Precision and personalized multidisciplinary management of a giant gastrointestinal stromal tumor (GIST) harboring KIT exon 11 and 13 mutations: a case report of long-term survival

Introduction

Gastrointestinal stromal tumors (GISTs) represent a milestone in the application of targeted therapy to solid tumors. However, while imatinib significantly improves the survival of patients with recurrent/metastatic GISTs, drug resistance is inevitable and typically develops in over half of patients within 2 years of treatment (1). First-line imatinib resistance in advanced GISTs involves multiple secondary drug resistance mutations and high spatiotemporal tumor heterogeneity, which pose significant challenges for subsequent treatments (2,3). Notably, patients with primary mutations in exon 11 of KIT (KIT proto-oncogene, receptor tyrosine kinase) exhibit greater number and more variety types of secondary resistance mutations compared to those with other primary mutations (4).

Clinical studies indicate that the standard second-line treatment, sunitinib, has a median progression-free survival (PFS) of 5.6 months and an objective response rate (ORR) of 6.8% (5), while the third-line treatment, regorafenib, has a median PFS of 4.8 months and an ORR of 4.5% (6). Limited in vitro data suggests sunitinib is more effective against KIT exon 13 mutation, while regorafenib is more effective against KIT exon 17 mutation, but its efficacy against KIT exon 13 mutation is limited (7). In addition to efficacy, safety is another major treatment consideration. Poor safety profiles of second- and third-line targeted therapies often necessitate dose modifications or discontinuation (6,8), adding to treatment uncertainty.

Ripretinib is a novel switch-control inhibitor that provides broad-spectrum inhibition of KIT and PDGFRA (platelet-derived growth factor receptor alpha) mutant kinases (9). The INTRIGUE study indicated that the PFS and overall survival (OS) were similar between ripretinib and sunitinib. Moreover, ripretinib demonstrated fewer grade 3/4 treatment-related adverse events and better tolerability (10,11). A Chinese study also showed that ripretinib demonstrated similar efficacy versus sunitinib as second-line treatment in Chinese GIST patients and provided greater clinically meaningful benefit in patients with KIT exon 11 mutations. In addition, the safety data was consistent across both global and Chinese populations, with ripretinib demonstrating a better safety profile compared to sunitinib (10,12), which was beneficial in terms of increasing patient compliance and optimizing disease management. Data on ripretinib as third-line therapy was very limited, with only a phase I study reporting a median PFS of 8.3 months (13).

In addition, debulking surgery (volume-reduction surgery, leaving residual lesions behind) or cytoreductive surgery (CRS, performed to achieve R0/R1 resection) can markedly reduce the tumor load or afford the resection of residual lesions following targeted therapy, potentially reducing the development of secondary drug resistance and increasing survival benefits. A prospective randomized controlled trial in China demonstrated that surgery plus imatinib significantly improved OS versus imatinib alone (14). Several retrospective studies suggested surgery combined with tyrosine kinase inhibitor (TKI) therapy offered superior survival compared to TKI therapy alone in advanced GIST (15-17). Both the National Comprehensive Cancer Network (NCCN) and Chinese Society of Clinical Oncology (CSCO) guidelines recommend that surgery may be suitable for patients showing a favorable response to targeted therapy or with unifocal/low-volume multifocal progressive disease or symptomatic disease (characterized by bleeding, obstruction, or perforation) (18,19). The European Society for Medical Oncology guidelines align with NCCN but emphasize individualized, shared decision-making (20).

We present a complex case of a giant gastric GIST harboring KIT exon 11 and 13 mutations, in which individualized treatment strategies were explored based on the patient’s characteristics, combining TKIs with surgery to provide meaningful insights for clinical practice. We present this article in accordance with the CARE reporting checklist (available at https://gist.amegroups.com/article/view/10.21037/gist-2025-aw-12/rc).

Case presentation

A 64-year-old female with no prior history of gastric disease, cardiovascular, diabetes, psychiatric disorders, tumors, or hereditary conditions presented to a local hospital with abdominal discomfort in December 2015. Computed tomography (CT) revealed a giant mass (144.6 mm × 114 mm × 132.5 mm in size) in the upper left quadrant of the abdomen, extending from the diaphragm to the left kidney, displacing the stomach and adhering to the spleen. In March 2016, gastroscopy and biopsy at Tianjin Medical University Cancer Institute & Hospital confirmed a gastric GIST, positive for CD117 and DOG-1.

Given the giant size of the tumor, the patient commenced neoadjuvant imatinib therapy [400 mg once daily (QD)]. In March 2017, after 12 months of neoadjuvant imatinib therapy, the tumor shrank to 32.8 mm × 52.4 mm. The patient was in good physical condition, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0. A laparoscopic procedure involving complex adhesion dissection and resection was performed (R0 resection). The patient recovered well after surgery and was discharged one week later. Postoperative pathology revealed a gastric spindle cell soft tissue tumor with extensive necrosis. In conjunction with immunohistochemical findings from a prior biopsy at an outside institution, these results were consistent with treatment-related changes of GIST. No KIT or PDGFRA mutations were detected on postoperative analysis. Adjuvant imatinib therapy (400 mg QD) was initiated.

In October 2018, upper abdominal CT revealed a space-occupying lesion in the left lobe of the liver, suggestive of metastasis. Follow-up endoscopic ultrasound showed a hypoechoic hepatic mass, and metastasis could not be excluded. In November 2018, upper abdominal CT demonstrated that the hepatic lesion in the left lobe had increased in size compared with the previous scan (October 2018), measuring 50 × 40 mm. The patient was in good physical condition with an ECOG PS 0 and expressed a strong desire for surgery. As the lesion was oligometastatic, following multidisciplinary team (MDT) discussion and in accordance with the patient’s preference, laparoscopic-assisted resection of the segment II liver lesion, diaphragmatic repair, and adhesiolysis were performed in Hepatobiliary Surgery Department at Tianjin Medical University Cancer Institute & Hospital on November 14, 2018. Postoperative pathology showed CD117 (+) and DOG-1 (+), consistent with GIST and confirmed negative hepatic margin, achieving R0 resection. First-generation genetic testing of the postoperative tissue sample revealed no KIT or PDGFRA mutations. Considering the progression on imatinib therapy, sunitinib (continuous 37.5 mg QD) was administered after the surgery.

In August 2021, the patient returned to Tianjin Medical University Cancer Institute & Hospital for follow-up. A CT scan performed 6 months prior to admission revealed a mass in the left lower pulmonary lobe and the current CT re-examination further clarified this lesion. The patient had been on sunitinib for 33 months, with a 2-year history of hypertension managed with oral nifedipine sustained-release tablets, and a 3-month history of diabetes treated with oral acarbose. The patient’s ECOG PS score remained 0 and she expressed a strong desire to undergo surgery. Following MDT discussion, the lesion was confirmed as an oligometastatic focus. Preoperative evaluation revealed no absolute contraindications to surgery, and blood pressure had normalized. A thoracoscopic wedge resection of the left lower lobe mass was performed, with the lesion measuring 38 mm × 20 mm × 20 mm and histopathology confirmed GIST. Genetic testing indicated mutations in KIT exons 11 (p. V559D) and 13 (p. V654A), and targeted therapy was discontinued during the postoperative recovery period.

Postoperative CT follow-up in October 2021 revealed new small nodules in the right lung. The patient had placed a strong emphasis on quality of life. April 2023 during sunitinib therapy, the patient experienced grade 2 hypertension, which was managed with standard antihypertensive medication. Notably, the GRID trial previously reported hypertension as the most frequent adverse event associated with regorafenib, with an incidence of 49% for all grades and 23% for grade ≥3 (6). Limited in vitro data suggest efficacy of regorafenib against KIT exon 13 mutation is limited (7). Ripretinib is a novel TKI with broad inhibitory activity against KIT and PDGFRA mutations and a favorable safety profile. It has been approved as a fourth-line therapy in the treatment of GIST. Considering the above information and the patient’s preference, ripretinib was selected as the preferred treatment option. This represents a personalized off-label therapeutic approach. The patient initiated ripretinib therapy at a dose of 150 mg QD on October 26, 2021. The safety profile during treatment was favorable, with only alopecia (grade 1–2) reported as an adverse reaction. Stable disease (SD) was achieved using modified Response Evaluation Criteria in Solid Tumors version 1.1 and the patient was followed up every 3 months (Figure 1). The patient was in good physical condition with an ECOG PS 0 and was able to maintain regular exercise.

Figure 1 CT findings before and after ripretinib treatment. (A) Baseline; (B) 2 months after ripretinib treatment; (C) 5 months after ripretinib treatment. The red arrow indicates small pulmonary nodules. CT, computed tomography.

After 18 months of ripretinib therapy, a color ultrasound scan at another hospital in April 2023 revealed an irregular, isoechoic/hypoechoic mass (60 mm × 33 mm × 20 mm in size) with clear borders in the subcutaneous muscle layer of the left posterior thoracic wall. Given that the patient’s metastasis was oligometastatic and there were no significant surgical contraindications, following MDT discussion and the patient’s preference for surgery, left thoracic wall excision with soft tissue reconstruction was performed in the Department of Bone and Soft Tissue Tumors at Tianjin Medical University Cancer Institute & Hospital. The procedure was uneventful, recovery was favorable, and histopathology confirmed GIST. Genetic testing revealed mutations in KIT exons 11 and 13 as before. After surgery, PS score was 0–1. Given the absence of new secondary mutations, the patient’s emphasis on drug safety and quality of life, and prior favorable disease control with ripretinib, ripretinib intrapatient dose escalation (IPDE) was resumed at 150 mg twice daily (BID), achieving SD. The patient demonstrated good tolerability, with only grade 2 alopecia and grade 1–2 hand-foot syndrome observed during ripretinib IPDE therapy. The patient maintained an ECOG PS 0–1 and expressed a high level of satisfaction with the overall clinical outcomes.

In January 2024, after 9 months of ripretinib IPDE, CT showed new lesions in the left chest wall. Treatment was switched to regorafenib (120 mg QD), which caused grade 2–3 diarrhea and hand-foot syndrome, with an ECOG PS 1–2. The dose was reduced intermittently. SD was achieved as of July 2, 2024 (Figure 2). The patient did not undergo regular follow-up and died in December 2024, with an OS of 105 months (approximately 8.8 years) since the initial GIST diagnosis. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Figure 2 Summary of treatments. BID, twice daily; GIST, gastrointestinal stromal tumor; QD, once daily; TKI, tyrosine kinase inhibitor.

International Multidisciplinary Team (iMDT) discussion

Discussion among physicians from Tianjin Medical University Cancer Institute & Hospital

Department of Gastric Surgery

Giant GISTs are associated with a high risk of recurrence and poor prognosis, posing significant challenges for clinical management. Precision and personalized multidisciplinary strategies have therefore become a critical area of research. This case describes a giant primary gastric GIST with a maximum diameter of 144.6 mm, with genetic testing revealing mutations in KIT exons 11 and 13 after sunitinib resistance. The patient underwent sequential TKI therapies—imatinib, sunitinib, ripretinib (including standard dose and IPDE), and regorafenib—along with four surgeries following oligometastatic progression. Through a personalized approach combining TKIs and surgery, the patient achieved nearly 9 years of survival.

After 20 months of adjuvant imatinib, the patient developed new liver lesions, highlighting the high recurrence risk of giant GISTs. Second-line sunitinib achieved good efficiency but caused grade 2 hypertension, managed with antihypertensives. The patient maintained good physical condition and prioritized quality of life. Following sunitinib resistance, ripretinib was initiated based on safety and efficacy considerations, resulting in 18 months of SD.

Ripretinib IPDE administered after disease progression (PD) may provide additional survival benefits, with a favorable safety profile. CSCO and NCCN guidelines recommend increasing the dose to 150 mg BID after failure of standard fourth-line therapy (150 mg QD). Phase I/II clinical trials and real-world studies in Western countries indicated that ripretinib IPDE delayed PD after standard therapy failed and had a median PFS period of 3–6 months (21,22). A Chinese real-world study also showed that ripretinib IPDE had a median PFS of 11 months with a favorable safety profile (23). In this case, after 18 months of SD on third-line ripretinib, the GIST patient with KIT exon 11 and 13 mutations developed new metastasis. Post-surgical genetic testing confirmed that KIT exon 11 and 13 mutations remained dominant, and drug selection remained challenging. Given prior efficacy and tolerability, ripretinib IPDE was resumed and achieved an additional 9 months of SD with favorable safety.

Future treatment after ripretinib progression remains uncertain. The INTRIGUE study showed second-line ripretinib therapy did not reduce the efficacy of subsequent TKIs (e.g., sunitinib) (11). Ripretinib also demonstrated strong front-line activity (10,12,24,25), while Multi-target TKIs appeared less affected by treatment sequence (11,26) and their complex resistance mechanisms might limit the efficacy of subsequent highly selective KIT inhibitors. In this case, regorafenib was initiated after new metastasis in January 2024, achieving 6 months of SD by July, indicating other TKIs can still be effective post-ripretinib. Intermittent dose reductions during regorafenib therapy underscore the need for close safety monitoring.

During TKI therapy, the patient developed oligometastatic lesions. Considering the patient’s physical condition, surgical preference, and MDT assessment, four surgeries were performed: the first two were R0 resections and the latter two were debulking procedures. All surgeries were uneventful, with no postoperative complications. Surgery may have contributed to prolonging TKI treatment duration and improving clinical outcomes. Nevertheless, the role of surgery in advanced GIST remains controversial. Current evidence mainly supports combining first-line imatinib with surgery, while data on later-line TKIs are limited. Optimal strategies should consider surgical timing, benefit predictors (response, disease extent, resection completeness), morbidity, and TKI choice. Multidisciplinary collaboration that integrates appropriate TKIs with surgical approaches may help extend TKI therapy and improve patient outcomes.

This is a rare case in which the patient carries mutations in exons 11 and 13 of KIT gene and has achieved long-term disease control under ripretinib treatment. A post hoc analysis of the INTRIGUE study suggests that ripretinib demonstrated moderate efficacy in patients with KIT exon 13 mutation subtype (4). However, the durable disease control observed in this case may be related to other factors, such as multidisciplinary management including surgical resection of oligo-progressive lesions, and the potential benefit of dose escalation, which may partially overcome resistance. Additionally, since first-generation sequencing was used for genetic testing, due to tumor heterogeneity and technical limitations, the possibility of undetected secondary mutations in KIT/PDGFRA cannot be ruled out. The broad inhibitory profile of ripretinib against KIT/PDGFRA mutations may also have contributed to the observed therapeutic effect.

Several issues on the treatment of the patient were further discussed as follows

What is your perspective on line-based treatment and precision individualized therapy in GISTs?

Alessandro Mazzocca: from a contemporary perspective, GISTs represent a paradigm in which precision oncology is increasingly applicable, particularly in the context of secondary resistance mutations that emerge under the selective pressure of imatinib. The molecular heterogeneity of resistance—most commonly involving secondary mutations in KIT exons 13/14 (ATP-binding pocket) and exons 17/18 (activation loop)—has clear implications for the relative sensitivity to subsequent TKIs.

In this regard, the post-hoc mutational analysis of the phase III INTRIGUE trial, although showing no overall superiority of ripretinib over sunitinib in the second-line setting, provided important insights: patients harboring secondary KIT exon 13/14 mutations derived greater benefit from sunitinib, whereas those with exon 17/18 mutations appeared more responsive to ripretinib. Such findings support the concept that treatment sequencing in advanced GIST should ideally be informed by the specific resistance mutation profile.

However, current regulatory approvals limit the routine clinical implementation of this approach. At present, mutationally guided TKI selection is formally incorporated only for certain contexts—such as the use of high-dose imatinib (800 mg daily) in patients with KIT exon 9 mutations and avapritinib in those with PDGFRA D842V-mutated disease. Beyond first-line therapy, treatment sequencing remains largely dictated by fixed line-based algorithms (imatinib → sunitinib → regorafenib → ripretinib), irrespective of the individual molecular resistance pattern.

In this scenario, enrollment in well-designed clinical trials is essential to allow patients access to the most biologically appropriate agents and to generate the prospective evidence necessary for broader regulatory adaptation.

Should patients with advanced GIST who experience PD after receiving imatinib or sunitinib undergo genetic testing to assess secondary mutations? If so, should tissue biopsy or liquid biopsy be employed for this purpose?

Alessandro Mazzocca: in advanced GIST, the acquisition of secondary resistance mutations—most often within KIT kinase domain—represents a major driver of therapeutic failure after imatinib and sunitinib. As our understanding of the mutation-specific sensitivity and resistance profiles to both approved and investigational TKIs continues to expand, there is a strong biological rationale for reassessing the mutational landscape at the time of PD. Such information could, in principle, guide a more tailored therapeutic approach and optimize sequencing strategies.

Both tissue biopsy and liquid biopsy can be employed for this purpose, each with distinct advantages and limitations.

• Tissue biopsy provides a direct assessment of the resistant clone(s) within the sampled lesion and can be particularly informative in cases of oligoprogression, where local ablative or surgical interventions may be considered. However, it is invasive, associated with procedural risks, and inherently limited in its ability to capture inter- and intratumoral heterogeneity, especially in a disease where multiple metastatic sites may harbor distinct resistance mutations.
• Liquid biopsy offers a minimally invasive means of detecting circulating tumor DNA (ctDNA) and, theoretically, provides a more comprehensive snapshot of the tumor’s molecular heterogeneity. Nevertheless, in GIST, the relatively low shedding of ctDNA can result in false-negative findings, and this technology still requires further validation for routine clinical use in this setting. Additionally, cost considerations remain non-negligible.

In summary, while both approaches have potential value, their use should be considered in the context of clinical feasibility, anticipated impact on therapeutic decision-making, and trial availability.

What is your current treatment strategy for patients with a primary KIT exon 11 mutation and a secondary KIT exon 13 mutation following PD on second-line therapy?

Alessandro Mazzocca: in the case of a patient with a primary KIT exon 11 mutation and a secondary KIT exon 13 mutation who has experienced PD after second-line therapy, treatment strategy is inevitably shaped by the prevailing regulatory framework. In Italy, in the absence of an available clinical trial, the therapeutic sequence is predefined: imatinib in the first line, followed by sunitinib, then regorafenib, and finally ripretinib. Consequently, after failure of imatinib and sunitinib, the standard next step is regorafenib, with ripretinib reserved for subsequent progression.

That said, knowledge of the resistance mutation profile may still inform nuanced clinical decision-making. In selected cases—particularly where in case of oligoprogressive disease—multidisciplinary evaluation is undertaken to assess the feasibility of locoregional approaches (e.g., surgical resection, radiofrequency ablation, or stereotactic radiotherapy) targeting progressing lesions. This strategy aims to prolong disease control with the ongoing systemic agent before switching to the next line in the sequence, thereby potentially maximizing the duration of benefit from each therapy.

Can debulking surgery provide survival benefits for selected patients with advanced GIST? What are the specific conditions or criteria that define these selected patients?

Alessandro Mazzocca: yes, CRS can confer benefit in carefully selected patients with advanced GIST, but the signal is strongest when (I) imatinib-sensitive biology is demonstrated; (II) macroscopic complete resection (R0/R1) is feasible; and (III) systemic TKI therapy is continued post-operatively. Several additional factors should be considered when selecting candidates: good patient performance status, multidisciplinary evaluation in high-volume sarcoma centers, disease kinetics showing radiological response or SD on imatinib or sunitinib, and scenarios of oligoprogression where locoregional control may prolong systemic benefit. Conversely, incomplete (R2) debulking and surgery undertaken in the setting of multifocal or generalized progression rarely provide meaningful benefit and should generally be avoided.

Conclusions

This case highlights that precision and personalized multidisciplinary strategies integrating TKIs and surgery can achieve long-term disease control in advanced GIST. Front-line treatment with ripretinib (including standard dose and IPDE) may provide survival benefits. Multidisciplinary collaboration remains critical for optimizing outcomes in complex cases.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gist.amegroups.com/article/view/10.21037/gist-2025-aw-12/rc

Peer Review File: Available at https://gist.amegroups.com/article/view/10.21037/gist-2025-aw-12/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-2025-aw-12/coif). A.M. receives travel grant from Deciphera Pharmaceuticals. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: L. Huleatt)