Ripretinib as a second-line therapy for advanced gastrointestinal stromal tumors in the era of precision medicine

Gastrointestinal stromal tumours (GISTs) are the most common sarcoma in the gastrointestinal tract. Surgery is the standard treatment for localized disease and tyrosine kinase inhibitors (TKIs), including imatinib, are recommended for locally advanced, inoperable, metastatic or recurrent disease (1-3). The proliferation of GIST cells is driven by various driver mutations, and frequent mutations found in primary GISTs include the KIT (80%) and PDGFRA (10%) genes. GIST with KIT exon 11 mutations is the most frequent and observed in any anatomical site throughout the gastrointestinal tract. On the other hand, GIST with KIT exon 9 mutations is mainly located in the intestine (1). GIST with KIT exon 9 mutations is less sensitive to imatinib compared with that with KIT exon 11 mutations. Additionally, GIST with PDGFRA mutations is mostly found in the stomach and the majority of PDGFRA mutations are found in exon 18. It is worth noting that the PDGFRA exon 18 D842V missense mutation, the most common mutation among PDGFRA mutations, is an activation-loop switch mutation and is resistant to imatinib, sunitinib, and regorafenib, all of which are type II inhibitors. Approximately 10% or less of GISTs have no mutations in KIT and PDGFRA, and are referred to as “wild-type GISTs” (1). Wild-type GIST may have other oncogenic driver mutations in the RAS family genes, BRAF, or NF1 genes, mutations or inactivating alterations of the SDH genes, and, very rarely, fusions involving the TRK family or FGFR family genes. It is important to note that these mutations, deficiencies or fusions are considered mutually exclusive in primary GIST. Positive staining for the KIT protein and/or DOG-1 protein is standard in the diagnosis of GIST, however, the efficacy of imatinib and sunitinib is considered to be related to genotype, particularly in treatment-naïve GIST (1).

The development of TKIs has revolutionized the prognosis of patients with metastatic/recurrent GIST. Overall survival has been improved from 1.5 years in pre-imatinib era to more than 6 years (1). Clinical trials have shown that imatinib is the first-line, followed by sunitinib as second-line and regorafenib as third-line therapy in the metastatic/recurrent setting as shown in Table 1 (2-4). The last two drugs are multi-target TKIs which are effective against imatinib-resistant GIST, however, they may have more serious adverse events (AEs) than imatinib (1-3). Recently, the United States Food and Drug Administration has approved ripretinib, a type II switch-control TKI, that broadly inhibits KIT and PDGFRA kinase through a dual action to bind to the switch pocket and the activation switch to lock the kinase in the inactive state (5), as the fourth-line therapy. Ripretinib is a selective inhibitor of KIT and PDGFRA kinases. The drug only inhibits four kinases with half-maximal inhibitory concentration <10 nM of DDR2, VEGFR2, PDGFRB, and TIE2 in addition to the two kinases (5). The approval is based on the results of the double-blind, randomized placebo-controlled phase 3 trial (the INVICTUS study). In the study, median progression-free survival (PFS) was 6.3 months [95% confidence interval (CI): 4.6 to 6.9] in the ripretinib group compared with 1.0 month (95% CI: 0.9 to 1.7) in the placebo [hazard ratio (HR) =0.15; 95% CI: 0.09 to 0.25; P<0.0001] (6). The ripretinib group (n=85) reported common (>2%) grade 3 or 4 treatment-related treatment-emergent AEs, such as lipase increase (5%), hypertension (4%), fatigue (2%), and hypophosphataemia (2%). Ripretinib has demonstrated maintained quality of life (QOL) compared with placebo (7). Now, ripretinib has been reimbursed in the United States of America (USA), European Union (EU), and China in the fourth-line treatment, but the drug is not approved in some countries. For instance, it is not approved in Japan, instead, pimitespib, a selective inhibitor of HSP90α and HSP90β, is approved and reimbursed as a fourth-line therapy as shown in Table 1 (4,8).

The GIST clinical guidelines of National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology recommend imatinib in the first-line, followed by sunitinib as the second-line treatment, regorafenib in the third-line, and ripretinib in the fourth-line treatment for GIST with imatinib-sensitive mutations (2,3). Avapritinib, a type I kinase inhibitor, is recommended for GIST with imatinib-insensitive PDGFRA exon 18 mutations, including D842V mutation, which can only be inhibited by type I inhibitors, but not type II as shown in Table 1 (2,3,9). Wild-type GISTs lacking KIT and PDGFRA mutations consist of a diverse group of GIST with heterogeneous molecular drivers. Treatment may depend on the driver mutations detected by various genetic analyses including comprehensive genomic profiling (2-4).

The preliminary data including phase 1 indicate that ripretinib may be effective in the second-line setting (10). In vitro preclinical data showed that ripretinib appeared to be more effective than sunitinib in inhibiting imatinib-resistant secondary KIT mutations (5). These data suggest that ripretinib could work as an alternative to sunitinib for second-line treatment of advanced GIST. The INTRIGUE study was a randomized, open-label, international, multicenter phase 3 study to examine the efficacy and safety of ripretinib vs. sunitinib in advanced GIST patients who progressed on or were intolerant to first-line imatinib (11). The study results have shown that, in the KIT exon 11 intention-to-treat (ITT) population, the median PFS for ripretinib and sunitinib was 8.3 and 7.0 months, respectively, and the median PFS in all ITT populations was 8.0 and 8.3 months, respectively (Table 2). Ripretinib neither demonstrates statistically significant superiority nor non-inferiority to sunitinib in terms of primary endpoints of PFS. The objective response rate (ORR), however, was higher for ripretinib vs. sunitinib in the KIT exon 11 ITT population (23.9% vs. 14.6%, P=0.03) and, in addition, ripretinib exhibited a more favorable safety profile and had better scores on patient-reported outcomes. This was confirmed as a separate analysis of the INTRIGUE study, showing that patients with ripretinib had better health-related QOL than those with sunitinib during the dosing period (18). Thus, this study does not alter the standard treatment in the second-line, sunitinib. However, ripretinib could be an alternative treatment for GIST patients who are intolerant to sunitinib because of its superior safety and similar efficacy, particularly for GIST patients with KIT exon 11 mutation. Based on these results, the NCCN GIST guidelines recommend sunitinib as the preferred regimen in the second-line. Nevertheless, when patients are unable to tolerate the drug, ripretinib may be a suitable option as indicated in Table 1 (3).

It is recognized that there are ethnic differences between Caucasian and Asian in AEs of sunitinib and dose adjustment may be considered for Asian patients (14,15,19). In contrast, ripretinib has shown no ethnic differences in efficacy and safety in the fourth-line setting, as evidenced by the results of a single-arm phase 2 study conducted in China (20) and the INVICTUS study conducted in the EU and USA (6). Median PFS was 6.3 months and ORR was observed in eight patients (9.4%, 95% CI: 4.2% to 17.7%) in the ripretinib group of the INVICTUS study (6). The Chinese phase 2 study reported a median PFS of 7.2 months (90% CI: 2.9 to 7.3) and an ORR of 18.4% (90% CI: 7.7% to 34.3%) (20). Both studies had comparable AEs, including treatment-related AEs leading to dose interruption and/or dose reduction.

The results of the bridging study of INTRIGUE, a randomized, open-label phase 2 study in the second-line setting have been reported in China (Table 2). In the bridging study, eligible patients with histologically confirmed advanced or metastatic GIST, who progressed or were intolerant to first-line imatinib, were randomly assigned to receive either ripretinib 150 mg once daily by continuous dosing or sunitinib 50 mg once daily by the 4 weeks-on and 2 weeks-off schedule until disease progression (12). The median PFS was comparable between ripretinib and sunitinib (10.3 vs. 8.3 months) in all patient ITT populations, respectively. In the KIT exon 11 ITT population, ripretinib showed longer PFS than sunitinib (median PFS not reached vs. 4.9 months; HR =0.46; 95% CI: 0.23 to 0.92; P=0.03, respectively). The safety profiles of ripretinib and sunitinib were compared. Ripretinib had fewer treatment-related AEs greater than grade 3 compared to sunitinib. Similarly, the incidences of treatment-related AEs leading to dose interruption and/or dose reduction are lower in ripretinib than in sunitinib (Table 2). Overall, the efficacy and safety results in the second-line setting are similar between the INTRIGUE study and the bridging study in China.

It could be argued, however, that ripretinib may have demonstrated greater clinical benefits for GIST patients with the KIT exon 11 mutations than sunitinib in the bridging study of China (12). In the study, the PFS of the ripretinib group appears to be longer while PFS of the sunitinib shorter in the KIT exon 11 IIT population compared to the INTRIGUE and other clinical trials with sunitinib as shown in Table 2 (11,14-17). It should be noted that, with dose adjustment, sunitinib appears to have more prolonged activity than the pivotal trial (14,16,17). Nevertheless, the number of patients recruited to the bridging study was limited in both ripretinib and sunitinib groups, with only 54 patients in each group for all IIT populations and 35 in the KIT exon 11 IIT population, compared to the INTRIGUE study (226 and 155 in each group), respectively. According to the law of large numbers, a fundamental theorem in statistics, as the sample size increases, the mean approaches to the true value in independent and random selection. The results of the INTRIGUE seem to be less biased than those of the bridging study.

Sunitinib is recognized for its effectiveness for GIST patients with secondary KIT mutations in the adenosine triphosphate (ATP)-binding pocket (exon 13 or 14), but not for those with activation-loop mutations (exon 17 or 18) (21). Conversely, ripretinib is more potent in inhibiting KIT kinase with acquired secondary KIT mutations in the activation-loop domain more strongly than those with secondary ATP-binding pocket mutations (10). In this regard, the exploratory analysis of the INTRIGUE study has been recently reported using a liquid biopsy (13). Although the number of patients analyzed is small in each group, patients with only KIT exon 11+13/14 mutations had a significantly better PFS with sunitinib compared to ripretinib (median PFS: 15.0 vs. 4.0 months; HR =3.94; 95% CI: 1.71 to 9.11; P=0.0005), respectively. In contrast, patients with only KIT exon 11+17/18 mutations had a significantly better PFS with ripretinib compared to sunitinib (14.2 vs. 1.5 months; HR =0.22; 95% CI: 0.11 to 0.44; P<0.0001), respectively. Regarding GIST with primary KIT exon 9 mutation, sunitinib was more effective than ripretinib, and both drugs exhibited comparable clinical benefits for patients with wild-type GIST in mutation-specific sub-analysis. Therefore, this exploratory study indicates that circulating tumor DNA (ctDNA) sequencing in the second-line therapy after imatinib could distinguish between GIST patients who may benefit from ripretinib and those who may benefit from sunitinib. The possibility is currently evaluated in a small randomized, open-label phase 3 study (ClinicalTrials.gov ID: NCT05734105). It would be worthwhile to investigate the mutation types of GISTs recruited to the bridging study, provided that liquid samples and/or solid specimens prior to the trial are available.

The utility of genotyping in the fourth-line therapy was examined using data obtained from the INVICTUS trial (22). The results showed that ripretinib had clinically meaningful activity similarly across all KIT mutation subgroups, including exon 9, 11, 13, and 17. GIST patients develop various resistant clones with different resistance mutations and increase tumor heterogeneity as treatment lines progresses, which result in lower ORR and shorter disease control during treatment. Therefore, identifying treatment effects based on genotype in later lines of treatment may be challenging compared to the first- or second-line.

In summary, the bridging study and the INTRIGUE study suggest that the preferred second-line regimen is sunitinib. Ripretinib is indicated when sunitinib is intolerant. Additionally, when ctDNA sequencing reveals secondary mutations in the activation-loop, ripretinib may be indicated. Further clinical studies are required to confirm the latter therapeutic option. In the era of precision medicine, we need to make better use of molecular oncology, including ctDNA, to optimize drug selection, especially in early lines of treatment. Genomic profiling may allow us to customize KIT-targeted therapy for better outcomes in GIST patients.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-14/coif). T.N. reports honoraria for lectures from Pfizer, Taiho Pharmaceutical, and Eisai Co., all of which are outside the submitted work. The other authors have no conflicts of interest to declare.

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