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Ref Type Journal Article
PMID (40700673)
Authors Noh S, Sharma AK, Fanta PT, Kato S, Kurzrock R, Sicklick JK
Title Personalized N-of-1 Combination Therapies for Advanced Gastrointestinal Stromal Tumors.
Journal Vol Issue Date Pages Journal Short Title
JCO precision oncology 9 2025 Jul e2500066 JCO Precis Oncol
URL
Abstract Text Gastrointestinal stromal tumor (GIST) resistance to imatinib and other tyrosine kinase inhibitors poses an ongoing clinical challenge. We investigated molecularly matched combination therapies for treatment-refractory GIST, including drugs not previously combined in human studies.Patients of all ages with unresectable and/or metastatic GIST treated with combination therapies were included (February 13, 2015-December 31, 2022). These patients were discussed at molecular tumor board and enrolled in the prospective Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) study (ClinicalTrials.gov identifier: NCT02534675). Patient demographics, tumor next-generation sequencing (NGS), treatment responses, and survival outcomes were retrospectively analyzed.Six (1.6%) patients met the inclusion criteria. The median age at diagnosis was 59.5 years with the majority (4/6) of patients being male. NGS revealed median of six deleterious genomic alterations per patient excluding variants of unknown significance. Five (5/6) patients had KIT-mutant GIST, and one patient had BRAFV600E-mutant GIST. Two thirds of tumors had CDKN2A/B loss. Patients received median of 1 (range, 1-3) customized combination therapy consisting of median of 2 (range, 2-3) drugs targeting median of 2 (range, 2-4) genomic alterations. One patient experienced a treatment-related grade ≥3 adverse event (hypertension). For all patients, the best response by RECIST v1.1 was stable disease (SD). Combination therapies led to SD ≥6 months (range, 6.2-11.3 months) in four (4/6) patients compared with none in the immediate previous single-agent targeted therapies (SD range, 1.5-5.4 months). Most (5/6) patients had at least 60% prolongation of their progression-free survival compared with their immediate previous single-agent targeted therapy.Our results demonstrate that a multitargeted, biomarker-matched combination approach can be safely administered to obtain disease control. Tailored combination therapies for advanced GIST with multiple genomic alterations warrant further investigation.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ATM R3008H KIT V559D KIT D579del KIT D820Y KIT A829P gastrointestinal stromal tumor predicted - sensitive Olaparib + Ripretinib Case Reports/Case Series Actionable In a clinical case study, treatment with the combination of Lynparza (olaparib) and Qinlock (ripretinib) resulted in stable disease with a progression-free survival of 6.2 months in a patient with recurrent gastrointestinal stromal tumor harboring KIT V559D, D579del, D820Y, and A829P and ATM R3008H (PMID: 40700673; NCT0253467). 40700673
KIT A502_Y503dup PTEN del exon1-2 gastrointestinal stromal tumor predicted - sensitive Everolimus + Imatinib Case Reports/Case Series Actionable In a clinical case study, treatment with the combination of Gleevec (imatinib) and Afinitor (everolimus) resulted in stable disease lasting 8.6 months in a patient with recurrent gastrointestinal stromal tumor harboring KIT A502_Y503dup (reported as Y503_F504insAY) and PTEN exon1-2 deletion, along with CDKN2A/B copy number loss (PMID: 40700673). 40700673