News - KIT exon 11 mutation

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 (AIOM 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. Previously presented at the 2024 ESMO Sarcoma and Rare Cancers Congress.

1 month ago

Clinical • Circulating tumor DNA • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 17 mutation

Guardant360® CDx

imatinib • sunitinib • Qinlock (ripretinib)

A Study of DCC-3116 in Combination with Anticancer Therapies in Participants with Advanced Malignancies (clinicaltrials.gov)

P1/2, N=94, Recruiting, Deciphera Pharmaceuticals, LLC | Trial completion date: Jun 2027 --> Mar 2029

1 month ago

Trial completion date

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

BRAF V600E • BRAF V600 • KIT mutation • KIT exon 11 mutation • PDGFRA mutation

Qinlock (ripretinib) • inlexisertib (DCC-3116)

2ms

Updated overall survival and safety data on ripretinib vs. sunitinib in patients with advanced gastrointestinal stromal tumor harboring KIT exon 11 + 17/18 mutations after prior treatment with imatinib: ctDNA analysis by INTRIGUE (DGHO 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 favorable for pts with KIT exon 11 + 17/18 mutations in the ripretinib arm.

2 months ago

Clinical • Circulating tumor DNA • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 17 mutation

Guardant360® CDx

imatinib • sunitinib • Qinlock (ripretinib)

2ms

MicroRNA expression signature in gastrointestinal stromal tumour & their molecular & histological features. (PubMed, Indian J Med Res)

Interpretation & conclusions The present study showed that the down-regulation of these miRNAs may help better molecular classification and characterization of GISTs. Our results offer new insight into the association between miRNAs and histological features, enabling a more thorough understanding of GISTs at the molecular level.

2 months ago

Journal • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • MIR34A (MicroRNA 34a-5p) • MIR221 (MicroRNA 221) • MIR494 (MicroRNA 494) • MIR222 (MicroRNA 222)

KIT exon 11 mutation • PDGFRA mutation • KIT expression

4ms

The INSIGHT study: a randomized, Phase III study of ripretinib versus sunitinib for advanced gastrointestinal stromal tumor with KIT exon 11 + 17/18 mutations. (PubMed, Future Oncol)

Exploratory baseline circulating tumor DNA analysis from the second-line INTRIGUE trial determined that patients with advanced GIST previously treated with imatinib harboring primary KIT exon 11 mutations and secondary resistance mutations restricted to KIT exons 17/18 had greater clinical benefit with ripretinib versus sunitinib. We describe the rationale and design of INSIGHT (NCT05734105), an ongoing Phase III open-label study of ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib exclusively harboring KIT exon 11 + 17/18 mutations detected by circulating tumor DNA.Clinical Trial Registration: NCT05734105 (ClinicalTrials.gov).

4 months ago

P3 data • Journal • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • KIT exon 11 mutation • KIT exon 17 mutation

imatinib • sunitinib • Qinlock (ripretinib)

8ms

Computed tomography radiogenomics: A potential tool for prediction of molecular subtypes in gastric stromal tumor. (PubMed, World J Gastrointest Oncol)

Our findings demonstrate that the combined modelCT sign + rad + clinic effectively distinguishes GISTs with KIT exon 11 mutation and KIT exon 11 codons 557-558 deletions. This combined model has the potential to be valuable in assessing the genotype of GISTs.

8 months ago

Journal • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation

10ms

Cross-Species Comparison of the Pan-RAF Inhibitor LY3009120's Anti-Tumor Effects in Equine, Canine, and Human Malignant Melanoma Cell Lines. (PubMed, Genes (Basel))

The anti-tumor effects of LY3009120 were observed in nine melanoma cell lines, indicating the potential feasibility of experimental trials with LY3009120. The present study reveals that the irradiation-resistant canine metastasis cells (cRGO1.2) harboring the NRAS p.G13R mutation are significantly LY3009120-sensitive, while the equine metastases-derived eRGO6 cells show significant resistance to LY3009120, which make them both valuable tools for studying resistance mechanisms in comparative oncology.

10 months ago

Preclinical • Journal

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • NRAS (Neuroblastoma RAS viral oncogene homolog)

KRAS mutation • BRAF mutation • NRAS mutation • KIT exon 11 mutation • NRAS Q61 • KRAS Q61H • KRAS exon 2 mutation • NRAS G13 • NRAS G13R • BRAF exon 11 mutation • BRAF exon 15 mutation

LY3009120

10ms

10 months ago

Clinical • Circulating tumor DNA • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 17 mutation

Guardant360® CDx

imatinib • sunitinib • Qinlock (ripretinib)

12ms

Genomic profiling in GIST: Implications in clinical outcome and future challenges. (PubMed, Neoplasia)

Moreover, mutations in Kit exon 9 and 11 are actionable, due to their response to imatinib, while mutations in PDGFRA respond to sunitinib and/or avapritinib. This allows the clinician to have an accurate picture of the genetic changes of the tumor over time. In this work, we aimed to discuss the implications of mutational testing in clinical outcomes, the methods to test ctDNA and the future challenges in the establishment of alternatives of personalized medicine.

12 months ago

Clinical data • Review • Journal

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

BRAF mutation • KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation

imatinib • sunitinib • Ayvakit (avapritinib)

12ms

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.

12 months ago

P3 data • Journal • Circulating tumor DNA • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 13 mutation • KIT exon 17 mutation

imatinib • sunitinib • Qinlock (ripretinib)

12ms

INTRIGUE: A Study of Ripretinib vs Sunitinib in Advanced GIST Patients After Treatment With Imatinib (clinicaltrials.gov)

P3, N=453, Active, not recruiting, Deciphera Pharmaceuticals LLC | Trial completion date: Mar 2022 --> Dec 2024

12 months ago

Trial completion date • Stroma • Metastases

KIT exon 11 mutation

imatinib • sunitinib • Qinlock (ripretinib)

1year

INSIGHT: A Study of Ripretinib vs Sunitinib in Patients With Advanced GIST With Specific KIT Exon Mutations Who Were Previously Treated With Imatinib (clinicaltrials.gov)

P3, N=54, Recruiting, Deciphera Pharmaceuticals LLC

1 year ago

Trial completion date • Trial initiation date • Trial primary completion date • Metastases

KIT exon 11 mutation • KIT exon 17 mutation

imatinib • sunitinib • Qinlock (ripretinib)

1year

Energy Spectral Computed Tomography for Predicting Mutation Status ofc-KIT exon 11 in Patients with Gastrointestinal Stromal Tumors (RSNA 2023)

Age and the quantitative parameters of energy spectrum CT can be used as preliminary evaluation indicators for the mutation status of GISTs c-KIT exon 11. The clinical combined energy spectrum CT quantitative parameters model has high efficiency in predicting the mutation status of GISTs c-KIT exon 11. *Clinical Relevance/Application: The quantitative parameters derived from energy spectrum CT may become a useful, and non-invasive clinical imaging index for predicting the mutation status of GISTs c-KIT exon 11, and can assist in clinical risk stratification and determining treatment plans for patients.

1 year ago

Clinical • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation

1year

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.

1 year ago

Next-generation sequencing

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

BRAF V600E • BRAF V600 • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 17 mutation

Ion AmpliSeq™ Cancer Hotspot Panel v2 • Oncomine Precision Assay

1year

Molecular landscape and clinical significance of exon 11 mutations in KIT gene among patients with gastrointestinal stromal tumor: a retrospective exploratory study. (PubMed, Front Oncol)

This study suggested that mutations in exon 11 of the KIT gene were common with intermediate/high recurrence risk in GISTs patients. Tumor diameter ≥5 cm, and deletions mutations might predict a worse prognosis.

1 year ago

Retrospective data • Journal • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation

1year

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.

1 year ago

Clinical • Circulating tumor DNA • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT exon 11 mutation • KIT exon 13 mutation • KIT exon 17 mutation

Guardant360® CDx

imatinib • sunitinib • Qinlock (ripretinib)

over1year

Ripretinib for the treatment of advanced, imatinib-resistant gastrointestinal stromal tumors. (PubMed, J Dig Dis)

Emerging evidence shows that ripretinib is superior to sunitinib as second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the precision of targeted GIST treatment.

over 1 year ago

Review • Journal • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • KIT exon 11 mutation • PDGFRA mutation

imatinib • sunitinib • Qinlock (ripretinib)

over1year

Clinical-radiomics-based treatment decision support for KIT Exon 11 deletion in gastrointestinal stromal tumors: a multi-institutional retrospective study. (PubMed, Front Oncol)

GIST patients could be divided into high or low risk subgroups of recurrence and mortality by the Radscore. The radiomics models based on enhanced CT for predicting KIT exon 11 deletion mutations have good diagnostic performance.

over 1 year ago

Retrospective data • Journal • Stroma

KIT exon 11 mutation

over1year

Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours. (PubMed, Cancers (Basel))

An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib...While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care...Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.

over 1 year ago

Review • Journal • Stroma

BRAF (B-raf proto-oncogene) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NTRK (Neurotrophic receptor tyrosine kinase)

BRAF mutation • KIT mutation • KIT exon 11 mutation • PDGFRA D842V • PDGFRA mutation

imatinib • sunitinib • Stivarga (regorafenib) • Ayvakit (avapritinib) • Qinlock (ripretinib)

over1year

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.

over 1 year ago

Clinical • Next-generation sequencing • Genomic analysis • Stroma • Metastases • Omic analysis

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)

KRAS mutation • BRAF mutation • KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation • KIT exon 13 mutation • KIT exon 17 mutation

imatinib • sunitinib • Stivarga (regorafenib) • Qinlock (ripretinib)

over1year

EFFICACY OF RIPRETINIB IN A MULTICENTER EXPANDED ACCESS PROGRAM IN PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMORS HARBOURING NON-KIT EXON 11 MUTATIONS. (CTOS 2023)

Objective: There remains an unmet need for effective and well tolerated systemic therapy for metastatic gastrointestinal stromal tumors (GISTs) after disease progression on imatinib is challenging. In the real world setting, ripretinib has durable benefit in metastatic GISTs harbouring non KIT exon 11 primary mutations. Ripretinib at a dose of 150 mg BD can be safely administered. Ripretinib is generally well tolerated with toxicity profile consistent with previous reports.

over 1 year ago

Clinical • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT exon 11 mutation • PDGFRA D842V • PDGFRA mutation • PDGFR wild-type

imatinib • Qinlock (ripretinib)

over1year

RIPRETINIB FOR THE TREATMENT OF CHINESE PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMORS HARBORING KIT SECONDARY MUTATIONS: A MULTICENTER, RETROSPECTIVE STUDY (CTOS 2023)

Approximately 70% and 77% of patients develop secondary resistance to first-line imatinib or at least three lines of treatment. The prevalence of secondary mutations among patients with primary exon 11 mutations seemes higher than those with exon 9 mutations. Ripretinib demonstrated promising mPFS and mOS benefit for patients with both primary and secondary KIT mutations, which was numerically superior to previously reported mPFS for sunitinib and regorafenib in patients with any secondary mutations.

over 1 year ago

Retrospective data • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation

imatinib • sunitinib • Stivarga (regorafenib) • Qinlock (ripretinib)

over1year

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.

over 1 year ago

Circulating tumor DNA • Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation • KIT exon 14 mutation

Ayvakit (avapritinib) • Qinlock (ripretinib)

over1year

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.

over 1 year ago

Clinical • Tumor mutational burden • Next-generation sequencing

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)

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

MSK-IMPACT

over1year

THE EFFICACY AND SAFETY OF RIPRETINIB IN THE TREATMENT OF CHINESE PATIENTS WITH ADVANCED GASTROINTESTINAL STROMAL TUMORS (GISTS): A SINGLE-INSTITUTION ANALYSIS (CTOS 2023)

Other analyses showed that duration of therapy(DOT)of imatinib did not seem to affect the survival data of ripretinib, while DOT of sunitinib seemed to have a trend to affect OS and DOT of regorafenib affected both the PFS and OS of ripretinib. Ripretinib has significant clinical benefit and good safety in Chinese patients with advanced GISTs. Earlier use of ripretinib may benefit the survival of the patients as well as for Chinese patients harboring exon 11 mutations. Dose escalation or combination of ripretinib with other TKIs after disease progression may provide additional clinically meaningful benefit with an acceptable safety profile.

over 1 year ago

Clinical • Stroma • Metastases

PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • KIT exon 11 mutation

imatinib • sunitinib • Stivarga (regorafenib) • Qinlock (ripretinib)

over1year

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.

over 1 year ago

Stroma

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 • PDGFRA exon 18 mutation

over1year

KIT and PDGFRA Variants and the Survival of Patients with Gastrointestinal Stromal Tumor Treated with Adjuvant Imatinib. (PubMed, Cancers (Basel))

Little evidence for OS benefit is available from randomized trials for patients whose GIST harbors KIT exon 9 mutation, KIT insertion mutation, PDGFRA D842V mutation, or lacks KIT and PDGFRA mutations. Adjuvant imatinib improves OS substantially if high-risk GISTs can be identified, treatment duration is long enough, and GISTs harbor an imatinib-sensitive mutation.

over 1 year ago

Review • Journal • Stroma

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 D842V • PDGFRA mutation

imatinib

over1year

A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies (clinicaltrials.gov)

P1/2, N=170, Recruiting, Deciphera Pharmaceuticals LLC | Not yet recruiting --> Recruiting

over 1 year ago

Enrollment open • Combination therapy • Metastases

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

BRAF V600E • BRAF V600 • KIT mutation • KIT exon 11 mutation • PDGFRA mutation

Erbitux (cetuximab) • Braftovi (encorafenib) • Qinlock (ripretinib) • inlexisertib (DCC-3116)

over1year

A Study of DCC-3116 in Combination With Anticancer Therapies in Participants With Advanced Malignancies (clinicaltrials.gov)

P1/2, N=170, Not yet recruiting, Deciphera Pharmaceuticals LLC

over 1 year ago

New P1/2 trial • Combination therapy • Metastases

BRAF (B-raf proto-oncogene) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

BRAF V600E • BRAF V600 • KIT mutation • KIT exon 11 mutation • PDGFRA mutation

Erbitux (cetuximab) • Braftovi (encorafenib) • Qinlock (ripretinib) • inlexisertib (DCC-3116)

over1year

Novel Genomic Risk Stratification Model for Primary Gastrointestinal Stromal Tumors (GIST) in the Imatinib and Adjuvant Therapy Era. (PubMed, Clin Cancer Res)

We developed a novel, next-generation genomic risk stratification model for primary gastric and small bowel GISTs, complementing traditional clinicopathologic models. Future independent validation of our model in external cohorts is essential.

over 1 year ago

Journal • Stroma

TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • SDHB (Succinate Dehydrogenase Complex Iron Sulfur Subunit B)

TP53 mutation • KIT mutation • KIT exon 11 mutation • SDHB deletion

MSK-IMPACT

imatinib

over1year

Whole-genome and Epigenomic Landscapes of Malignant Gastrointestinal Stromal Tumors Harboring KIT Exon 11 557-558 Deletion Mutations. (PubMed, Cancer Res Commun)

These genomic and epigenomic profiling results revealed that KIT Δ557-558 mutations are associated with increased genomic instability in malignant GISTs. We present genomic and epigenomic insights into the malignant progression of GISTs with KIT exon 11 deletions involving in 557-558, demonstrating their unique chromosomal instability and global intergenic DNA hypomethylation.

over 1 year ago

Journal • Stroma

TP53 (Tumor protein P53) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • SNAI2 (Snail Family Transcriptional Repressor 2)

KIT mutation • KIT exon 11 mutation • TP53 expression

over1year

CT radiomics for the preoperative prediction of molecular subtypes in gastric stromal tumor (ESMO-GI 2023)

Our results demonstrated that the radiomic model can effectively distinguish GISTs with KIT exon 11 mutation and KIT exon 11 codons 557-558 deletions based on CE-CT images.

over 1 year ago

Stroma

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation

over1year

MSI analysis in patients with GIST with Lynch syndrome. (ASCO 2023)

For the first time we observed in Lynch Syndrome MSH2 mutated, simolutaneous GIST and colon cancer in the same site of ileum and PCR analisys detected a rare exemple of microsatellite instability in GIST.

over 1 year ago

Clinical • MSi-H Biomarker

BRAF (B-raf proto-oncogene) • MSI (Microsatellite instability) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • MLH1 (MutL homolog 1) • MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • PMS2 (PMS1 protein homolog 2) • NTRK (Neurotrophic receptor tyrosine kinase)

MSI-H/dMMR • NTRK2 fusion • KIT mutation • BRAF wild-type • KIT exon 11 mutation • MSH2 mutation • PDGFR wild-type

EasyPGX® ready MSI

over1year

Multi-omic characterization of gastrointestinal stromal tumor (GIST) in a large real-world patient cohort. (ASCO 2023)

This series provides unprecedented resolution of KIT/PDGFRAmut GIST with features of clinical aggressiveness associated with KIT exon 11 indels and resistance mutations, illustrating a specific cytogenetic genotype with more aggressive growth and malignant behavior. Identification of less common molecular alterations that drive kinase activation and impaired DNA damage repair warrant further investigation.

over 1 year ago

Real-world evidence • Clinical • BRCA Biomarker • Real-world • Stroma

BRAF (B-raf proto-oncogene) • TP53 (Tumor protein P53) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • BRCA1 (Breast cancer 1, early onset) • PTEN (Phosphatase and tensin homolog) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • NTRK3 (Neurotrophic tyrosine kinase, receptor, type 3) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • RB1 (RB Transcriptional Corepressor 1) • ARID1A (AT-rich interaction domain 1A) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NF1 (Neurofibromin 1) • CHEK2 (Checkpoint kinase 2) • TSC1 (TSC complex subunit 1) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • DEPDC5 (DEP Domain Containing 5, GATOR1 Subcomplex Subunit) • MAX (MYC Associated Factor X)

PIK3CA mutation • NTRK3 fusion • PTEN mutation • KIT mutation • NF1 mutation • KIT exon 11 mutation • CHEK2 mutation • PDGFRA mutation • TSC1 mutation • PDGFR wild-type

MI Tumor Seek™

over1year

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.

over 1 year ago

Clinical • Stroma

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)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation • KIT L576P • KIT D820G

FoundationOne® CDx • FoundationOne® Liquid CDx

imatinib

over1year

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.

over 1 year ago

Clinical • Circulating tumor DNA • Stroma • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 17 mutation • PDGFR wild-type

Guardant360® CDx

imatinib • sunitinib • Qinlock (ripretinib)

over1year

KIT And PDGFRA Mutations And Survival of Gastrointestinal Stromal Tumor Patients Treated With Adjuvant Imatinib in a Randomized Trial. (PubMed, Clin Cancer Res)

Compared to 1 year of imatinib, 3 years of adjuvant imatinib led to 66% reduction in the estimated risk of death and a high 10-year OS rate in the subset of patients with a KIT exon 11 deletion/indel mutation.

over 1 year ago

Journal • Stroma

PDGFRA (Platelet Derived Growth Factor Receptor Alpha)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • PDGFRA mutation

imatinib

over1year

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

over 1 year ago

Trial completion • Enrollment change • Metastases

KIT (KIT proto-oncogene, receptor tyrosine kinase)

KIT mutation • KIT exon 11 mutation • KIT exon 13 mutation • KIT exon 17 mutation • KIT wild-type • PDGFR wild-type

Stivarga (regorafenib)

almost2years

PDR001 Plus Imatinib for Metastatic or Unresectable GIST (clinicaltrials.gov)

P1/2, N=39, Completed, Asan Medical Center | Recruiting --> Completed

almost 2 years ago

Trial completion • Metastases

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)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT exon 13 mutation • KIT exon 17 mutation

imatinib • sunitinib • Stivarga (regorafenib) • spartalizumab (PDR001)

2years

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.

2 years ago

Review • Journal

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)

2years

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.

2 years ago

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)

KIT mutation • KIT exon 11 mutation • KIT exon 9 mutation • KIT positive • KIT D816V • KIT exon 17 mutation

Rydapt (midostaurin) • Ayvakit (avapritinib) • bezuclastinib (PLX9486)

2years

Co-Localization of Gastrointestinal Stromal Tumors (GIST) and Peritoneal Mesothelioma: A Case Series. (PubMed, Ann Surg Oncol)

One in 17 GIST patients undergoing resection in this series have PM, which is significantly higher than expected if these two diseases were considered as independent events. Our results indicate that synchronous co-occurrence of GIST and PM is an underrecognized finding, suggesting a possible relationship that deserves further investigation.

2 years ago

Retrospective data • Journal

PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • PBRM1 (Polybromo 1) • BAP1 (BRCA1 Associated Protein 1)

PBRM1 mutation • BAP1 mutation • KIT exon 11 mutation • PDGFRA D842V • PDGFRA mutation