Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GIST is addicted to mutations in the oncogenes KIT or PDGFRA in a mutually exclusive manner, which demonstrated a model for targeted drug development (1). KIT/PDGFRA wild-type GISTs are deficient in succinate dehydrogenase or have alterations in the mitogen-activated protein kinase signaling pathway (2, 3). The approval of second-line sunitinib and third-line regorafenib has substantially changed the management of advanced GISTs, leading to the standard sequences of tyrosine kinase inhibitors (TKIs) after imatinib failure (4, 5). First-line imatinib is effective and has a favorable safety profile, whereas second-line sunitinib and third-line regorafenib are reportedly less effective. The median progression-free survival (PFS) of patients receiving sunitinib was approximately 6–9 months (6, 7). Studies have indicated that third-line regorafenib exerted a weaker antitumor effect, resulting in a median PFS of 4.4–4.8 months (5, 8). The management of GISTs in the late-line setting in terms of overcoming the resistance of TKIs was an unmet need until the recent approval of ripretinib.

Ripretinib is a novel, type II tyrosine switch control inhibitor targeting a broad spectrum of primary and TKI-resistant KIT and PDGFRA variants (9). Blockage of both switches (kinase switch pocket and activation loop) induces kinases to stabilize in the inactive state and prevents them from adopting an active conformation. A phase I study reported promising results of ripretinib when used as the second-, third-, and fourth-line drug, with median PFS ranging from 5.5 to 10.7 months. The phase III INVICTUS study explored and compared the efficacy and safety of ripretinib (150 mg once daily) with those of placebo in advanced GIST refractory to at least three-line TKIs. Ripretinib demonstrated higher efficacy when used as the fourth-line drug with an overall response and median PFS of 9% and 6.3 months, respectively (10). The safety profile of ripretinib is generally acceptable, and the most common adverse events (AEs) include alopecia, fatigue, and nausea. On the basis of the aforementioned results, ripretinib was approved for use as the fourth-line drug by the US Food and Drug Administration (FDA) for patients with advanced GIST after treatment with three or more TKIs, including imatinib, sunitinib, and regorafenib.

In the INVICTUS study, races were classified as white and non-white. The treatment outcomes of the patients of Chinese ethnicity, including Taiwanese and Hong Kongers, were not examined. Therefore, we conducted this multi-institutional study to investigate the antitumor efficacy and safety of ripretinib. In addition, we performed a literature review to compare the treatment outcomes of ripretinib observed in our study with those reported in previous studies.

This multi-institutional study investigated the outcomes of ripretinib treatment administered on a compassionate-use basis in patients from Taiwan and Hong Kong with heavily pretreated metastatic GISTs. Our study revealed several points of interest regarding ripretinib use in advanced GISTs.

First, the median PFS and OS of the 20 patients were 6.1 and not reached, respectively. The clinical efficacy of ripretinib observed in our study is similar to that reported in the INVICTUS trial (10). The treatment efficacy in our study is even more favorable because of a median time lag of 2.7 months (i.e., treatment-free period) between the application of ripretinib on a compassionate-use basis and the first dose of ripretinib. Although tissue re-biopsy is usually impractical for patients with heavily pretreated metastatic GISTs, molecular profiling can be conducted to identify KIT/PDGFRA variants that respond to ripretinib. The findings of molecular profiling can be valuable for drug development.

Second, in terms of ripretinib-associated AEs, the toxicity profiles of all the patients in our study are similar to those of the patients in the INVICTUS trial (10). Alopecia was the most frequently observed AE in the present study. Although alopecia is not a severe AE, this condition is associated with substantial unfavorable consequences, such as psychological and physical impact; therefore, dose reduction may be suggested (12). Of note, alopecia upon targeted drug use is relatively rare, suggesting this unique feature of ripretinib use. The calculated overall incidence of all-grade alopecia was 14.7% (95% CI: 12.6%–17.2%), which is lower than that of bortezomib (2.2%; 95% CI: 0.4%–10.9%) and higher than that of vismodegib (56.9%; 95% CI: 50.5%–63.1%). An increased risk of all-grade alopecia [relative risk (RR): 7.9; 95% CI: 6.2–10.09, p ≤ 0.01] compared with placebo was observed; however, the risk was lower when compared with chemotherapy [(RR: 0.32; 95% CI: 0.2–0.55, p ≤ 0.01)] (12). Thus, ripretinib is regarded as the common molecular targeted agent that usually causes alopecia.

In the present study, two independent prognostic factors for PFS were identified: pretreatment albumin level and disease control by ripretinib. Disease control by ripretinib was consistently observed to be an independent factor for prolonged PFS in the present study; this finding agrees with those of previous studies in which disease control status was consistently demonstrated to be a favorable factor for PFS and OS (8, 13).

A previous study reported that higher pretreatment serum albumin levels were not a favorable factor associated with prolonged OS after the treatment of patients with advanced GISTs with two lines of TKIs (8). In a meta-analysis examining studies on the cancer of the gastrointestinal tract, 26 of 29 studies reported that higher serum albumin levels were associated with prolonged survival (14). Future basic or translational studies should be conducted to elucidate molecular mechanisms underlying the association between serum albumin levels and survival.

For patients who demonstrated disease progression following treatment with 150 mg of ripretinib, an additional clinical benefit may be obtained by increasing the dose of ripretinib to 300 mg (15). However, the standard treatment beyond ripretinib failure is uncertain; therefore, referral to a clinical trial is strongly recommended for patients still experiencing disease progression after an increase in ripretinib dose.

This study has some limitations. First, this study is observational in nature, which may lead to underreported AEs. Second, because of the short follow-up period, the median OS could not be determined. Finally, because we did not perform the profiling of genetic variants, potential response biomarkers could not be identified.

In this real-world study, the efficacy and safety profile of the late-line use of ripretinib in patients with advanced GIST from Taiwan and Hong Kong are comparable with those reported in the INVICTUS trial. Higher pretreatment albumin levels and satisfactory disease control predicted favorable PFS.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by The Institutional Review Board of the Chang Gung Memorial Hospital (IRB number: 201601745B0, Taoyuan, Taiwan). The patients/participants provided their written informed consent to participate in this study.

C-NY designed the study. L-CL and C-NY collected the data and reviewed the literature. L-CL, W-KH, and C-NY wrote the manuscript. J-SC, C-CY, C-YY, M-TS, SW, and DC provided the patient data, interpreted the data, and critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

This work was supported in part by the Chang Gung Memorial Hospital CMRPG3J0971~3 CORPG3J0251~3. We thank to Zai Lab (Taiwan) Limited for the educational grant to Taiwan Society of Molecular Medicine. The funder Zai Lab (Taiwan) was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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