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Evolution of tumor volume during the treatment, presented as relative tumor volume (% change compared with normalized, baseline value) AE SD in UZLX-GIST9 KIT 11þ17 (A), -GIST3 KIT 11 (B), and -GIST2B KIT 9 (C).
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Objective: Patients with advanced and treatment-resistant GIST are treated with tyrosine kinase inhibitors (TKI) such as imatinib (IMA), sunitinib (SUN) or regorafenib (REG). Resistance to these TKI is mainly caused by the emergence of on-target secondary KIT mutations in exons 13 and 17. We tested the activity of BLU-285 (Blueprint Medicines), a p...
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... resulting suspension was kept at 4 C protected from light; a fresh suspension was prepared every 3 days. Chemical structures of all drugs used in the study are presented in Supplementary Fig. S1, the structure of avapritinib has been previously published by Evans and colleagues (11). When tumor growth had reached a threshold of 500 mm 3 , mice were treated with the oral compounds for 16 days by gavaging. ...
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... the 16-day treatment period, vehicle-treated tumors from all models showed a steady and statistically significant increase in relative tumor volume (216% of the baseline volume for UZLX-GIST9 KIT 11þ17 , 293% for -GIST3 KIT 11 , and 172% for -GIST2B KIT 9 ; P < 0.05 for all, WMP; Fig. 1). Consistent with previous reports, no significant difference was observed in the UZLX-GIST9 KIT 11þ17 model between the relative tumor volume of the vehicle-and imatinib-treated tumors ...
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... dose of imatinib (50 mg/kg) grew significantly. In this model, doubling the dose of imatinib led to tumor stabilization owing to the dose-dependent sensitivity to imatinib previously observed in this model and in line with the known behavior of KIT exon 9-mutated GIST in the clinic (1). Sunitinib caused significant tumor shrinkage in this model (Fig. ...
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... all three xenograft models, avapritinib (10 mg/kg) resulted in tumor volume stabilization compared with the baseline value. This effect was comparable to the effects induced by the higher dose of imatinib in UZLX-GIST2B KIT 9 (100 mg/kg) or to regorafenib in UZLX-GIST9 KIT 11þ17 (Fig. 1). Remarkably, at the dose of 30 mg/kg, avapritinib treatment resulted in substantial tumor regression as compared with baseline in two of the tested models, to 27% in UZLX-GIST9 KIT 11þ17 (P ¼ 0.005) and to 26% in -GIST3 KIT 11 (P ¼ 0.008, both WMP), and tumor volume stabilization (90%) in UZLX-GIST2B KIT 9 (P ¼ 0.08, WMP). Similarly, ...
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... ¼ 0.005) and to 26% in -GIST3 KIT 11 (P ¼ 0.008, both WMP), and tumor volume stabilization (90%) in UZLX-GIST2B KIT 9 (P ¼ 0.08, WMP). Similarly, in UZLX-GIST3 KIT 11 , higher dose of avapritinib (100 mg/kg), led to a significant tumor regression to 26% of baseline value (P ¼ 0.005, WMP), which was similar to the effect of imatinib in this model (Fig. 1B). In addition, in UZLX-GIST2B KIT 9 , avapritinib at a dose of 60 mg/kg led to tumor shrinkage, which was significantly better than imatinib (at both doses) and comparable with sunitinib (Fig. 1C). Taken together, avapritinib induced remarkable and dose-dependent effects on tumor volume in all three ...
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... (100 mg/kg), led to a significant tumor regression to 26% of baseline value (P ¼ 0.005, WMP), which was similar to the effect of imatinib in this model (Fig. 1B). In addition, in UZLX-GIST2B KIT 9 , avapritinib at a dose of 60 mg/kg led to tumor shrinkage, which was significantly better than imatinib (at both doses) and comparable with sunitinib (Fig. 1C). Taken together, avapritinib induced remarkable and dose-dependent effects on tumor volume in all three ...
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... and acquired resistance to treatment with established TKI represents the ultimate challenge in the clinical setting of GIST, as there is no approved therapy for those who progress n/a n/a n/a n/a #2.5 a #2.1 a Sunitinib n/a n/a n/a n/a ### a ### a Regorafenib ¼ ¼ n/a n/a n/a n/a Avapritinib (10 mg/kg Avapritinib (60 mg/kg) n/a n/a n/a n/a # 13.9 a #7.9 a Avapritinib (100 mg/kg) n/a n/a ### a ### a n/a n/a n/a n/a n/a n/a #6.8 a #2.4 a Sunitinib n/a n/a n/a n/a #3.7 #1.3 a Regorafenib "3.0 Ã "2.6 Ã n/a n/a n/a n/a Avapritinib (10 mg/kg) ...
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Introduction: The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence.
Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics.
Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using “liquid biopsy”.
