A groundbreaking case report from Peking Union Medical College Hospital demonstrates the successful use of ripretinib as neoadjuvant therapy for gastrointestinal stromal tumor (GIST), achieving complete tumor resection in a patient who failed to respond adequately to standard imatinib treatment.
The case involved a 57-year-old Asian female who presented with a large irregular soft tissue mass measuring 12.3 cm × 9.1 cm in the space between the spleen, stomach, and pancreas. Pathological assessment confirmed GIST with a KIT exon 11 V559D mutation, a missense mutation characterized by the substitution of valine with aspartic acid at position 559 of the KIT protein.
Limited Response to Standard Therapy
Initial treatment with imatinib 400 mg daily for 14 months yielded minimal tumor reduction, with the mass decreasing only slightly from 12.3 cm to 11.5 cm in maximum diameter. The tumor remained poorly demarcated from the pancreas and continued to wrap around the splenic artery, presenting significant surgical risks. During imatinib therapy, the patient experienced pronounced adverse reactions including persistent nausea, vomiting, edema, pallor, and moderate anemia.
Given the suboptimal response and the tumor's proximity to vital organs, surgical intervention at this stage would have required extensive resection, potentially including multiple organs. The medical team advised considering alternative tyrosine kinase inhibitors as neoadjuvant therapy to further reduce tumor size and improve surgical outcomes.
Ripretinib Treatment Success
After comprehensive patient consultation and informed consent, treatment was switched to ripretinib 150 mg daily monotherapy, administered for 8 months. The results were remarkable: the tumor decreased from 11.5 cm to 8.5 cm in largest diameter, representing a 26% reduction. Crucially, the tumor's demarcation from the pancreatic tissue and splenic artery became well-defined, enabling complete R0 surgical resection while preserving surrounding organs.
The tolerability profile of ripretinib proved superior to imatinib. The anemia, nausea, vomiting, and edema that occurred with imatinib completely resolved. The patient experienced only mild adverse events with ripretinib, including slight gingival bleeding (CTCAE grade 1) and alopecia with myalgia (CTCAE grade 2). Pain was effectively managed with acetaminophen-containing analgesics, and routine blood, liver, and kidney function tests remained within normal ranges.
Surgical Outcome and Follow-up
Following cessation of ripretinib 2 weeks prior to surgery, laparoscopic partial gastrectomy was successfully performed. Intraoperative exploration confirmed the tumor's presence on the gastric posterior wall of the fundus's greater curvature, with the majority extending beyond the gastric contour but not invading the splenic hilum, pancreas, or splenic vessels. The tumor was completely resected without rupture, maintaining intact tumor capsule.
Postoperative pathology confirmed GIST with a tumor size of 8.5 cm × 6 cm and pathologically negative margins. The tumor showed degenerative necrosis with no involvement of the gastric mucosa. Genetic analysis confirmed the KIT exon 11 V559D mutation. The patient demonstrated satisfactory recovery with no disease progression or recurrence observed during 12-month follow-up evaluations.
Clinical Significance and Safety Profile
This case represents the first reported use of ripretinib as neoadjuvant therapy for GIST, providing compelling evidence for its potential value in this setting. The timing of neoadjuvant therapy is critical, with studies showing median time to objective response with imatinib ranging from 13 weeks to 107 days. Current clinical practice typically involves 6-12 months of neoadjuvant therapy.
Ripretinib is a novel switch control inhibitor that effectively suppresses various primary and secondary mutations in KIT/PDGFRA. In second-line treatment studies, it demonstrated objective response rates of 22-30% in the overall population and 24-37% in patients with KIT exon 11 mutations. The drug's favorable safety profile, with most treatment-related adverse events being grade 1/2, makes it particularly suitable for perioperative use.
Comparative Safety Analysis
Real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) database provides additional insights into ripretinib's safety profile compared to other GIST treatments. Analysis of 3,636 ripretinib reports versus 34,768 sunitinib reports revealed distinct adverse event patterns.
The most commonly reported adverse events for ripretinib included general disorders and administration site conditions, skin and subcutaneous tissue disorders, and gastrointestinal disorders. Notably, ripretinib showed fewer grade 3 or 4 treatment-emergent adverse events compared to sunitinib (41.3% versus 65.6%; p < 0.0001) in clinical trials.
Gender-based analysis revealed that male patients receiving ripretinib most frequently reported alopecia, extra dose administration, and neoplasm progression, while females commonly experienced underdose, extra dose administration, and palmar-plantar erythrodysesthesia syndrome. The overall safety profile remained favorable across both genders.
Future Implications
The Chinese Society of Clinical Oncology has proposed ripretinib as an alternate second-line treatment option for GIST based on clinical trial data, with a level 1A evidence rating and strength of recommendation II in its 2024 update. This case report extends the potential applications of ripretinib to the neoadjuvant setting, offering new insights for clinical practice.
The success of this case suggests that ripretinib may represent a viable alternative for patients with GISTs who exhibit poor response to imatinib for neoadjuvant treatment. However, due to the lack of large-scale studies involving multiple patients, ripretinib as neoadjuvant therapy for GISTs requires further exploration and evaluation through controlled clinical trials.
This pioneering case provides proof-of-concept validation of ripretinib's effectiveness and safety in the neoadjuvant setting, potentially expanding treatment options for GIST patients and improving surgical outcomes while preserving organ function.
