Ripretinib for the treatment of metastatic gastrointestinal stromal tumors harboring dual mutations in KIT exons 11+17: a case report

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, originating from the interstitial cells of Cajal (ICCs), with an incidence of over 10 cases per 1,000,000 annually (1). Surgery remains the gold standard treatment for localized GISTs (2). The pharmacological treatment of GIST is predominantly based on tyrosine kinase inhibitors (TKIs) that specifically target mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes, which are observed in roughly 80% of GIST diagnoses. These mutations can activate tyrosine kinase receptors, and TKI medications exert their efficacies by inhibiting the activities of these receptors. Moreover, some rare wild-type GIST subtypes, including those associated with neurofibromatosis type 1 (NF1), succinate dehydrogenase (SDH), BRAF, and NTRK gene alterations and those related to K/N-RAS mutations, are insensitive to TKIs (3). Imatinib mesylate was one of the earliest registered TKIs and remains the first-line therapy for GISTs. Unfortunately, the wide use of imatinib has led to the gradual emergence of drug resistance due to secondary KIT mutations (4). To combat such resistance, a range of novel TKIs for the treatment of drug-resistant GISTs in the second-, third-, fourth-, and higher-line settings have been developed.

Ripretinib is an innovative TKI that has demonstrated considerable efficacy in the treatment of advanced GISTs by selectively inhibiting the activity of secondary mutation-linked KIT kinases (5,6). In multiple clinical trials, ripretinib showed significant efficacy in patients with advanced GIST in the fourth-line setting, notably in patient cohorts who had failed TKIs. For instance, ripretinib has shown significant promise in extending progression-free survival (PFS) in a pivotal phase III clinical trial. Additionally, it has demonstrated therapeutic efficacy in managing GIST patients with dual mutations in KIT exons 11 and 17. The INTRIGUE phase III trial, which compared ripretinib to sunitinib in the second line, revealed that patients with KIT exon 11+17/18 secondary mutations, as detected through liquid biopsy, benefited more from ripretinib in terms of both PFS and overall survival (OS). This trial highlights the potential of ripretinib as a treatment option for specific patient populations (5). In our current case report, the patient experienced disease progression despite multiple lines of medical therapy and three surgical interventions; however, subsequent metastasis was successfully controlled with the use of ripretinib therapy. Although ripretinib may trigger adverse effects in some patients, its safety and tolerability have been well validated in clinical trials. This case report highlights the exceptional efficacy of ripretinib in advanced GISTs with dual KIT mutations and multidrug resistance. Specifically, as a fourth-line treatment, ripretinib demonstrates superior efficacy in certain cases compared to prior treatment lines, underscoring its importance in overcoming drug resistance. This novel finding supports its inclusion in therapeutic guidelines for complex GIST cases. We present this article in accordance with the CARE reporting checklist (available at https://gist.amegroups.com/article/view/10.21037/gist-24-6/rc).

Case presentation

Patient information

A 46-year-old Han Chinese male patient was admitted to Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital in December 2005 following the detection of a jejunal mass during a routine health check-up. He denied any physical discomfort. Previously, he had maintained good health and had not experienced any illness. His parents and siblings were in good health, and there was no family history of neoplastic disorders. The patient was covered by local health insurance. 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 (as revised in 2013). 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.

Clinical findings

The patient presented as clinically healthy, exhibiting neither abnormal abdominal signs nor peripheral lymphadenopathy. Physical examination showed no other abnormality.

Diagnostic assessment and therapeutic intervention

Laboratory findings were within normal limits. Contrast-enhanced computed tomography (CECT) revealed an intra-abdominal mass, indicative of a GIST, fibroma, or liposarcoma as potential diagnoses. Following the exclusion of surgical contraindications, a resection of the jejunal mass was performed, resulting in the excision of a segment of the small intestine (approximately 15 cm in length), the mass, and parts of the associated mesentery. The mass, which was sized 5.3 cm × 3.5 cm × 5 cm, was visible in the intestinal lumen and serous membrane after the intestinal canal had been dissected. No tumor rupture occurred during the dissection process. The excised mass was encapsulated, and upon sectioning, it presented a grayish-red appearance with areas of variable nature (intermediate, and soft in some areas) and color (dark red in some areas). Multiple nodules were palpated within the mesentery, with the largest nodule measuring 1.2 cm × 0.7 cm × 0.7 cm, and the smallest measuring 0.5 cm × 0.3 cm × 0.3 cm. Postoperative histopathology revealed a fascicular pattern of spindle cell proliferation, with visible mitotic figures ranging from ≥5 to ≤10 cells per 50 high-power fields (HPF); no tumor cells were identified at the margins of the resected mass. Additionally, no metastatic tumor cells were identified in the 10 sampled mesenteric lymph nodes. Immunohistochemical analysis yielded positive staining for CD117, smooth muscle actin (SMA) (parts), vimentin, and neuron-specific enolase (NSE), whereas staining for CD34, desmin, actin, and neurofilament (NF) showed negative results. Consequently, the mass was pathologically confirmed as a moderately malignant small intestinal GIST. The patient did not receive TKI treatment following surgery due to financial constraints.

In December 2008, a new metastasis measuring 6.2 cm × 3.3 cm was detected in the right lobe of the liver during routine follow-up. At that time, genetic mutation testing was not yet widely accessible and was quite costly. As a result, the patient initiated oral imatinib therapy at a daily dosage of 400 mg as the standard treatment option. The disease became stable and the metastatic lesion showed no change during follow-up visits, and the patient had no drug-related adverse reactions. However, in May 2018, disease progression was noted again in follow-up visits, with the emergence of an additional metastatic lesion in the right hepatic lobe, measuring approximately 2.3 cm × 1.4 cm × 0.5 cm. Accordingly, the patient underwent another surgical procedure to excise the metastatic stromal tumor from the right liver. The postoperative pathology identified two discrete nodules within the right hepatic tissue, measuring 6.5 cm × 3.5 cm × 3.5 cm and 2.2 cm × 1.2 cm × 0.5 cm, respectively. Microscopically, the tumor cells had a characteristic spindle-cell morphology. Immunohistochemical assays demonstrated positivity for CD117, CD34, and DOG-1, which are major biomarkers for the diagnostic and treatment of tumors. Genetic profiling revealed the presence of the p.Y823D mutation in exon 17 and the p.558_565del non-frameshifting deletion in exon 11 of the KIT gene. Thus, the patient was initiated on sunitinib therapy at a daily dosage of 37.5 mg, with an attempt to curb disease progression.In November 2019, a recurrence of liver metastases from GIST was detected during follow-up examinations. The patient remained on sunitinib therapy (37.5 mg/day) despite the recurrence. In November 2021, imaging studies indicated an increase in the size of the right liver metastases to approximately 7 cm × 5 cm, resulting in another surgical intervention to excise the metastatic lesions. Pathology revealed that the tumor cells within the liver tissue morphologically resembled those located near the diaphragm, highlighting the aggressiveness and complexity of the tumors. Subsequent genetic testing identified the presence of the p.N822K missense mutation in exon 17 and the p.V559_G565del non-frameshifting deletion in exon 11 of the KIT gene. After the surgery, the patient started oral regorafenib therapy and continued the treatment despite the occurrence of skin rashes [Common Terminology Criteria for Adverse Events (CTCAE) (7) grade 1], diarrhea (CTCAE grade 2), hypertension (CTCAE grade 2), and hand-foot syndrome (CTCAE grade 2) as the side effects of the medication.In November 2022, the disease recurred again, with two nodular slightly high-density shadows identified within the abdominal cavity. The larger of the two measured approximately 24 mm × 22 mm. Due to financial constraints, the patient continued on regorafenib therapy (160 mg/day). In March 2023, the treatment protocol was changed to ripretinib 150 mg/day. This new regimen did not elicit significant adverse reactions in the patient. Subsequent follow-up examinations conducted in May 2023, September 2023, and May 2024 revealed progressive reduction in the nodule sizes (Figure 1).

Figure 1 Change in the size of an abdominal metastatic nodule before and after treatment with ripretinib. (A) Tumor size (arrow indicates the metastatic nodule) when the lesion was detected in November 2022. (B) Tumor size at the first follow-up visit following two courses of ripretinib treatment in May 2023 (arrow indicates the metastatic nodule). (C) Tumor size after 6 months of ripretinib treatment in September 2023 (arrow indicates the metastatic nodule). (D) Tumor size after 1 year of ripretinib treatment in May 2024 (arrow indicates the metastatic nodule). SE, sequence; SFOV, scan field of view; DFOV, display field of view; KV, kilovoltage; mA, milliamperage; LOCA, local; W/C, window width/window level.

Follow-up and outcomes

Currently, the patient is receiving ripretinib 150 mg/day treatment for GIST abdominal metastases for more than one year. No adverse drug reaction has been noted during the follow-up, and the medication has been well-tolerated. Notably, prior to initiating treatment with ripretinib, the patient’s tumor measured 24 mm × 22 mm. Subsequently, during the course of ripretinib therapy, CECT scans conducted at follow-up time points in May 2023, September 2023, and May 2024 revealed a progressive reduction in the size of the abdominal metastatic tumor to 14 mm × 19 mm, 12 mm × 14 mm, and 11 mm × 8 mm, respectively. The timeline of all treatment regimens and final follow-up visits are detailed in Figure 2.

Figure 2 Schedule, duration, and final follow-up visit for all treatments (the metastasis sizes were measured by CECT). GIST, gastrointestinal stromal tumor; CECT, contrast-enhanced computed tomography.

International multidisciplinary team (iMDT) discussion

Discussion among physicians from Peking University Shenzhen Hospital

Department of Gastrointestinal Surgery

The patient was initially diagnosed with a small intestine GIST in 2005, and the disease course has lasted for about 18 years since then. Although postoperative adjuvant therapy is recommended for high-risk GIST patients (8), it was not adopted in our present case, possibly due to financial constraints (9). Since acquired mutations that impair the tyrosine kinase function of the KIT or PDGFRA receptors are the primary drivers of the majority of GISTs (approximately 75% harboring KIT mutations and 10–20% exhibiting PDGFRA mutations) (10,11), imatinib, as a representative TKI, has demonstrated notable efficacy in the treatment of advanced GISTs. Although approximately 50% of patients experienced varying degrees of resistance to imatinib within 2 years of follow-up in clinical trials (12), imatinib, sunitinib, regorafenib, ripretinib, and avapritinib have become established treatment options for metastatic GIST over the decades, as a result of the continuous discovery of different TKIs and the new findings from ongoing clinical trials (13). In our present case, the patient developed liver metastases 3 years post-diagnosis, and imatinib therapy was initiated accordingly. Nine years later, new liver metastases occurred, and a new surgical intervention on metastasis was performed. Postoperative genetic testing identified mutations in KIT exons 11 and 17. KIT exon 17 mutation is infrequent in GISTs, accounting for less than 5% of cases, as primary mutation and is commonly linked to resistance to imatinib therapy (14-16). The majority of KIT exon 17 mutations that have been identified to date are missense mutations affecting codons 820, 822, or 823. Given that ripretinib had not yet become clinically available at that time, the patient was administered second-line sunitinib treatment. Less than 18 months after commencing sunitinib, abdominal computed tomography (CT) revealed the enlargement of liver metastases. In November 2021, the patient underwent a third surgical intervention, with genetic testing yielding the same results as in the previous surgery. Following the administration of regorafenib, the patient experienced a range of adverse reactions including rashes, diarrhea, and hypertension. The disease recurred approximately one year after the initiation of regorafenib therapy. In the face of multi-line therapy resistance and gene mutations, a new targeted therapeutic option was urgently needed.The double mutation in KIT exons 11+17 is a rare event clinically. Although it is currently challenging for us to find similar individual clinical case reports, existing clinical trials (NCT03673501) have shown that for patients with GISTs harboring KIT exon 11+17 mutations, ripretinib provides a longer PFS compared to sunitinib (median, 14.2 vs. 1.5 months). Additionally, there is an ongoing clinical trial (NCT05734105) specifically investigating the efficacy of ripretinib in advanced GIST patients who have previously received imatinib treatment and harbor KIT exon 11+17/18 mutations. Based on our knowledge, 10 high-level hospitals in China have each encountered one case of GIST characterized by a KIT exon 11+17 mutation. These patients exhibited resistance to standard therapies but demonstrated tumour regression with ripretinib.

The resistance mechanisms of GISTs are intricate and diverse, closely tied to KIT and PDGFRA gene mutations. Imatinib, a first-line treatment, targets KIT and PDGFRA tyrosine kinases. Resistance to imatinib primarily stems from secondary KIT mutations, often in the kinase domain’s activation loop (AL) region of exon 17, with involvement in exons 13 and 14. These mutations may stabilize the active conformation of the KIT kinase, thereby preventing the binding of imatinib. Additionally, the drug resistance may be associated with the amplification of the KIT gene and the activation mechanism of transcriptional proteins (17,18). Sunitinib, a second-line agent, partially inhibits imatinib-resistant KIT mutations (T670I in exon 14) but efficacy is limited due to KIT mutation heterogeneity (19,20). Resistance to sunitinib may involve specific KIT mutations altering drug binding. Regorafenib, a third-line option, faces similar resistance issues, potentially due to specific KIT mutations altering adenosine triphosphate (ATP)-binding pockets (AP) (20). The KIT gene mutation sites reported in this case of GISTs are located in exons 11 (p.558_565del) and 17 (p.Y823D, p.N822K), suggesting the occurrence of KIT secondary mutations that evade the targets of these drugs, leading to insensitivity to current first, second, and third-line therapies.

Currently, the clonal heterogeneity of secondary KIT mutations that arise following imatinib treatment for GIST represents a significant barrier to the management of drug-resistant GISTs (21). Ripretinib is an inhibitor of primary or secondary KIT mutations, representing a novel targeted therapeutic agent specifically developed to overcome drug resistance in GISTs. Its mechanism of action differs from that of traditional TKIs such as imatinib and sunitinib, which primarily compete with ATP to bind to the ATP-binding domain, thereby preventing the activation of KIT or PDGFRA kinases (22). In contrast, ripretinib binds to the switch pocket of the receptor tyrosine kinases, thereby inhibiting the switch pocket and the AL, maintaining the kinases in a non-active state, and thus achieving broad inhibition of various primary and secondary mutations. As the first and only United States Food and Drug Administration (US FDA)-approved fourth-line therapeutic agent, ripretinib has exhibited noteworthy efficacy and safety in its pivotal clinical trial, INVICTUS (6). The recent INVICTUS bridging study (23) conducted in China has also demonstrated that, even after multiple drug resistances, GIST patients receiving ripretinib as a fourth- or later-line therapy could still achieve substantial benefits, with a median OS of 25.56 months. In our present case, after the patient received the standard fourth-line ripretinib therapy, the abdominal nodules continued to shrink, indicating a positive trajectory of the disease condition. Moreover, there were no significant adverse reactions during the treatment, which notably enhanced the patient’s therapeutic experience and quality of life. At the forefront of therapeutic interventions for advanced GISTs, ripretinib has been officially approved for the treatment of fourth-line or higher-line advanced GISTs, providing a renewed therapeutic option for patients refractory to first-line (imatinib), second-line (sunitinib), and third-line (regorafenib) regimens. An actual case report has demonstrated the success of ripretinib in treating advanced GIST with KIT exon 11 mutations (24). Additionally, a study also showed that ripretinib exhibits significant inhibitory effects on KIT exon 17 or 18 mutations (25). In light of the case reported here, a question worth exploring is whether patients with GIST who initially screen positive for dual mutations in KIT exons 11 and 17 can be directly treated with ripretinib. However, the effectiveness of this treatment strategy requires further clinical research for validation.

In this case study, the patient with GIST who underwent treatment with ripretinib as a fourth-line therapy exhibited a significant reduction in tumor burden, potentially presenting an opportunity for surgical resection. However, the determination of the optimal timing for surgery necessitates a comprehensive assessment that takes into account various factors, including the patient’s overall health status, tumor location, size, growth rate, and associated surgical risks. In clinical practice, personalized treatment strategies should be based on each patient’s specific conditions.

Department of Medical Oncology

Ripretinib not only benefits GIST patients in later-line settings but also performs well in second-line therapy, particularly for patients with primary KIT exon 11 mutations. The INTRIGUE trial and its bridging study confirmed that ripretinib outperformed sunitinib in extending PFS and reducing the risk of disease progression or death by 54% [hazard ratio (HR) =0.46; P=0.003] (5,26). Additionally, ripretinib exhibited a high objective response rate (ORR) of 37.1%, whereas that of sunitinib was 22.9%. In 2023, the Chinese Society of Clinical Oncology (CSCO) revised the second-line treatment recommendations for GISTs in their guidelines, elevating ripretinib from a previous level II (class 1A) recommendation to a level I (class 1A) recommendation, specifically for patients with primary KIT exon 11 mutations. Moreover, for patients with dual mutations in KIT exons 11 and 17, as seen in our present case, the benefits of ripretinib should not be underestimated (6). In the INTRIGUE trial that utilized circulating tumor DNA (ctDNA) analysis, ripretinib demonstrated superior PFS (14.2 vs. 1.5 months), ORR (44.4% vs. 0%), and OS [not estimable (NE) vs. 17.5 months] compared to sunitinib in patients with KIT exons 11+17/18 mutations (6).

To further validate and clarify the efficacy and safety of ripretinib in the second-line treatment of KIT exons 11+17/18-mutant GISTs, a phase 3 trial, INSIGHT (NCT05734105), is currently comparing ripretinib with sunitinib in this patient population (27). We anticipate the publication of further data from studies related to ripretinib to identify additional patient populations that may benefit from this innovative treatment early. Notably, although ripretinib holds significant promise as a second-line therapy for GISTs, the emergence of resistance to this drug is inevitable. Recent studies have posited that AP/AL homeopathic mutations may represent one mechanism of resistance to ripretinib (4,28). Accordingly, ongoing research into KIT secondary mutations is essential to foster the development of KIT inhibitors with distinct mechanisms of action, thereby addressing ripretinib resistance and expanding treatment options for GIST patients.

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

Question 1: how can we distinguish whether a new mass that appears in the abdominal cavity after the resection of GISTs in patients is primary tumor or metastatic tumor?

Expert opinion 1: Dr. Alessandro Mazzocca

In a patient who has undergone surgery for GIST, disease recurrence typically represents a metastasis of the previously operated disease rather than a new primary tumor. However, more rarely, in patients with genetic syndromes such as NF1 or Carney-Stratakis syndrome, the presence of a new mass may raise suspicion for a second primary tumor. Therefore, imaging studies can be helpful through the evaluation of the mass characteristics, size and location.

Expert opinion 2: Dr. Paolo Pizzini

To determine whether a new abdominal mass after GIST resection is a primary or metastatic tumor, integrate clinical history, imaging studies, histopathology, and genetic analysis. Clinical history and imaging [CT, magnetic resonance imaging (MRI), positron emission tomography (PET)] help assess the mass’s location and growth patterns, indicating if it is a local recurrence or distant metastasis. Histopathological examination and immunohistochemistry identify whether the mass is a GIST or another type of tumor. Genetic testing for c-KIT or PDGFRA mutations further confirms the tumor type. Evaluating the mass’s response to targeted therapies and considering the patient’s treatment history also provide crucial insights into its nature.

Question 2: how can we determine if the recurrence of GISTs detected by imaging examination in the abdominal cavity is within the gastrointestinal tract or outside of it?

Expert opinion 1: Dr. Alessandro Mazzocca

Several methods can provide a clearer understanding of the recurrence’s location.

• Imaging studies: high-resolution CT or MRI scans to assess the location and relationship of the mass to the gastrointestinal tract.
• Endoscopic evaluation: endoscopy to visualize the gastrointestinal tract directly. This can help identify any lesions that may be within the lumen.
• Clinical symptoms: some symptoms that may suggest gastrointestinal involvement, such as bleeding, obstruction, or changes in bowel habits.
• Surgical exploration: in some cases, surgical intervention may be necessary to definitively assess the location of the recurrence.

Expert opinion 2: Dr. Paolo Pizzini

To determine whether GIST recurrence is within or outside the gastrointestinal tract, a combination of imaging techniques, clinical evaluation, and possibly surgical exploration is used. CECT and MRI provide detailed images to assess the mass’s location relative to the bowel, while endoscopy allows for direct visualization and biopsy of intra-gastric or intra-intestinal masses. PET scans can identify metabolically active tumors, and abdominal ultrasound helps in assessing mass characteristics. Clinical symptoms and a biopsy, if needed, offer additional insights, and surgical exploration may be performed if non-invasive methods are inconclusive, providing definitive information on the tumor’s location.

Question 3: several studies have indicated that a subset of GISTs may originate from smooth muscle cells. Is it possible for smooth muscle cells undergoing de-differentiation, shifting in phenotype towards ICCs and ultimately, the development of GISTs?

Expert opinion 1: Dr. Alessandro Mazzocca

Yes, it is possible for smooth muscle cells to undergo de-differentiation and shift in phenotype towards ICCs, which could lead to the development of GISTs. This process involves the transformation of smooth muscle cells into a more stem-like state, allowing them to adopt characteristics similar to ICCs, which are the presumed cell of origin for GISTs. Factors influencing this de-differentiation may include genetic mutations, microenvironmental changes, and signaling pathways that affect cell differentiation.

Expert opinion 2: Dr. Paolo Pizzini

The prevailing view is that GISTs originate from ICCs or ICC-like cells, which are specialized pacemaker cells in the gastrointestinal tract expressing the c-KIT receptor. The hypothesis that GISTs might also arise from smooth muscle cells undergoing de-differentiation into ICC-like cells is intriguing but less established. While smooth muscle cells and ICCs have distinct roles and markers, the idea suggests that if smooth muscle cells could revert to a less specialized state and acquire c-KIT expression, they might contribute to GIST formation. Current research primarily supports the ICC origin theory, but exploring smooth muscle cell plasticity could provide new insights into GIST biology and potentially other tumors.

Conclusions

In summary, this case exemplifies the 18-year treatment journey of a patient with small intestine GIST, underscoring the significance of personalized therapy. The patient encountered multiple recurrences and metastases, and resistance to imatinib was identified during the course of treatment. As a novel TKI, ripretinib has demonstrated substantial efficacy in the treatment of patients with dual mutations in KIT exons, offering a novel therapeutic option for this specific patient cohort. Although drug resistance remains a challenge, the successful utilization of ripretinib instills hope for the management of GIST patients. Future research is anticipated to further improve patient outcomes.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://gist.amegroups.com/article/view/10.21037/gist-24-6/rc

Peer Review File: Available at https://gist.amegroups.com/article/view/10.21037/gist-24-6/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-24-6/coif). A.M. receives travel and host costs from Boehringer, Pharmamar, Novartis, Gentili. 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 (as revised in 2013). 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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