the last two decades, various options have been considered as the mainstay for the treatment of metastatic RCC (mRCC), including angiogenesis inhibitors, vascular endothelial growth factor receptor inhibitors, other tyrosine kinase inhibitors (TKIs), as well as MET inhibitors and mammalian targeting of rapamycin (mTOR) inhibitors. More recently, the therapeutic armamentarium has been enriched with immunotherapy, alone or in combination with targeted agents that have been shown to significantly improve outcomes of mRCC patients, if compared to TKI single-agent. It has been widely proven that non-clear cell RCC is a morphologically and clinically distinct entity from its clear cell counterpart but more knowledge about its biology is certainly needed. Histology-specific collaborative trials are in fact now emerging to investigate different treatments for non-clear cell RCC. This review summarizes pathogenetic mechanisms of non-clear cell RCC, the evolution of treatment paradigms over the last few decades, with a focus on immunotherapy-based trials, and future potential treatment options.

scholarly journals HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ilana Schlam ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

AbstractHuman epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

scholarly journals EGFR inhibitors switch keratinocytes from a proliferative to a differentiative phenotype affecting epidermal development and barrier function

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Nicolas Joly-Tonetti ◽  
Thomas Ondet ◽  
Mario Monshouwer ◽  
Georgios N. Stamatas
Keyword(s):  
Growth Factor ◽  
Barrier Function ◽  
Kinase Inhibitors ◽  
Treatment Protocol ◽  
Growth Factor Receptor ◽  
Skin Barrier ◽  
Keratinocyte Differentiation ◽  
Skin Barrier Function ◽  
Epidermal Keratinocytes ◽  
Epidermal Structure

Abstract Background Cutaneous adverse drug reactions (CADR) associated with oncology therapy involve 45–100% of patients receiving kinase inhibitors. Such adverse reactions may include skin inflammation, infection, pruritus and dryness, symptoms that can significantly affect the patient’s quality of life. To prevent severe skin damages dose adjustment or drug discontinuation is often required, interfering with the prescribed oncology treatment protocol. This is particularly the case of Epidermal Growth Factor Receptor inhibitors (EGFRi) targeting carcinomas. Since the EGFR pathway is pivotal for epidermal keratinocytes, it is reasonable to hypothesize that EGFRi also affect these cells and therefore interfere with the epidermal structure formation and skin barrier function. Methods To test this hypothesis, the effects of EGFRi and Vascular Endothelial Growth Factor Receptor inhibitors (VEGFRi) at therapeutically relevant concentrations (3, 10, 30, 100 nM) were assessed on proliferation and differentiation markers of human keratinocytes in a novel 3D micro-epidermis tissue culture model. Results EGFRi directly affect basal keratinocyte growth, leading to tissue size reduction and switching keratinocytes from a proliferative to a differentiative phenotype, as evidenced by decreased Ki67 staining and increased filaggrin, desmoglein-1 and involucrin expression compared to control. These effects lead to skin barrier impairment, which can be observed in a reconstructed human epidermis model showing a decrease in trans-epidermal water loss rates. On the other hand, pan-kinase inhibitors mainly targeting VEGFR barely affect keratinocyte differentiation and rather promote a proliferative phenotype. Conclusions This study contributes to the mechanistic understanding of the clinically observed CADR during therapy with EGFRi. These in vitro results suggest a specific mode of action of EGFRi by directly affecting keratinocyte growth and barrier function.

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