Advanced Gastrointestinal Stromal Tumors Research Articles

Clinical and Biomarker Analysis of a Phase I/II Study of PDR001 plus Imatinib for Advanced Treatment-refractory Gastrointestinal Stromal Tumors.

In this phase Ib/II study, we aimed to evaluate the safety and efficacy of PDR001, an anti-PD-1 antibody, in combination with imatinib in patients with treatment-refractory gastrointestinal stromal tumor (GIST). Advanced GIST patients whose disease had progressed on imatinib, sunitinib, and regorafenib were enrolled. In phase Ib, the standard 3+3 dose escalation scheme was applied. PDR001 400 mg intravenously every 4 weeks plus imatinib (300 mg and 400 mg daily for dose levels I and II, respectively) was given. The primary outcome for phase II was the disease control rate (DCR) at 12 weeks. Exploratory biomarker analysis was performed based on PD-L1 immunohistochemistry, next-generation sequencing, and multiplexed immunohistochemistry. No dose-limiting toxicity was observed in the phase Ib part (n=10), and dose level 2 was selected as the recommended phase II dose. In the phase II part (n=29), there was no objective response and the DCR at 12 weeks was 37.9%, not meeting the primary efficacy endpoint. For patients in phase Ib-dose level II and phase II (n=36), the median progression-free survival (PFS) and overall survival were 2.3 and 9.5 months, respectively. The most common grade 3-4 adverse event was anemia. Exploratory biomarker analysis indicated that a higher CD8+ T cell density was associated with a favorable PFS, but to a limited degree. Tumor mutation burden and PD-L1 were not associated with better PFS. In patients with treatment-refractory GIST, PDR001 in combination with imatinib was generally tolerable, but it was not effective.

Monitoring advanced gastrointestinal stromal tumor with circulating tumor DNA.

This review explores the role of circulating tumor (ct)DNA as a biomarker for clinical decision-making and monitoring purposes in metastatic gastrointestinal stromal tumor (GIST) patients. We discuss key insights from recent clinical trials and anticipate the future perspectives of ctDNA profiling within the clinical landscape of GIST. The identification and molecular characterization of KIT/platelet-derived growth factor receptor alpha (PDGFRA) mutations from ctDNA in metastatic GIST is feasible and reliable. Such identification through ctDNA serves as a predictor of clinical outcomes to tyrosine-kinase inhibitors (TKIs) in metastatic patients. Additionally, conjoined ctDNA analysis from clinical trials reveal the evolving mutational landscapes and increase in intratumoral heterogeneity across treatment lines. Together, this data positions ctDNA determination as a valuable tool for monitoring disease progression and guiding therapy in metastatic patients. These collective efforts culminated in the initiation of a ctDNA-based randomized clinical trial in GIST, marking a significant milestone in integrating ctDNA testing into the clinical care of GIST patients. The dynamic field of ctDNA technologies is rapidly evolving and holds significant promise for research. Several trials have successfully validated the clinical utility of ctDNA in metastatic GIST, laying the foundations for its prospective integration into the routine clinical management of GIST patients.

Safety outcomes of low versus high dose imatinib mesylate in patients with advanced, metastatic, or nonresectable gastrointestinal stromal tumors: A systematic review.

Gastrointestinal stromal tumors (GIST) are a rare cancer where tumors grow along the gastrointestinal tract. While treatment options aim towards surgical resection, some patients present with advanced metastatic and/or nonresectable diseases. The tyrosine kinase inhibitor imatinib mesylate is approved for this indication. However, dose escalation from 400 to 600 mg/d or 800 mg/d is allowed. The present study systematically evaluates the safety outcomes, particularly the incidence of grade ⩾ 3 adverse events (AEs) with low dose compared with high dose imatinib in these patients. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines were utilized to identify relevant studies through the PubMed, Cochrane Library, and Ovid databases and included randomized and non-randomized clinical trials comparing a low dose intervention of imatinib 400 mg/d with a high dose comparator of 600 or 800 mg/d in patients with histologically confirmed advanced metastatic and/or nonresectable GIST. Four studies were reviewed regarding study summaries and patient characteristics, patient demographics, and risk of bias, with a main emphasis on the evaluation of both efficacy outcomes and safety outcomes. Three of the four studies did not provide significant differences in response outcomes; however, all four studies reported a higher incidence of grade ⩾ 3 AEs in the high dose imatinib groups. Individual study reports of more high dose patients experiencing a grade ⩾ 3 event ranged from 0.6% to 19.8%, while combined low and high dose patient arms revealed a 17.1% difference favoring a high dose patient event. A sub-analysis of the three most frequently occurring categories, blood and lymphatic system disorders, gastrointestinal disorders, and general disorders and administration site conditions each revealed more high dose patients experiencing said category events compared to those low dose counterparts. Low dose imatinib provides clinically meaningful response and demonstrated better tolerability with less frequently reported reactions. This evidence supports further research into the maintenance of 400 mg/d for this patient population compared to a dose escalation.

Deciphering the tumor immune microenvironment of imatinib-resistance in advanced gastrointestinal stromal tumors at single-cell resolution

The heterogeneous nature of tumors presents a considerable obstacle in addressing imatinib resistance in advanced cases of gastrointestinal stromal tumors (GIST). To address this issue, we conducted single-cell RNA-sequencing in primary tumors as well as peritoneal and liver metastases from patients diagnosed with locally advanced or advanced GIST. Single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Immunohistochemistry and multiplex immunofluorescence staining were used to further validate it. This analysis revealed unique tumor evolutionary patterns, transcriptome features, dynamic cell-state changes, and different metabolic reprogramming. The findings indicate that in imatinib-resistant TME, tumor cells with activated immune and cytokine-mediated immune responses interacted with a higher proportion of Treg cells via the TIGIT-NECTIN2 axis. Future immunotherapeutic strategies targeting Treg may provide new directions for the treatment of imatinib-resistant patients. In addition, IDO1+ dendritic cells (DC) were highly enriched in imatinib-resistant TME, interacting with various myeloid cells via the BTLA-TNFRSF14 axis, while the interaction was not significant in imatinib-sensitive TME. Our study highlights the transcriptional heterogeneity and distinct immunosuppressive microenvironment of advanced GIST, which provides novel therapeutic strategies and innovative immunotherapeutic agents for imatinib resistance.

Surgical outcomes of locally advanced gastrointestinal stromal tumors after multivisceral resection: A retrospective study of 64 patients at a single institution.

To analyze the outcome in patients who have undergone multivisceral resection (MVR) for locally advanced gastrointestinal stromal tumors (GISTs), and identify the risk factors for tumor recurrence and postoperative morbidity. Sixty-four patients who operated for locally advanced GISTs with MVR in PPeking University Cancer Hospital Sarcoma Center (PUCHSC) between 2013 and 2021 were identified. Clinicopathologic characteristics, surgical outcomes, recurrence, and 5-year recurrence-free and overall survival were evaluated. The mean age of the patients was 60 years. Mean tumor size was 11.1 cm. Complete resection was achieved in all patients. The estimated 5-year recurrence-free and overall survival were 86.6% and 90.0%, respectively. Independent factor of recurrence following surgery was mitotic count on multivariate analysis. Overall postoperative morbidity was 53.1% (n = 34). Severe morbidity was 21.9% (n = 14). The most common severe complication was clinically relevant pancreatic fistula (n = 12, 18.8%), followed by anastomotic leakage (n = 4, 6.3%) and Intraabdominal abscess (n = 4, 6.3%). Multivariate analysis showed that preoperative imatinib therapy could reduce overall morbidity. Long operation time, combined colectomy and pancreatectomy were independent risk factors for postoperative severe morbidity. Compared to partial pancreatectomy, pancreaticoduodenectomy (PD) was significantly increased the incidence of severe morbidity. In conclusion, compared to systemic therapy alone, the outcome of locally advanced GISTs after MVR was more favorable. Despite the high overall morbidity, the postoperative severe morbidity and mortality of MVR were acceptable. Preoperative imatinib therapy should be recommended whenever possible. Combined pancreatectomy and colectomy are associated with significant postoperative severe morbidities. PD should be thoroughly discussed and be subject to MDT approach before surgery.

Efficacy and Safety of Ripretinib in Advanced Gastrointestinal Stromal Tumors within an Expanded Access Program: A Cohort Study.

Ripretinib, a novel tyrosine kinase inhibitor used in advanced gastrointestinal stromal tumors (GIST) resistant to standard therapies, was assessed in the United Kingdom (UK) within an Expanded Access Program (EAP). A retrospective review of patients treated between January 2020 and October 2021 within the ripretinib EAP in our Institution was conducted. Clinician-documented and mRECIST 1.1 assessments were collected. The primary endpoints were progression-free survival (PFS) and time to treatment discontinuation (TTD). Treatment beyond progression (TBP), overall survival (OS), objective response rates and safety data were also analyzed. Survival curves were constructed using the Kaplan-Meier method, and univariate and multivariate Cox regression analyses were performed. All analyses were performed with R software. Overall, forty-five patients were included. After a median follow-up of 24.2 (95% CI 19.7-29.7) months, the median PFS of the group receiving 150 mg ripretinib once daily (OD) was 7.9 (95% CI 5.6-19.3) months. In the cohort of 22 patients with dose escalation upon tumor progression to 150 mg ripretinib twice daily (BD), the median PFS from BD was 5.4 (95% CI 2.8-9.3) months. Overall, median PFS and OS values for patients on ripretinib were 9.7 (95% CI 8.3-18.1) and 14.0 (95% CI 9.9-NA) months, respectively. TTD was similar to PFS. TBP was observed in about one third of all patients. Objective responses to ripretinib OD and BD treatments were observed in 16.7% and 10.0% of the patients, respectively. No new safety signals were identified. In conclusion, patients with advanced GIST receiving ripretinib in the UK within the EAP reported prolonged benefits, in line with the recent phase III clinical trials.

Advanced gastrointestinal stromal tumor: reliable classification of imatinib plasma trough concentration via machine learning

AimPatients with advanced gastrointestinal stromal tumors (GISTs) exhibiting an imatinib plasma trough concentration (IM Cmin) under 1100 ng/ml may show a reduced drug response rate, leading to the suggestion of monitoring for IM Cmin. Consequently, the objective of this research was to create a customized IM Cmin classification model for patients with advanced GISTs from China.MethodsInitial data and laboratory indicators from patients with advanced GISTs were gathered, and the above information was segmented into a training set, validation set, and testing set in a 6:2:2 ratio. Key variables associated with IM Cmin were identified to construct the classification model using the least absolute shrinkage and selection operator (LASSO) regression and forward stepwise binary logistic regression. Within the training and validation sets, nine ML classification models were constructed via the resampling method and underwent comparison through the Brier scores, the areas under the receiver-operating characteristic curve (AUROC), the decision curve, and the precision-recall (AUPR) curve to determine the most suitable model for this dataset. Two methods of internal validation were used to assess the most suitable model's classification performance: tenfold cross-validation and random split-sample validation (test set), and the value of the test set AUROC was used to evaluate the model's classification performance.ResultsSix key variables (gender, daily IM dose, metastatic site, red blood cell count, platelet count, and percentage of neutrophils) were ultimately selected to construct the classification model. In the validation set, it is found by comparison that the Extreme Gradient Boosting (XGBoost) model has the largest AUROC, the lowest Brier score, the largest area under the decision curve, and the largest AUPR value. Furthermore, as evaluated via internal verification, it also performed well in the test set (AUROC = 0.725).ConclusionFor patients with advanced GISTs who receive IM, initial data and laboratory indicators could be used to accurately estimate whether the IM Cmin is below 1100 ng/ml. The XGBoost model may stand a chance to assist clinicians in directing the administration of IM.

Ripretinib in the treatment of patients with advanced gastrointestinal stromal tumors (GIST)

Ripretinib in the treatment of patients with advanced gastrointestinal stromal tumors (GIST)

Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors (GIST) is effective and safe: results from a prospective single center study with 108 patients

Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors (GIST) is effective and safe: results from a prospective single center study with 108 patients

INSIGHT: A phase 3, randomized, open-label study of ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib with KIT exon 11 + 17/18 mutations.

TPS767 Background: Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma with approximately 80% of cases driven by KIT mutations. Most patients (pts) with advanced GIST experience disease progression following first-line treatment with imatinib due to KIT secondary resistance mutations occurring most commonly in the ATP-binding pocket (exons 13/14) and/or activation loop (exons 17/18). Sunitinib is approved as second-line therapy for advanced GIST. Ripretinib is a switch-control tyrosine kinase inhibitor approved for pts with GIST who received prior treatment with 3 or more kinase inhibitors, including imatinib. In the phase 3 INTRIGUE study (NCT03673501) in second-line advanced GIST, ripretinib was not superior to sunitinib in terms of progression-free survival (PFS); however, a more favorable safety profile was observed with ripretinib vs sunitinib.1 Exploratory mutational analysis from INTRIGUE using baseline circulating tumor DNA (ctDNA) demonstrated that pts harboring primary KIT exon 11 mutations with secondary resistance mutations exclusively in KIT exons 17/18 derived PFS benefit with ripretinib vs sunitinib (median, 14.2 vs 1.5 months; HR, 0.22; 95% CI, 0.11 to 0.44; nominal P <0.0001).2 Here, we describe a planned phase 3 study for pts with advanced GIST previously treated with imatinib harboring KIT exon 11 + 17/18 mutations. Methods: INSIGHT (NCT05734105) is a phase 3, randomized, open-label study aiming to evaluate the efficacy of ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib and who harbor KIT exon 11 + 17/18 mutations. Eligible pts must be ≥18 years old with histologically confirmed GIST and co-occurring KIT exon 11 + 17/18 mutations confirmed by ctDNA analysis. Pts must also have advanced disease with ≥1 measurable lesion per modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, radiologic progression on imatinib, and an Eastern Cooperative Oncology Group performance status ≤2. Key exclusion criteria include a KIT exon 9, 13, or 14 mutation confirmed via ctDNA analysis at screening and prior treatment with another line of therapy in addition to imatinib for advanced GIST. A total of 54 pts will be randomized (2:1) to receive ripretinib 150 mg once daily (QD; continuous) or sunitinib 50 mg QD (4 weeks on/2 weeks off) in 6-week cycles. The primary endpoint is PFS by independent radiologic review (IRR) per mRECIST v1.1; key secondary endpoints are objective response rate by IRR using mRECIST v1.1 and overall survival. Safety and patient-reported outcome measures will also be assessed. Pts randomized to the sunitinib arm may cross over to the ripretinib arm upon disease progression. 1. Bauer S et al. J Clin Oncol. 2022. 2. Bauer S et al. J Clin Oncol. 2023; abstract 397784. Clinical trial information: NCT05734105 .

Overall survival and long-term safety with ripretinib vs sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: Final analyses from INTRIGUE.

748 Background: Ripretinib is a switch-control tyrosine kinase inhibitor approved for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with 3 or more kinase inhibitors, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. In the second interim analysis of overall survival (OS) from the phase 3 INTRIGUE study, the OS event rate was 41% in the all-patient (AP) intent-to-treat (ITT) population, and OS was similar between treatment arms in both the KIT exon 11 ITT and AP ITT populations. Here, we present the final OS and updated safety from INTRIGUE. Methods: INTRIGUE (NCT03673501) is an open-label, phase 3 study of adults with advanced GIST who had disease progression on or intolerance to imatinib. Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 weeks on/2 weeks off) and was stratified by KIT mutational status and imatinib intolerance. OS was a key secondary endpoint (the primary endpoint of progression-free survival was reported previously); final OS analysis was prespecified to occur with ≥200 and ≥145 events in the AP ITT and KIT exon 11 ITT populations, respectively. Data cutoff was March 15, 2023. Results: Of 453 pts, 444 received treatment; 40 remain on treatment (ripretinib, 28/223 [13%]; sunitinib, 12/221 [5%]). Treatment discontinuation was due to progressive disease (PD) by independent radiologic review (56%), PD by investigator (11%), clinical PD (6%), withdrawal of consent (6%), and adverse events (AEs; 5%). Fewer pts discontinued treatment due to AEs with ripretinib vs sunitinib (3% vs 6%). There were 211 OS events (47%) in the AP ITT population and 151 OS events (46%) in the KIT exon 11 ITT population. OS was similar with ripretinib vs sunitinib in the 2 ITT populations (Table). Fewer pts had grade 3/4 treatment-emergent AEs with ripretinib vs sunitinib (43% vs 67%). Dose interruptions and reductions were lower with ripretinib vs sunitinib. Median treatment duration for ripretinib vs sunitinib was 7.9 vs 6.5 months. Conclusions: In the finalOS analysis from the INTRIGUE study, OS was similar between treatment arms. The safety profile remained consistent and more favorable for ripretinib vs sunitinib in pts with advanced GIST previously treated with imatinib. Clinical trial information: NCT03673501 . [Table: see text]

A retrospective analysis of the efficacy and safety of imatinib in elderly patients with advanced gastrointestinal stromal tumor.

730 Background: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor arising from the gastrointestinal tract, characterized by a high predominance of the elderly population. Imatinib is the standard first-line therapy for advanced GIST with a median survival of around 4 years in pivotal clinical trials. However, clinical data for the elderly population is not known well. The aim of this study is to evaluate the efficacy and safety of imatinib for advanced GIST in the elderly population in comparison with the non-elderly population. Methods: We extracted clinical data of patients with advanced GIST treated with imatinib as first-line therapy at our institution between January 2010 and July 2023. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs) were assessed and compared between the elderly group (age: ≥ 70 years, E group) and the non-elderly group (age: < 70 years, NE group). Multivariable analyses were performed using Cox proportional hazard models to evaluate the prognostic significance of age groups. Results: A total of 91 patients were included in this analysis with 32 patients in the E group and 59 patients in the NE group with a median follow-up duration of 39.8 months. Patient characteristics were as follows (the E group vs. the NE group): median age 76 (70–90) vs. 54 (29–69) years, male: 50% vs. 56%, performance status 0: 19% vs. 63%, disease status (: 47% vs. 44%), stomach primary 44% vs. 34%, KIT mutation (exon 11: 50% vs. 61%), and maximum tumor diameter (≥8cm: 66% vs. 51%). The proportion of patients with a reduced starting dose of imatinib was significantly higher in the E group (34% vs. 2%, p <0.0001). Median PFS in the E group and the NE group were 29.4 months and 60.0 months (HR=2.04, log-rank p=0.035). Median OS in the E group and the NE group were 91.5 months and not reached (HR=2.74, log-rank p=0.02). ORR was 53% in the elderly group and 66% in the non-elderly group (p=0.32). In for OS, age was not an independent prognostic factor (HR=2.09, p=0.14) with a significant independent prognostic factor of disease status (unresectable/initially metastatic vs. recurrent (reference): HR=3.58, p=0.03). The occurrence of ≥ grade 2 non-hematologic AEs was more common in the elderly group compared to the non-elderly group (78% vs. 32%, p<0.001). Conclusions: The elderly population with advanced GIST may achieve a survival period comparable to that observed in pivotal trials with imatinib. Even with reduced doses of imatinib, careful monitoring is necessary because of the high frequency of non-hematologic ≥ grade 2 AEs in the elderly population.

Regorafenib: A comprehensive drug profile.

Regorafenib is a small molecule tyrosine kinase inhibitor administered orally drug, act by inhibiting the activity of the VEGF receptors. It is used for the treatment of patients with metastatic colorectal cancer (CRC), advanced gastrointestinal stromal tumors, and hepatocellular carcinoma. This comprehensive profile on regorafenib includes an original data as well as data collected from the literature on Profiles of Methods of Drug Synthesis, different Physical Drug Profiles, Drug Analytical methods and Pharmacological profile (ADME). This chapter is divided into five main sections: General Description of the drug, Physical Characteristics, Methods of Preparation, Methods of Analysis, Pharmacology and List of References. These main sections are further divided to many sub-titles to cover most aspect of the drug in the light of the available literature. Among these sub-titles are the formulae, Elemental Analysis, physical characteristics which include constant of ionization, solubility, X-ray powder diffraction pattern, TGA, thermal conduct and spectroscopic and stability. Additionally, analytical techniques including Electrochemical, Spectrophotometric and chromatographic methods, ADME profiles and pharmacological effects were also discussed. Furthermore, methods and schemes are outlined for the preparation of the drug substance.

A systematic review and meta-analysis of neoadjuvant imatinib use in locally advanced and metastatic gastrointestinal stromal tumours

A systematic review and meta-analysis of neoadjuvant imatinib use in locally advanced and metastatic gastrointestinal stromal tumours

Pimitespib for the treatment of advanced gastrointestinal stromal tumors and other tumors.

Pimitespib (TAS-116) is the first heat shock protein 90 (HSP90) inhibitor approved in Japan, and it is indicated for the treatment of gastrointestinal stromal tumors (GIST) that have progressed after treatment with imatinib, sunitinib and regorafenib. This review describes the preclinical and clinical research with pimitespib, including its mechanism of action, pharmacokinetics, clinical antitumour activity and safety. In a phase III study, pimitespib significantly prolonged progression-free survival compared with placebo (median 2.8 vs 1.4months; hazard ratio 0.51; 95% CI 0.30-0.87;p=0.006). Common treatment-related adverse events were diarrhoea, decreased appetite, increase in serum creatinine, malaise, nausea and eye disorders. The efficacy and safety of pimitespib are being investigated in other tumour types and in combination with other anticancer therapies.

Propylene carbonate as an ecofriendly solvent: Stability studies of Ripretinib in RPHPLC and sustainable evaluation using advanced tools

Ripretinib (RPB) is a U.S. Food and Drug Administration approved drug for the treatment of advanced gastrointestinal stromal tumour. According to literature search, there are no RP-HPLC methods developed for the recently approved drug RPB due to its terrible solubility. In this current study, Green Analytical Chemistry (GAC) was employed using the RP-HPLC technique to study the stability of RPB under different stress conditions. Two reported polymorphs of RPB were analysed using the mobile phase mixture of phosphate buffer, propylene carbonate and ethanol (50: 35: 15) on a 250 × 4.6 mm, i.d. 5 μm Inertsil ODS-2 C18 column, at a wavelength of 260 nm. In this study, method development for RPB quantification was accomplished within a linearity range of 1400–2600 ng/mL, yielding an R2 value of 0.9973. The method exhibited a LOD of 103 ng/mL and a LOQ of 312 ng/mL, demonstrating high sensitivity and accuracy. The utilization of assessment tools for evaluating greenness and whiteness offered valuable insights into the environmental impact and sustainability of the proposed methodology. The results substantiated its positive performance in terms of eco-friendliness, thereby emphasizing its alignment with seven sustainable development goals include 7 (Affordable and Clean Energy), 9 (Industry, Innovation, and Infrastructure), 12 (Responsible Consumption and Production), 13 (Climate Action), 14 (Life Below Water), 15 (Life on Land), 17 (Partnerships for the Goals). This further enhances the credibility and significance of the developed method in advancing the cause of a greener and more sustainable future.

Recent advances for treatment of upper gastrointestinal malignancy.

Recent prospective trials for esophageal cancer, gastric cancer, and gastrointestinal stromal tumor (GIST)are encouraging. This manuscript reviews selected recently published studies. Not surprisingly, immunotherapy dominates the current clinical trial landscape. However, targeted biologic therapies and standard chemotherapy remain critical to the treatment of gastric and esophageal cancer while imatinib remains the backbone for advanced or metastatic GISTs. For all three cancers, surgical resection remains important when intent of treatment is potential cure.

Efficacy and safety of ripretinib vs. sunitinib in patients with advanced gastrointestinal stromal tumor previously treated with imatinib: A phase 2, multicenter, randomized, open-label study in China

AimA bridging study of INTRIGUE study to assess the efficacy and safety of ripretinib versus sunitinib as second-line treatment in Chinese GIST patients. MethodsThis was a phase 2, multicenter, randomized, open-label study in China. GIST patients previously treated with imatinib were randomized (1:1) to receive ripretinib 150 mg once daily (QD) by continuous dosing in 42-day cycles or sunitinib 50 mg QD in 42-day cycles (four weeks on/two weeks off). Primary endpoint was progression-free survival (PFS) by independent radiological review (IRR). ResultsBetween 6 December 2020 and 15 September 2021, 108 patients were randomized to receive ripretinib (n = 54) or sunitinib (n = 54) (all-patient [AP] intention-to-treat [ITT] population). Seventy patients had primary KIT exon 11 mutations (ripretinib, n = 35; sunitinib, n = 35; Ex11 ITT population). By data cut-off (20 July 2022), in AP ITT population, PFS by IRR was comparable between ripretinib and sunitinib arms (HR 0·99, 95 % CI 0·57, 1·69; nominal p = 0·92; median PFS [mPFS] 10·3 vs 8·3 months). In Ex11 ITT population, PFS by IRR was longer for ripretinib than sunitinib (HR 0·46, 95 % CI 0·23, 0·92; nominal p = 0·03; mPFS not reached in ripretinib arm and 4·9 months in sunitinib arm). Fewer patients experienced grade 3/4 treatment-related treatment-emergent adverse events with ripretinib (17%) versus sunitinib (56%). ConclusionsRipretinib demonstrated similar efficacy and a favorable safety profile versus sunitinib as second-line treatment in Chinese GIST patients. Furthermore, ripretinib provided greater clinically meaningful benefit versus sunitinib in patients with KIT exon 11 mutation.

Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor.

Most gastrointestinal stromal tumors (GISTs) express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. The relationship between mutations in these kinases and clinical response to imatinib was examined in a group of patients with advanced GIST. GISTs from 127 patients enrolled onto a phase II clinical study of imatinib were examined for mutations of KIT or PDGFRA. Mutation types were correlated with clinical outcome. Activating mutations of KIT or PDGFRA were found in 112 (88.2%) and six (4.7%) GISTs, respectively. Most KIT mutations involved exon 9 (n = 23) or exon 11 (n = 85). All KIT mutant isoforms, but only a subset of PDGFRA mutant isoforms, were sensitive to imatinib, in vitro. In patients with GISTs harboring exon 11 KIT mutations, the partial response rate (PR) was 83.5%, whereas patients with tumors containing an exon 9 KIT mutation or no detectable mutation of KIT or PDGFRA had PR rates of 47.8% (P = .0006) and 0.0% (P < .0001), respectively. Patients whose tumors contained exon 11 KIT mutations had a longer event-free and overall survival than those whose tumors expressed either exon 9 KIT mutations or had no detectable kinase mutation. Activating mutations of KIT or PDGFRA are found in the vast majority of GISTs, and the mutational status of these oncoproteins is predictive of clinical response to imatinib. PDGFRA mutations can explain response and sensitivity to imatinib in some GISTs lacking KIT mutations.

Individualized surgical treatment in patients with advanced gastrointestinal stromal tumor — a case series

Individualized surgical treatment in patients with advanced gastrointestinal stromal tumor — a case series