Purpose: The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non–PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007–001 trials. Patients and Methods: Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS). Results: Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6–10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). Conclusions: 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 ≥4 line settings.

Background: The liver is the most common site of metastasis from gastrointestinal stromal tumors (GISTs). The authors aimed to evaluate imatinib (IM) combined with hepatic resection (HR) or other local treatments such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE), compared to IM monotherapy in long-term survival benefits in patients suffering from GIST liver metastases. Methods: Our research encompassed 238 patients diagnosed with liver metastases of GISTs from January 2002 to April 2022 at the First Affiliated Hospital of Sun Yat-Sen University. The oncological outcomes of concern included overall survival (OS), progression-free survival (PFS), and liver-specific PFS. Results: Of all 238 patients, 126 were treated with IM alone (IM group), 81 with IM combined with HR (IM+HR group), and 31 with IM combined with RFA/TACE (IM+RFA/TACE group). The median follow-up time was 44.83 months. The median OS in the IM group was 132.60 months and was not reached in either the IM+HR group or the IM+RFA/TACE group. The 10-year OS rate in the IM+HR group was significantly superior to the IM group and the IM+RFA/TACE group (91.9% vs. 61.1% vs. 55.2%, respectively, P=0.015), and the liver-specific PFS (P=0.642) and PFS (P=0.369) in the three groups showed a beneficial trend in the combined treatment group. Multivariate analyses showed that age less than or equal to 60 years (HR 0.280, P<0.001) and IM+HR (HR 0.361, P=0.047) were independently associated with better OS. Achieving no evidence of disease through surgical intervention was independently correlated with enhanced OS (HR 0.099, P=0.034), liver-specific PFS (HR 0.388, P=0.014), and PFS (HR 0.402, P=0.004). Conclusions: In patients with GIST liver metastases, IM combined with HR might improve OS in selected patients compared with IM alone and IM combined with RFA/TACE. Achieving no evidence of disease status with surgical treatment of patients results in significant prolonging of OS, liver-specific PFS, and PFS.

Background: Accurately and promptly predicting the response of gastrointestinal stromal tumors (GISTs) to targeted therapy is essential for optimizing treatment strategies. However, some fractions of recurrent or metastatic GISTs present as non-FDG-avid lesions, limiting the value of [¹⁸F]fluorodeoxyglucose positron emission tomography/computed tomography ([¹⁸F]FDG PET/CT) in treatment evaluation. This study evaluated the efficacy of [¹⁸F]F-fibroblast activation protein inhibitor (FAPI)-42 [¹⁸F]FAPI-42) PET/CT for assessing the treatment response in recurrent or metastatic GISTs, in comparison to [¹⁸F]FDG PET/CT and explores a model integrating PET/CT imaging and clinical parameters to optimize the clinical use of these diagnostic tools. Methods: Our retrospective analysis included 27 patients with recurrent or metastatic GISTs who underwent [¹⁸F]FAPI-42 PET/CT and [¹⁸F]FDG PET/CT at baseline before switching targeted therapy. Treatment response status was divided into a progression group (PG) and a non-progression group (NPG) based on the Response Criteria in Solid Tumors (RECIST) 1.1, according to the contrast-enhanced computed tomography (CT) scan at six months. [¹⁸F]FAPI-42 and [¹⁸F]FDG PET/CT parameters including the mean standardized uptake value (SUV_mean), the standard uptake value corrected for lean body mass (SUL_peak), the maximum standardized uptake value (SUV_max), tumor-to-blood pool SUV ratio (TBR), tumor-to-liver SUV ratio (TLR), metabolic tumor volume (MTV)/FAPI-positive tumor volume (GTV-FAPI), total lesion glycolysis (TLG)/FAPI-positive total lesion accumulation (TLF) were correlated with the response status to identify indicative of treatment response. The predictive performance of them was quantified by generating receiver operating characteristic curves (ROC), calibration curves, and cross-validation. Results: A total of 110 lesions were identified in 27 patients. Compared with PG, NPG was associated with lower levels of TBR and SUV_mean in FDG PET/CT (TBR-FDG, SUV_mean-FDG; P=0.033 and P=0.038, respectively), with higher SUL_peak and TLF in FAPI PET/CT (SUL_peak-FAPI, TLF-FAPI; P=0.10 and P=0.049, respectively). The predictive power of a composite-parameter model, including TBR-FDG, SUL_peak-FAPI, gene mutation, and type of targeted therapy [area under the curve (AUC) =0.865], was superior to the few-parameter models incorporating TBR-FDG (AUC =0.637, P<0.001), SUL_peak-FAPI (AUC =0.665, P<0.001) or both (AUC =0.721, P<0.001). Conclusions: Both [¹⁸F]FAPI-42 PET/CT and [¹⁸F]FDG PET/CT have value in predicting the treatment response of recurrent or metastatic GISTs. And [¹⁸F]FAPI-42 PET/CT offers synergistic value when used in combination with [¹⁸F]FDG PET/CT. Notably, the nomogram generated from the model incorporating [¹⁸F]FAPI-42 PET/CT, [¹⁸F]FDG PET/CT parameters, gene mutation, and type of targeted therapy could yield more precise predictions of the response of recurrent metastatic GISTs.

Background: Many studies reporting that down-regulation of SOCS6 plays vital roles in promoting progression of malignant tumors have been published. The present study was performed to evaluate whether SOCS6 was significantly associated with prognosis of GIST patients. Methods: Immunohistochemical staining was accomplished to evaluate the expression levels of SOCS6 among GIST patients. The impacts of SOCS6 expression on overall survival (OS) and recurrence-free survival (RFS) of GIST patients were assessed by Cox proportional hazard regression model analysis and Kaplan-Meier curve analysis. Results: It was demonstrated that the expression level of SOCS6 was significantly associated with tumor size (P=0.001). Then according to Kaplan-Meier curve analysis, low expression of SOCS6 was significantly correlated with worse OS and RFS of GIST patients. Ultimately, it was revealed by Cox proportional regression model analysis that low expression of SOCS6 was an independent predictive factor for OS and RFS. Conclusions: Low expression of SOCS6 was an independent prognostic factor for GIST, suggesting its potential as a novel biomarker predicting survival of GIST patients.