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BIOMARKER:

KIT exon 17 mutation

i
Other names: KIT, C-Kit, CD117, PBT, SCFR, Stem Cell Factor Receptor, V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog
Entrez ID:
1m
Updated overall survival and safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib and harboring KIT exon 11 + 17/18 mutations: ctDNA analysis from INTRIGUE (Sarcoma-RC 2024)
In this updated exploratory analysis from INTRIGUE, OS was longer for ripretinib vs sunitinib for pts with KIT exon 11 + 17/18 mutations identified by baseline ctDNA. The safety profile was consistent and more favorable for ripretinib vs sunitinib in these pts.
Clinical • Circulating tumor DNA • Stroma • Metastases
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT exon 11 mutation • KIT exon 17 mutation
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Guardant360® CDx
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imatinib • Sutent (sunitinib) • Qinlock (ripretinib)
3ms
Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial. (PubMed, Nat Med)
INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.
P3 data • Journal • Circulating tumor DNA • Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT exon 11 mutation • KIT exon 13 mutation • KIT exon 17 mutation
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imatinib • Sutent (sunitinib) • Qinlock (ripretinib)
3ms
A multi-center retrospective comparison between systemic mastocytosis with t(8;21) AML and KIT mutant t(8;21) AML. (PubMed, Blood Adv)
For all patients in our cohort, age > 60 years, KITD816 mutations and BCOR mutations were showed to be independent unfavorable predictors for OS and EFS. Our results revealed that SM-t(8;21) AML shared more similar clinical characteristics, molecular features and clinical outcomes with KITD816 t(8;21) AML.
Retrospective data • Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • BCOR (BCL6 Corepressor)
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KIT mutation • BCOR mutation • KIT D816V • KIT exon 17 mutation
4ms
Analysis of Safety and Efficacy of Avapritinib As Targeted Therapy for Pediatric Acute Myeloid Leukemia Patients with KIT Mutation after Transplantation (ASH 2023)
2 patients did not achieve continuous RUNX1: : RUNX1T1 negative after preemptive therapy with Decitabine (DAC) and donor lymph infusion (DLI), and then was treated with Avapritinib, one's RUNX1: : RUNX1T1 fusion achieved continuously negative after 1 month treatment of Avapritinib, the other's achieved continuous negative after 7 months treatment of Avapritinib. Avapritinib is safe and effective in the prophylactic and preemptive treatment of AML with KIT mutation after allo-HSCT in children, which provides a clinical drug for the prevention of relapse after transplantation.
Clinical
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1)
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KIT mutation • RUNX1 mutation • KIT N822K • KIT exon 17 mutation • RUNX1-RUNX1T1 fusion • KIT fusion
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decitabine • Ayvakit (avapritinib)
4ms
Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies. (PubMed, Clin Cancer Res)
Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ³4 line settings.
P1/2 data • Retrospective data • Journal • Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • KIT exon 9 mutation • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation
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Ayvakit (avapritinib)
4ms
Trial completion date • Trial initiation date • Trial primary completion date • Metastases
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KIT exon 11 mutation • KIT exon 17 mutation
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imatinib • Sutent (sunitinib) • Qinlock (ripretinib)
4ms
KIT exon 17 mutations are predictive of inferior outcome in pediatric acute myeloid leukemia with RUNX1::RUNX1T1. (PubMed, Pediatr Blood Cancer)
Exon 17 KIT mutations serve as an important predictor of relapse in RUNX1::RUNX1T1 pediatric AML. In addition, a high KIT VAF may predict poor outcomes in these patients. These results emphasize the need to incorporate KIT mutational analysis into risk stratification for pediatric CBF-AML.
Journal
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RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1)
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KIT mutation • KIT exon 17 mutation • CBFB-MYH11 fusion
5ms
Integrated Analysis of KIT Exon 17 Mutations and Flow-MRD Refines Risk Stratification in Pediatric Acute Myeloid Leukemia with RUNX1::RUNX1T1 (ASH 2023)
Patients with both non-mutated KIT exon 17 and negative MRD have the best prognosis, while positive MRD and KIT exon 17 mutations are associated with poorer outcomes. These findings indicated that integrated analysis of flow-MRD and KIT exon 17 status enables optimal risk assignment strategies in pediatric AML with RUNX1::RUNX1T1.
Clinical
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NRAS (Neuroblastoma RAS viral oncogene homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD19 (CD19 Molecule) • RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • CD33 (CD33 Molecule) • ARID1B (AT-Rich Interaction Domain 1B) • NCAM1 (Neural cell adhesion molecule 1)
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NRAS mutation • KIT mutation • CD19 expression • KIT exon 17 mutation • ARID1B mutation • NCAM1 expression • CD33 expression
5ms
Dideoxy Sequencing Enhances Detection of KIT Variants in GISTs Initially Evaluated by NGS Hotspot Panels (AMP 2023)
Our results suggest that short read NGS-based assays may miss a significant number of clinically actionable KIT variants, and that follow-up of KIT and PDGFRA NGS-negative cases by alternative testing modalities should be considered.
Next-generation sequencing
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BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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BRAF V600E • BRAF V600 • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 17 mutation
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Ion AmpliSeq™ Cancer Hotspot Panel v2 • Oncomine Precision Assay
5ms
Trial initiation date • Combination therapy • Metastases
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PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • PDGFRA D842V • PDGFRA mutation • KIT D816V • KIT exon 17 mutation • PDGFRA fusion
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azacitidine • elenestinib (BLU-263)
5ms
A COLLECTION OF PATIENT-DERIVED XENOGRAFT MODELS OF GASTROINTESTINAL STROMAL TUMORS (CTOS 2023)
One model is characterized by an imatinib-resistant PDGFRA exon 18 p.D842V mutation... We are expanding our established platform of well-characterized GIST PDX models, that were proven to serve as an excellent tool for preclinical drug testing and tumor biology studies. The platform is available for cooperative projects with academic and commercial partners.
Preclinical • Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • PDGFRA D842V • PDGFRA mutation • KIT exon 17 mutation • PDGFRA exon 18 mutation
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imatinib
5ms
New P2 trial
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SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B)
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KIT exon 17 mutation • SDHB mutation • KIT exon 17 mutation + KIT exon 18 mutation
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imatinib • Stivarga (regorafenib)
6ms
Mutational heterogeneity of imatinib resistance and efficacy of ripretinib vs sunitinib in patients with gastrointestinal stromal tumor: ctDNA analysis from INTRIGUE (DGHO 2023)
While KIT ATP-BP mutations were associated with clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of KIT mutations to predict the clinical benefit of second-line therapy in pts with advanced GIST. These data were presented in part at the Jan 2023 ASCO plenary session.
Clinical • Circulating tumor DNA • Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT exon 11 mutation • KIT exon 13 mutation • KIT exon 17 mutation
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Guardant360® CDx
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imatinib • Sutent (sunitinib) • Qinlock (ripretinib)
7ms
ctDNA-Guided Sunitinib And Regorafenib Therapy for GIST (clinicaltrials.gov)
P2, N=48, Recruiting, University of Miami | Trial completion date: Jul 2028 --> Dec 2028 | Trial primary completion date: Jul 2026 --> Dec 2026
Trial completion date • Trial primary completion date • Circulating tumor DNA • Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT exon 13 mutation • KIT exon 17 mutation
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Sutent (sunitinib) • Stivarga (regorafenib)
7ms
Core-binding factor abnormalities involving chromosome 16 in acute myeloid leukaemia: prognostic and therapeutic implications. (PubMed, BMJ Case Rep)
She had an aggressive clinical course following initiation of cytarabine-based induction chemotherapy. The underlying mutational landscape may significantly influence the biological behaviour of otherwise favourable risk of CBF-AML cases.
Journal
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KRAS (KRAS proto-oncogene GTPase) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CBFB (Core-Binding Factor Subunit Beta 2)
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KRAS mutation • KRAS exon 2 mutation • KIT exon 17 mutation • CBFB-MYH11 fusion
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cytarabine
8ms
CIRCULATING TUMOR DNA (CTDNA) ANALYSES AND RESISTANCE MECHANISMS EXPLORATION OF KIT-MUTANT GASTROINTESTINAL STROMAL TUMORS (GISTS) TREATED WITH AVAPRITINIB OR RIPRETINB (CTOS 2023)
Different KIT mutation types and signaling pathways atlerations were detected in progression samples of KIT-mutant GISTs after avapritinib or ripretinib failure compared with baseline, which may be associated with mechanism of resistance.
Circulating tumor DNA • Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation • KIT exon 14 mutation
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Ayvakit (avapritinib) • Qinlock (ripretinib)
8ms
COMPREHENSIVE ANALYSIS OF THE GENOMIC LANDSCAPE AND CLINICAL BEHAVIOR IN GIST USING NEXT GENERATION SEQUENCING (NGS, MSK-IMPACT) (CTOS 2023)
This study represents a one of the most comprehensive analyses of the genomic landscape and integration of genomic features with clinicopathologic attributes and survival outcome in GIST.
Clinical • Tumor mutational burden • Next-generation sequencing
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BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • TSC1 (TSC complex subunit 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • TNFRSF14 (TNF Receptor Superfamily Member 14) • GATA3 (GATA binding protein 3)
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TP53 mutation • BRAF mutation • PIK3CA mutation • PTEN mutation • CDKN2A mutation • KIT exon 11 mutation • PDGFRA D842V • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation • TSC1 mutation • KIT exon 17 mutation + KIT exon 18 mutation
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MSK-IMPACT
8ms
UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR-ASSOCIATED PROTEIN AS A POTENTIAL NEXT GENERATION MOLECULAR TARGET FOR TREATMENT OF GASTROINTESTINAL STROMAL TUMOR (CTOS 2023)
uPARAP is highly expressed in several GIST xenograft models across multiple passages of ex-mouse tumors. Considering its preferential expression in GIST and other mesenchymal tumors and the recycling character of this molecular target, uPARAP may serve as a powerful emerging target for systemic treatment of GIST beyond traditional kinase inhibitors or in combination with the latter. uPARAP positive xenograft models can be used for in vivo evaluation of such anti-uPARAP treatment.
Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation • PDGFRA exon 18 mutation
8ms
GENOMIC ANALYSIS OF SECONDARY KIT MUTATIONS IN CHINESE PATIENTS WITH IMATINIB-RESISTANT ADVANCED GASTROINTESTINAL STROMAL TUMORS USING NEXT-GENERATION SEQUENCING (NGS) (CTOS 2023)
As sunitinib and regorafenib are only effective against certain secondary mutations, ripretinib can broadly inhibit a wide range of primary and secondary KIT mutations. The proportion of secondary mutations in KIT Exon 11 primary mutations is significantly higher than that in KIT Exon 9 primary mutations following progression on first-line imatinib treatment. Furthermore, the main resistance mechanism of KIT Exon 11 mutant GISTs continues to rely on complex secondary mutations in KIT signaling. Differences in resistance mechanisms among various primary mutations imply that subsequent treatment should take into account both the patient 's primary and resistance mutations.
Clinical • Next-generation sequencing • Genomic analysis • Stroma • Metastases • Omic analysis
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B) • SDHC (Succinate Dehydrogenase Complex Subunit C) • SDHD (Succinate Dehydrogenase Complex Subunit D) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)
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KRAS mutation • BRAF mutation • KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation
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imatinib • Sutent (sunitinib) • Stivarga (regorafenib) • Qinlock (ripretinib)
11ms
Clinical utility of liquid-based comprehensive genomic profiling (CGP) in gastrointestinal stromal tumors (GIST). (ASCO 2023)
In liquid, 58% (39/67) of samples with a KIT-driver mutation had a co-occurring imatinib-resistant KIT alteration... Known driver and TKI-resistant mutations of both somatic and potential germline origin are identified in peripheral blood ctDNA of GIST patients. Liquid biopsy shows high concordance to tissue in identifying driver mutations in the presence of elevated TF and may exhibit TKI-resistant specific alterations. This study indicates that liquid biopsy may be useful in the molecular classification of GIST during the medical management of advanced GIST patients.
Clinical • Stroma
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BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • SDHA (Succinate Dehydrogenase Complex Flavoprotein Subunit A)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation • KIT L576P • KIT D820G
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FoundationOne® CDx • FoundationOne® Liquid CDx
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imatinib
11ms
Outcomes in patients with advanced gastrointestinal stromal tumor who did not have baseline ctDNA detected in the INTRIGUE study. (ASCO 2023)
Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 kinase inhibitors, including imatinib. Pts with ctDNA-ND had better efficacy outcomes vs pts with ctDNA-D in both treatment arms; PFS was numerically higher with ripretinib vs sunitinib in pts with ctDNA-ND. Although little is known about the biology driving ctDNA in GIST, these data suggest pts may have improved outcomes and different treatment sensitivity based on ctDNA detectability. Clinical trial information: NCT03673501.
Clinical • Circulating tumor DNA • Stroma • Metastases
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 17 mutation • PDGFR wild-type
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Guardant360® CDx
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imatinib • Sutent (sunitinib) • Qinlock (ripretinib)
12ms
Enrollment open • Combination therapy • Metastases
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PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • PDGFRA D842V • PDGFRA mutation • KIT D816V • KIT exon 17 mutation • PDGFRA fusion
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azacitidine • elenestinib (BLU-263)
12ms
ctDNA-Guided Sunitinib And Regorafenib Therapy for GIST (clinicaltrials.gov)
P2, N=48, Recruiting, University of Miami | Trial completion date: Apr 2028 --> Jul 2028 | Initiation date: Apr 2023 --> Jul 2023 | Trial primary completion date: Apr 2026 --> Jul 2026
Trial completion date • Trial initiation date • Trial primary completion date • Circulating tumor DNA • Stroma
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT exon 13 mutation • KIT exon 17 mutation
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Sutent (sunitinib) • Stivarga (regorafenib)
12ms
AZURE: Study of Elenestinib (BLU-263) in Advanced Systemic Mastocytosis (AdvSM) and and Other KIT Altered Hematologic Malignancies (clinicaltrials.gov)
P1/2, N=67, Not yet recruiting, Blueprint Medicines Corporation | N=108 --> 67 | Trial completion date: Nov 2027 --> Nov 2029 | Initiation date: Dec 2022 --> Apr 2023 | Trial primary completion date: Nov 2027 --> Nov 2029
Enrollment change • Trial completion date • Trial initiation date • Trial primary completion date • Combination therapy • Metastases
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PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • PDGFRA D842V • PDGFRA mutation • KIT D816V • KIT exon 17 mutation • PDGFRA fusion
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azacitidine • elenestinib (BLU-263)
1year
REGISTRI: Single Agent Regorafenib in First-line for Metastatic/Unresectable KIT/PDGFR Wild Type GIST (clinicaltrials.gov)
P2, N=15, Completed, Grupo Espanol de Investigacion en Sarcomas | Recruiting --> Completed | N=39 --> 15
Trial completion • Enrollment change • Metastases
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT exon 11 mutation • KIT exon 13 mutation • KIT exon 17 mutation • KIT wild-type • PDGFR wild-type
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Stivarga (regorafenib)
1year
ctDNA-Guided Sunitinib And Regorafenib Therapy for GIST (clinicaltrials.gov)
P2, N=48, Recruiting, University of Miami | Trial completion date: Jan 2028 --> Apr 2028 | Initiation date: Jan 2023 --> Apr 2023 | Trial primary completion date: Jan 2026 --> Apr 2026
Trial completion date • Trial initiation date • Trial primary completion date • Circulating tumor DNA • Stroma
|
KIT (KIT proto-oncogene, receptor tyrosine kinase)
|
KIT exon 13 mutation • KIT exon 17 mutation
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Sutent (sunitinib) • Stivarga (regorafenib)
1year
PDR001 Plus Imatinib for Metastatic or Unresectable GIST (clinicaltrials.gov)
P1/2, N=39, Completed, Asan Medical Center | Recruiting --> Completed
Trial completion • Metastases
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • LAG3 (Lymphocyte Activating 3) • ANO1 (Anoctamin 1) • MSR1 (Macrophage Scavenger Receptor 1)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation
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imatinib • Sutent (sunitinib) • Stivarga (regorafenib) • spartalizumab (PDR001)
over1year
Ripretinib: A Review in Gastrointestinal Stromal Tumours as Fourth-or Later-Line of Therapy. (PubMed, Drugs)
Ripretinib has acceptable tolerability, with the most common drug-related grade 3 or 4 adverse events being lipase increases, hypertension, fatigue and hypophosphataemia. Ripretinib is therefore a valuable additional line of therapy available for the management of gastrointestinal stromal tumours.
Review • Journal
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
|
KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation
|
Qinlock (ripretinib)
over1year
Summit: A 3-Part, Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Nonadvanced Systemic Mastocytosis (NonAdvSM) (ASH 2022)
There are currently no approved therapies for patients with NonAdvSM. Data from the Summit study will support further development of bezuclastinib in SM.
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • KDR (Kinase insert domain receptor) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
|
KIT mutation • KIT D816V • KIT exon 17 mutation
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bezuclastinib (PLX9486)
over1year
Preliminary Safety and Efficacy from Apex, a Phase 2 Study of Bezuclastinib (CGT9486), a Novel, Highly Selective, Potent KIT D816V Tyrosine Kinase Inhibitor, in Adults with Advanced Systemic Mastocytosis (AdvSM) (ASH 2022)
Patients with a history of prior TKI therapy (e.g., avapritinib, midostaurin) are permitted in the study. Early data suggest that bezuclastinib is well-tolerated and is associated with encouraging early signs of clinical activity as demonstrated by meaningful reductions in serum tryptase, MC burden, and KIT D816V VAF. Enrollment is currently ongoing. Updated safety and clinical activity as well as initial clinical objective response data will be presented.
Clinical • P2 data
|
KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT positive • KIT D816V • KIT exon 17 mutation
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Rydapt (midostaurin) • Ayvakit (avapritinib) • bezuclastinib (PLX9486)
over1year
Gastrointestinal stromal tumors caused by novel germline variants in SDHB and KIT: a report of two cases and literature review. (PubMed, Clin J Gastroenterol)
The first case is a 28-year-old female who developed multiple gastric GISTs with widespread abdominal metastases that were resistant to imatinib...Next-generation sequencing revealed a germline KIT exon 17 mutation (NM_000222.3, c.2459A > T, p.D820V). These cases highlight the diverse clinical presentations of patients with germline variants and raise several important points about the diagnosis and management of these patients, in particular: mutation in the SDH family of genes (somatic or germline) should be suspected in KIT and PDGFRA wild-type tumors; germline testing should be considered in patients with multiple GISTs or those who present with disease at a young age; and somatic next-generation sequencing cannot only help identify optimal therapy in all patients with GISTs but also help guide referral to Medical Genetics for appropriate patients.
Review • Journal
|
PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B)
|
KIT mutation • KIT exon 17 mutation • PDGFR wild-type
|
imatinib
over1year
PEAK STUDY: A PHASE 3 RANDOMIZED, OPEN-LABEL, MULTICENTER CLINICAL STUDY OF BEZUCLASTINIB (CGT9486) AND SUNITINIB VERSUS SUNITINIB IN PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS (CTOS 2022)
There remains a high unmet need for more effective and better tolerated second- and later-line treatments for patients with GIST. Phase 1/2 bezuclastinib data in advanced solid tumors, including GIST, were encouraging and support further clinical investigation of co-targeting the complementary conformational states of the same kinase with bezuclastinib and sunitinib. The Peak Study aims to assess the efficacy and safety of bezuclastinib in combination with sunitinib as second-line treatment in adult patients with imatinib-resistant, or intolerant, GIST.
Clinical • P3 data
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation
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imatinib • Sutent (sunitinib) • bezuclastinib (PLX9486)
over1year
COMBINATION THERAPY OF TYROSINE KINASE INHIBITORS WITH RIPRETINIB AS THERAPEUTIC EXPLORATION FOR REFRACTORY GASTROINTESTINAL STROMAL TUMORS AFTER PROGRESSION FROM STANDARD THERAPY: A CASE REPORT (CTOS 2022)
Standard treatment for metastatic or unresectable GISTs includes tyrosine-kinase inhibitors (TKIs) such as imatinib as first-line therapy followed by sunitinib, regorafenib and ripretinib as second-, third- and fourth-line therapies, respectively (2). This case report is a microcosm of the latest GIST treatments. It provides the evidence that combination therapy of ripretinib with sunitinib or imatinib can be an efficacious therapeutic option for arresting GIST progression in selective patients, who are refractory to current standard therapies.
Clinical • Combination therapy
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KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)
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KIT mutation • KIT exon 11 mutation • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation
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imatinib • Sutent (sunitinib) • Stivarga (regorafenib) • Qinlock (ripretinib)
over1year
Differential activity of avapritinib in patients with metastases from mucosal melanoma and thymic carcinoma harbouring KIT exon 17 mutations: Initial experience from a Compassionate Use Program in Italy. (PubMed, Eur J Cancer)
Taken together, the inactivity of imatinib on KIT exon 17 mutations, the general low clinical efficacy of immunotherapy, as well as the consequent formal lack of standard available and active second line systemic treatments in both mucosal melanoma and thymic carcinoma, support the implementation of avapritinib in the therapeutic armamentarium, even though further prospective evidence is warranted.
Journal • IO biomarker
|
KIT (KIT proto-oncogene, receptor tyrosine kinase)
|
KIT mutation • KIT exon 17 mutation
|
imatinib • Ayvakit (avapritinib)
over1year
Intratumoural heterogeneity with different resistant subclones in a treatment resistant gastrointestinal stromal tumour revealed through a novel tissue masking technology (ECP 2022)
Background & objectives: A 73-year-old man with a history of metastatic small bowel gastrointestinal stromal tumour (GIST) who have undergone liver and small bowel resections was found to have recurrent peritoneal nodules on follow-up despite being on Imatinib... This case demonstrated the utilization of Quantumcyte Oncomask, a novel tissue masking technology in detection of heterogeneous resistant subclones in a treatment resistant GIST. It enables the sampling of targeted areas in a tumour section to increase the cellular purity for molecular sequencing especially for the analysis of tumour heterogeneity which is known to be associated with therapeutic resistance. The presence of different mutation subclones in GIST is also important in guiding oncologists on the treatment choices.
ANO1 (Anoctamin 1)
|
KIT mutation • KIT exon 11 mutation • KIT N822K • KIT exon 17 mutation • KIT N822Y
|
imatinib
over1year
Ckit mutations in patients with Gastrointestinal stromal tumours (ECP 2022)
They also function as predictive markers for response to imatinib... Overall Ckit mutation rate was lower (73%) than reported in literature, thus concluding that incidence of ckit muta-tions could be lower in Indian population. Ckit exon 9 mutations had consistent duplication while deletions and substitutions were found in in exon 11. Exon 9 mutations guided treatment decisions.
Clinical
|
ANO1 (Anoctamin 1)
|
KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation
|
imatinib
over1year
ctDNA-Guided Sunitinib And Regorafenib Therapy for GIST (clinicaltrials.gov)
P2, N=48, Recruiting, University of Miami | Not yet recruiting --> Recruiting
Enrollment open • Circulating tumor DNA
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT exon 13 mutation • KIT exon 17 mutation
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Sutent (sunitinib) • Stivarga (regorafenib)
almost2years
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden)
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KIT mutation • KIT D816V • KIT exon 17 mutation
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bezuclastinib (PLX9486)
almost2years
In Vivo Evaluation of Fibroblast Growth Factor Receptor Inhibition in Mouse Xenograft Models of Gastrointestinal Stromal Tumor. (PubMed, Biomedicines)
The present preclinical study evaluated the potential use of the fibroblast growth factor receptor inhibitors infigratinib and dovitinib alone or in combination with the mitogen-activated protein kinase inhibitor binimetinib in mouse models of GIST with different sensitivity or resistance to imatinib. In a model with KIT exon 11 and 17 mutations, dovitinib induced tumor necrosis, most likely due to anti-angiogenic effects. Additive effects combining dovitinib with binimetinib were limited.
Preclinical • Journal
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FGFR (Fibroblast Growth Factor Receptor)
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KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 17 mutation • KIT exon 11 mutation + KIT exon 17 mutation
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imatinib • Mektovi (binimetinib) • Truseltiq (infigratinib) • dovitinib (TKI258)
almost2years
Molecular Portrait of GISTs Associated With Clinicopathological Features: A Retrospective Study With Molecular Analysis by a Custom 9-Gene Targeted Next-Generation Sequencing Panel. (PubMed, Front Genet)
Targeted NGS can simultaneously and efficiently detect nine GIST-related gene mutations and provide reference for clinicians' individualized diagnosis and treatment. Our results have important implications for clinical management.
Retrospective data • Journal • Next-generation sequencing
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KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1)
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KRAS mutation • BRAF mutation • KIT mutation • NF1 mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation
almost2years
A PHASE 2 STUDY OF BEZUCLASTINIB (CGT9486), A NOVEL, HIGHLY SELECTIVE, POTENT KIT D816V INHIBITOR, IN ADULTS WITH ADVANCED SYSTEMIC MASTOCYTOSIS (APEX): METHODS, BASELINE DATA, AND EARLY INSIGHTS (EHA 2022)
Part 1 of the Apex study aims to determine the optimal dose to further evaluate in Part 2. Early insights into the safety and tolerability profile and biomarker data will further inform clinical development of bezuclastinib in AdvSM.
Clinical • P2 data • Tumor Mutational Burden
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TMB (Tumor Mutational Burden) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • CSF1R (Colony stimulating factor 1 receptor)
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KIT mutation • KIT D816V • KIT exon 17 mutation
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bezuclastinib (PLX9486)
almost2years
ctDNA-Guided Sunitinib And Regorafenib Therapy for GIST (clinicaltrials.gov)
P2, N=48, Not yet recruiting, University of Miami
New P2 trial • Circulating tumor DNA
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KIT (KIT proto-oncogene, receptor tyrosine kinase)
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KIT exon 13 mutation • KIT exon 17 mutation
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Sutent (sunitinib) • Stivarga (regorafenib)