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Multi-disciplinary management of recurrent gastrointestinal stromal tumor harboring KIT exon 11 mutation with the switch-control kinase inhibitor ripretinib and surgery.

ABSTRACT: Ripretinib is a tyrosine kinase inhibitor that was approved by the United States FDA in 2020 for treatment of advanced gastrointestinal stromal tumor (GIST) in patients who received prior treatment with three or more tyrosine kinase inhibitors. In this case report, we show the durable clinical benefit achieved in a patient with GIST by using ripretinib and repeated timely surgical resection of limited disease progression. The total time on ripretinib was 43 months which is longer than the current reported data from ripretinib clinical trials. Such approach for using multi-disciplinary disease management can improve the durability of response to tyrosine kinase inhibitors, including ripretinib, and associated clinical outcomes.

SUBMITTER: Gouda MA

PROVIDER: S-EPMC10511119 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Multi-disciplinary management of recurrent gastrointestinal stromal tumor harboring KIT exon 11 mutation with the switch-control kinase inhibitor ripretinib and surgery.

Gouda Mohamed A MA Janku Filip F Somaiah Neeta N Hunt Kelly K KK Yedururi Sireesha S Subbiah Vivek V

Oncoscience 20230920

Ripretinib is a tyrosine kinase inhibitor that was approved by the United States FDA in 2020 for treatment of advanced gastrointestinal stromal tumor (GIST) in patients who received prior treatment with three or more tyrosine kinase inhibitors. In this case report, we show the durable clinical benefit achieved in a patient with GIST by using ripretinib and repeated timely surgical resection of limited disease progression. The total time on ripretinib was 43 months which is longer than the curren ...[more]

PMID: 37736254

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Project description:Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal tract of humans and dogs. Little is known about the pathogenesis of these tumors. This study evaluated the role of c-KIT in canine GISTs; specifically, we investigated activating mutations in exons 8, 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), all of which have been implicated in human GISTs.Seventeen canine GISTs all confirmed to be positive for KIT immunostaining were studied. Exons 8, 9, 11, 13 and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA, were amplified from DNA isolated from formalin-fixed paraffin-embedded samples.Of these seventeen cases, six amplicons of exon 11 of c-KIT showed aberrant bands on gel electrophoresis. Sequencing of these amplicons revealed heterozygous in-frame deletions in six cases. The mutations include two different but overlapping six base pair deletions. Exons 8, 9, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA had no abnormalities detected by electrophoresis and sequencing did not reveal any mutations, other than synonymous single nucleotide polymorphisms (SNPs) found in exon 11 of c-KIT and exons 12 and 14 of PDGFRA.The deletion mutations detected in canine GISTs are similar to those previously found in the juxtamembrane domain of c-KIT in canine cutaneous mast cell tumors in our laboratory as well as to those reported in human GISTs. Interestingly, none of the other c-KIT or PDGFRA exons showed any abnormalities in our cases. This finding underlines the critical importance of c-KIT in the pathophysiology of canine GISTs. The expression of KIT and the identification of these activating mutations in c-KIT implicate KIT in the pathogenesis of these tumors. Our results indicate that mutations in c-KIT may be of prognostic significance and that targeting KIT may be a rational approach to treatment of these malignant tumors. This study further demonstrates that spontaneously occurring canine GISTs share molecular features with human GISTs and are an appropriate model for human GISTs.

Project description:BackgroundMutation screening for gastrointestinal stromal tumor (GIST) is crucial and the c kit gene (KIT) exon 11 mutation is the most common type. This study aimed to explore the associations between GIST with KIT exon 11 mutation and contrast-enhanced computed tomography (CT) images.MethodsPathologically proven GISTs with definitive genotype testing results in our hospital were retrospectively included. Abdominal contrast-enhanced CT images were analyzed. Conventional CT image features and radiomic features were recorded and extracted to build the following models: model [CT], model [radiomic + clinic] and model [CT + radiomic + clinic]. The diagnostic performances of GISTs with KIT exon 11 mutation and KIT exon 11 deletion involving codons 557-558 were evaluated.ResultsIn total, 327 GISTs (255 with KIT exon 11 mutation, and 73 with KIT exon 11 mutation deletion involving codons 557-558) were included. Significant CT features were found for GISTs with KIT exon 11 mutation. The area under curves (AUCs) of the models for KIT exon 11 mutation were 0.7158, 0.7530, and 0.8375 in the training cohort, and 0.6777, 0.7349, and 0.8105 in validation cohort, respectively. The AUCs of the models for KIT exon 11 mutation deletion involving codons 557-558 were 0.7155, 8621, and 0.8691 in the training cohort, and 0.7099, 0.8355, and 0.8488 in the validation cohort, respectively. The model [CT + radiomic + clinic] demonstrated the highest AUCs for prediction of KIT exon 11 mutation and those with deletion involving codons 557-558 (P<0.05), respectively. The model [radiomic + clinic] showed higher diagnostic performance than model [CT] significantly.ConclusionsOur results demonstrated the associations between GIST with KIT exon 11 mutation and contrast-enhanced CT images. We found combing conventional image analysis and texture analysis is a useful tool to distinguish GIST with KIT exon 11 mutation. CT radiogenomics exhibited good application potential in predict the KIT exon 11 mutation of GIST.

Project description:PurposeIn advanced gastrointestinal stromal tumor (GIST), there is an unmet need for therapies that target both primary and secondary mutations of pathogenic KIT/PDGFRA oncoproteins. Ripretinib is a novel switch-control kinase inhibitor designed to inhibit a wide range of KIT and PDGFRA mutations.Patients and methodsThis first-in-human, to our knowledge, phase I study of ripretinib (ClinicalTrials.gov identifier: NCT02571036) included a dose-escalation phase and subsequent expansion phase at the recommended phase II dose (RP2D). Eligible patients included those with advanced GIST, intolerant to or experienced progression on ≥ 1 line of systemic therapy, and other advanced malignancies. Safety, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), and preliminary antitumor activity were evaluated.ResultsAt data cutoff (August 31, 2019), 258 patients (n = 184 GIST) were enrolled, with 68 patients in the dose-escalation phase. Three DLTs were reported: grade 3 lipase increase (n = 2; 100 mg and 200 mg twice a day) and grade 4 increased creatine phosphokinase (n = 1; 150 mg once daily). MTD was not reached (maximum dose evaluated, 200 mg twice a day); 150 mg once daily was established as the RP2D. The most frequent (> 30%) treatment-emergent adverse events in patients with GIST receiving ripretinib 150 mg once daily (n = 142) were alopecia (n = 88 [62.0%]), fatigue (n = 78 [54.9%]), myalgia (n = 69 [48.6%]), nausea (n = 65 [45.8%]), palmar-plantar erythrodysesthesia (n = 62 [43.7%]), constipation (n = 56 [39.4%]), decreased appetite (n = 48 [33.8%]), and diarrhea (n = 47 [33.1%]). Objective response rate (confirmed) of 11.3% (n = 16/142) ranging from 7.2% (n = 6/83; fourth line or greater) to 19.4% (n = 6/31; second line) and median progression-free survival ranging from 5.5 months (fourth line or greater) to 10.7 months (second line), on the basis of investigator assessment, were observed.ConclusionRipretinib is a well-tolerated, novel inhibitor of KIT and PDGFRA mutant kinases with promising activity in patients with refractory advanced GIST.

Project description:Background and aimsConsidering the indication of adjuvant therapy, the recurrence risk for primary gastrointestinal stromal tumor (GIST) after surgery needs to be accurately estimated. However, current risk stratification schemes may still have room for improvement. This study seeks to analyze prognostic factors for primary GISTs from 3 aspects, including clinicopathological parameters, immunohistochemical biomarkers, and gene mutational status, and attempts to find novel valuable factors predicting the malignancy potential of GISTs.MethodsRetrospective data from 114 primary GIST patients after R0 resection were collected. Clinicopathological data was obtained from medical records and re-evaluated. Immunohistochemical analysis was performed using the Tissue Microarray method for Ki67, p16, p27, p53, SKP2, CD133, and actin. KIT gene exons 9, 11, 13, and 17 and PDGFRα gene exons 12 and 18 were tested for mutations using PCR.ResultsUnivariate analysis revealed the following factors as poor prognostic indicators for relapse-free survival with a median follow-up of 50 months: male gender, gastrointestinal bleeding, mitotic index >5/50HPFs, tumor size >5 cm, non-gastric site, necrosis, epithelioid or mixed cell type, surrounding tissue invasion, Ki67>5%, p16>20%, p53 index >10, SKP2>10%, and KIT exon 11 deletion. Besides mitotic index, tumor size and site, SKP2 high expression (RR = 2.91, 95% CI: 1.41-5.99, P = 0.004) and KIT exon 11 deletion (RR = 2.73, 95% CI: 1.04-7.16, P = 0.041) were also independent risk factors in multivariate analysis, with gastrointestinal bleeding also showing a trend towards significance (RR = 1.88, 95% CI: 0.98-3.64, P = 0.059). In addition, gastrointestinal bleeding and SKP2 high expression showed a good ability to stratify high-risk patients further.ConclusionOur results show that gastrointestinal bleeding, SKP2 high expression, and KIT exon 11 deletions may be useful indicators of high recurrence risk for primary GIST patients.

Dataset Information

Multi-disciplinary management of recurrent gastrointestinal stromal tumor harboring KIT exon 11 mutation with the switch-control kinase inhibitor ripretinib and surgery.

Publications

Multi-disciplinary management of recurrent gastrointestinal stromal tumor harboring KIT exon 11 mutation with the switch-control kinase inhibitor ripretinib and surgery.

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