A case report of ripretinib combined with surgery in the treatment of a patient with multidrug-resistant cKIT exon 9 mutation in advanced gastrointestinal stromal tumor
Highlight box
Key findings
• Ripretinib combined with hepatectomy may provide good results in patients with late-stage plasma with multiple liver metastases.
What is known and what is new?
• Patients with imatinib resistant metastatic gastrointestinal stromal tumors (GISTs) have faced a treatment bottleneck.
• Ripretinib, as a drug that broadly inhibits kit gene mutation, may achieve unexpected results in patients with advanced GISTs with exon 9 mutation, and may win the chance of surgery to reduce tumors and prolong patients’ lives.
What is the implication, and what should change now?
• Patients with advanced GISTs with c-kit 9 exon mutation and multiple liver metastases can be treated with ripretinib after imatinib resistance. At present, a large number of clinical data are needed to confirm the efficacy of ripretinib in such patients.
Introduction
The past 2 decades have witnessed the evolution of the therapeutic approach to gastrointestinal stromal tumors (GISTs) from surgical resection alone to a more multidisciplinary strategy incorporating sequential tyrosine kinase inhibitor (TKI) targeted therapies with surgical interventions. The availability of multiline targeted drugs has significantly prolonged the overall survival of patients with stromal tumors. However, extended treatment for malignant GISTs leads to more primary or secondary drug resistance, complicating doctors’ treatment choices. GIST management now requires that organ function, drug tolerance, survival, and quality of life are considered as key factors in treatment decision-making. Timely adjustments in pharmacotherapy and surgical interventions have the potential to markedly enhance patient outcomes. In the present study, we document the case of a patient with advanced GIST who had experienced progressive disease (PD) following therapy with 2 TKIs. KIT-9 exon mutations were identified in 3 sessions of genetic testing. Following the administration of ripretinib for a duration of 15 months, the patient achieved a partial remission (PR). A second surgery was performed to remove some of the metastases, and the ripretinib treatment was continued postoperatively. The remaining small lesions maintained a stable disease (SD) status and showed partial liquefaction. All of the drugs and surgical tolerance remained within the controllable ranges during the treatment. The difficulty in the treatment of this patient lies in the fact that the patient was in the midst of the novel coronavirus epidemic during the progression of his disease, and the replacement of targeted drugs was affected by certain objective factors. For example, if the patient was replaced by sunitinib for treatment, it was difficult to travel to and from the hospital at that time, and the data of ripretinib showed that it was safe and had a high objective remission rate. In the case of ensuring safety, it can also bring further tumor shrinkage effect to patients, and finally, after the treatment of ripretinib, the curative effect is good, and finally get the second chance of surgery. This treatment mode may provide an idea for the treatment of some special late period GIST patients. We present this article in accordance with the CARE reporting checklist (available at https://gist.amegroups.com/article/view/10.21037/gist-24-7/rc).
Case presentation
Basic information
A 63-year-old male was admitted to our hospital on 27 September 2017, presenting with gastrointestinal hemorrhage and was subsequently diagnosed with a bleeding duodenal tumor. 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 Helsinki Declaration (as revised in 2013). Verbal informed consent was obtained from the patient for the publication of this case report and accompanying images.
The course of treatment
On 27 September 2017, the patient underwent duodenal tumor resection and duodenojejunostomy at The First Affiliated Hospital of Soochow University, during which a mass measuring approximately 6 cm × 5 cm × 5 cm was identified at the junction of the horizontal and ascending part of duodenum and the beginning of the jejunum.
Pathological diagnosis
The excised specimen was identified as a small intestine GIST (Figure 1). The mitotic activity was 6 per 50 high-power fields (HPFs). No evidence of tumor involvement was detected at both surgical margins.
Genetic testing
Molecular testing identified an cKIT gene exon 9 mutation, with no mutation detected in the PDGFRA gene.
Imaging studies
Abdominal contrast-enhanced computed tomography (CT) (Figure 2) performed during hospitalization revealed approximately 14 intrahepatic lesions, the largest of which had a diameter of 5.1 cm, ruling out surgery as a treatment option.
On 18 October 2017, due to the presence of KIT gene exon 9 mutation, the patient was orally administered with 600 mg/day imatinib as per guidelines. Regular follow-up visits (every 3 months) for 2 years after surgery showed no progression, with some lesions regressing or resolving. Subsequently, follow-up visits were reduced to semi-annual.
On 30 March 2021, a routine follow-up examination identified PD in the liver lesions, predominantly characterized by an increase in the size of the tumor in the left hepatic lobe (approximately 5.7 cm in diameter).
Amidst the coronavirus disease 2019 (COVID-19) pandemic, the patient’s compromised immune status and persistently elevated hepatic glutamyl transpeptidase levels (115–130 U/L) precluded the administration of the second-line agent sunitinib. Given the patient’s prior tolerance to imatinib and the inability to withstand the more pronounced side effects associated with sunitinib, the decision was made to continue with an increased dose of imatinib at 800 mg/day for an 8-month duration starting in April 2021. During this period, the disease progressed slowly.
Sequential magnetic resonance imaging (MRI) conducted in May and July 2021 (Figure 3) revealed a progressive increase in liver lesions, predominantly characterized by the enlargement of the left hepatic lobe lesions, which expanded to 7.4 and 8.4 cm in diameter, respectively. Upon readmission to the hospital on 3 August 2021, the biopsy results of the liver lesion indicated a diagnosis of GIST, with immunohistochemical staining positive for CD117 and DOG1. Concurrent genetic testing confirmed the presence of a KIT gene exon 9 mutation.
Despite the lesion’s continued slow growth, considerations regarding the patient’s physical status during the pandemic and concerns over the potential side effects of sunitinib, coupled with the remaining supply of 800 mg imatinib, led to a decision to maintain the current therapy. However, after a 4-month period on 800 mg/day imatinib, the tumors continued to progress, albeit at a slow pace. During this period, findings from a phase 3 clinical trial comparing avapritinib versus regorafenib suggested that avapritinib demonstrated non-inferior efficacy and safety in patients with advanced GISTs. Following consultation with his doctor, the patient opted to initiate treatment with avapritinib.
On 18 October 2021, the patient commenced therapy with avapritinib at a dose of 300 mg/day. Subsequent monitoring during the treatment period revealed a progressive enlargement of lesions in the left hepatic lobe. Additionally, the patient experienced significant toxicities, including a sustained elevation of lactate dehydrogenase levels (with a peak value of 507 U/L recorded on 3 May 2022) and muscle weakness.
On 11 May 2022, the largest lesion in the left hepatic lobe was sized approximately 12.7 cm (Figure 4). The therapeutic response was assessed as PD after 7 months of avapritinib treatment.
The patient had exhibited a suboptimal response to avapritinib. The patient discussed with his doctor the many clinical studies and case reports that had demonstrated that ripretinib provided clinically meaningful activity against a broad range of KIT mutations in patients with advanced GISTs. He was initiated on orally administered ripretinib treatment at a dosage of 150 mg/day on 18 May 2022.
The main toxicities during the treatment were grade 1 dermatitis and alopecia. Regular MRI monitoring revealed that the liver metastases remained stable and exhibited a gradual reduction in size. PR was achieved after 1 year (Figure 5).
On 20 July 2023, the subsequent MRI (Figure 6) revealed that the hepatic lesions had further stabilized since prior assessments, with partial liquefaction noted. As there was no further reduction in tumor sizes (maximum diameter: approximately 7.7 cm), and the patient had a good physical and mental status, surgical debulking was scheduled after adequate communication with the patient.
A laparoscopic hemihepatectomy of the left liver was performed on 28 August 2023, along with a laparoscopic partial hepatectomy for the resection of the tumor in segment V and a concomitant laparoscopic cholecystectomy. Postoperative pathology identified GIST metastases. Genetic testing confirmed the presence of an exon 9 mutation in the cKIT gene.
In September 2023, the patient initiated a reduced-dose oral ripretinib regimen of 100 mg/day, which was based on both the significant prior efficacy and the high economic burden of ripretinib therapy. Routine re-examinations conducted every 3 months indicated that the residual metastatic lesions in the liver remained stable, with partial liquefaction observed.
The most recent re-examination also demonstrated that the residual lesions in the right liver were stable, with evidence of partial liquefaction (Figure 7). Thus, the outcomes of ripretinib treatment were deemed satisfactory.
The patient’s treatment process is shown in the figure below (Figure 8).
Discussion
GISTs are typical gene-driven malignancies and pioneer in precision oncology. More than 80% of GISTs have KIT mutations, with exon 11 accounting for 60% and exon 9 for 10% (1). Imatinib has significantly extended progression-free survival (PFS) to nearly 2 years for patients with advanced GISTs. However, imatinib’s 400 mg/day dose is often insufficient for cKIT exon 9 mutants, requiring dose escalation to 600 mg/day, potentially up to 800 mg/day if well tolerated (2,3). In our present case, genetic testing consistently revealed cKIT exon 9 mutation. Following 41 months of treatment with imatinib at a dose of 600 mg/day, PD was observed. Due to the patient’s favorable tolerance to imatinib throughout the treatment period, the dosage was increased to 800 mg/day to maintain therapy, which, however, failed to achieve effective tumor control. Throughout the disease trajectory, the patient placed a higher priority on the safety profile of the medication over the pursuit of efficacy. Despite PD, the patient chose to continue imatinib therapy. Hence, choosing a later-line therapy that balances both efficacy and safety is crucial.
The special circumstance in this case is that the patient was highly involved in the treatment process after having read a significant amount of literature on advanced GISTs. Furthermore, the patient’s PD coincided with the period of stringent COVID-19 control measures in China. With compromised immune status and abnormal liver function, the patient frequently communicated with his doctor regarding treatment options. For instance, in 2021, amidst widespread anticipation surrounding the VOYAGER phase 3 trial (4), the safety and efficacy of avapritinib versus regorafenib became highly interesting. In particular, it was reported that that avapritinib achieved a PFS of 5 months in patients with advanced GIST harboring cKIT exon 9 mutations, with adverse effects limited to grade 2 rash (5). This information ultimately influenced our treatment decision, despite the patient’s experience with avapritinib aligning with the failed outcomes of the VOYAGER study. Upon the subsequent switching of targeted therapies, it was observed that ripretinib demonstrated considerable clinical efficacy and a favorable safety profile across various clinical studies in China and internationally. In the second-line and first-in-human (FIH) studies of ripretinib conducted in China, the median PFS (mPFS) for ripretinib at a dose of 150 mg/day was 13.8 months in a second-line setting and 8.3 months in a third-line setting, with durability observed once a therapeutic response was achieved (6,7). In the INVICTUS study, ripretinib significantly extended the mPFS by 6.3 months in patients receiving fourth- and later-line treatments. Subgroup analysis based on gene mutation status revealed that patients treated with ripretinib exhibited improved PFS compared to those receiving placebo, irrespective of the specific KIT mutations (exon 11, P<0.0001; exon 9, P=0.0023; exon 13, P<0.0001; and exon 17, P<0.0001) (8,9). In our present case, the patient was administered ripretinib at a dose of 150 mg/day during PD, resulting in SD for 15 months, during which no serious adverse reactions occurred (only mild dermatitis and alopecia were noted). This observation underscored that ripretinib could effectively inhibit various primary and secondary KIT mutations, including those within exon 9.
It is widely recognized that the treatment paradigm for advanced GISTs has evolved from a reliance solely on surgical intervention to a more multidisciplinary approach that integrates surgical procedures with targeted pharmacotherapies. As effective surgical debulking can significantly extend patient survival, it is imperative to meticulously select the best drug and decide the optimal surgery timing. According to the US National Comprehensive Cancer Network (NCCN) and the Chinese Society of Clinical Oncology (CSCO) guidelines, surgical resection may be contemplated when tumors achieve maximal remission or fail to regress during targeted therapy (3,10). It has been reported that a better response to preoperative TKI therapy is linked to a more pronounced surgical benefit (11). Moreover, the surgical management of patients with advanced GIST should be predicated on the principle of safety, with meticulous attention to a range of intraoperative and postoperative complications. Ripretinib, with its unique mechanism of action, can achieve a high objective response rate (ORR) by significantly shrinking the tumors. Its good safety profile relative to other TKIs undeniably provides favorable conditions and opportunities for subsequent surgical intervention, it has been suggested that in the era of precision therapy, reverapitinib can be tried as a second-line drug for the treatment of advanced GISTs (12). In our present case, clinical remission was achieved for the first time after 1 year of ripretinib treatment, and the criteria and conditions for surgical intervention were met, however, the mPFS of imatinib-resistant late-stage GIST patients during the course of post-line drug therapy was only 5.3–9.7 months in a report (13). A second surgery was then performed to maximize the patient’s survival benefit. The postoperative genetic testing re-confirmed the persistence of the cKIT exon 9 mutation. Given that the lesions had been surgically resected and the patient responded well to the prior ripretinib treatment, the postoperative ripretinib dosage was reduced to 100 mg/day. This regimen has been maintained for 8 months, with the outcomes including SD and partial liquefaction. As of the reporting date, the survival time of this patient was more than 80 months, exceeding the maximum survival time of late-stage GIST reported by some centers (14), A better efficacy is expected in the future. As for the mechanism of the patient’s long survival time as a late-stage GIST patient, the patient obtained 41 months of PFS after emergency tumor reduction surgery combined with imatinib, which may indicate that the biological behavior of the patient’s GIST is somewhat “inert”. After imatinib resistance, the treatment with additional dose of imatinib and avatinib did not control the tumor progression. However, ripretinib, such a drug targeting the widespread inhibition of ckit gene mutations, has produced good effects, which may be related to the dual mechanism of action of ripretinib (15), because secondary mutations leading to imatinib have been reported to occur mainly in the adenosine triphosphate (ATP) binding domain and activation ring (16).
Conclusions
In our case, we observed that a patient with cKIT exon 9 mutation was resistant to imatinib after 41 months of treatment, and after 3 times of adjustment of targeted drugs, finally achieved tumor remission after 13 months treatments with ripretinib. In addition, partial liver resection was performed to reduce tumor load when liver metastases stopped shrinking. The overall survival was over 80 months. We seem to see that targeted therapy combined with timely tumor reduction surgical intervention can benefit patients with such late-stage GIST, of course, whether this phenomenon is widespread still needs to be verified by large-scale clinical data.
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-24-7/rc
Peer Review File: Available at https://gist.amegroups.com/article/view/10.21037/gist-24-7/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gist.amegroups.com/article/view/10.21037/gist-24-7/coif). The 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 Helsinki Declaration (as revised in 2013). Verbal informed consent was obtained from the patient for the publication of this case report and accompanying images.
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: J. Jones)
Cite this article as: Hu Y, Chen X, Xu L, Hu H, Zhou X. A case report of ripretinib combined with surgery in the treatment of a patient with multidrug-resistant cKIT exon 9 mutation in advanced gastrointestinal stromal tumor. Gastrointest Stromal Tumor 2024;7:3.