A Multicenter Study of Avapritinib Efficacy and Safety of Metastatic or Unresectable Gastrointestinal Stromal Tumors

Overview

This is a prospective, multicenter, observational real-world study to explore the therapy patterns and clinical outcomes of Avapritinib in patients with metastatic or unresectable gastrointestinal stromal tumors.

INTRODUCTION AND RATIONALE Gastrointestinal stromal tumors (GIST) are thought to develop from the interstitial cells of Cajal or their stem cell precursors. They are the most common mesenchymal tumors occurring in the gastrointestinal (GI) tract. The annual incidence of GIST is about 1/100,000 \~ 2/100,000 globally. Biological behavior can range from benign to malignant, and immunohistochemical staining is usually positive for CDs 117 and DOG-1, showing Cajal cell differentiation. Eighty-five percent of GISTs is caused by activating mutations in the receptor tyrosine kinase KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene. Targeted therapy for KIT and PDGFRA alters metastatic or unresectable GISTs without effective drug therapy, allowing tumor control and significantly prolonging patient survival. Imatinib, a first-line drug, has been shown to control in 80% of patients, whereas 50% of patients develop tumor progression after twenty-four months of treatment, with an estimated ten-year progression-free survival (PFS) rate of approximately 9 %. The most significant cause of progression was secondary mutations in the ATP binding domain or activation ring of KIT results in resistance to imatinib. Sunitinib, the second-line standard of care, and regorafenib, the third-line standard of care, inhibit some of the secondary mutations, with median PFSs of about 5.6 months for sunitinib and 4.8 months for regorafenib. However, imatinib and other targeted drugs that have been approved for the treatment of GISTs are naturally resistant to the activated ring exon 18 D842V mutation of PDGFRA, which accounts for 5 %-6 %\[10% of the primary mutations in GISTs. Avapritinib was approved for marketing in January 2020 for the treatment of PDGFRA D842V mutant GISTs, thus making this type of GISTs medically acceptable. Avapritinib is a type I tyrosine kinase inhibitor (TKI) that has significant inhibitory effects on KIT or PDGFRA in activated configurations, such as mutations in the KIT or PDGFRA activated loop. Preclinical studies have found broad-spectrum inhibition of KIT or PDGFRA, including mutations in exons 11,17,18 of KIT, and mutations in exon 18 of PDGFRA, with a 24 hr, concentration-dependent inhibitory effect. Weak affinity for wild-type KIT and PDGFRA, PDGFRB, CSF1R, and FLT3. In the Phase 1 clinical study in patients with metastatic or unresectable PDGFRA D842V-mutated GISTs, the objective response rate (ORR) for avapritinib was 91%, with a complete response rate of 13%, a median duration of efficacy (DOR) of 27.6 m (95% CI 17.6-N%), and a median PFS of 34 m (95% CI 22.9-N%) estimated to be 61% at 36months. The daily 30-600 mg of Avapritinib showed an initial anti-tumor effect, but the time to effect at the high dose was significantly shorter than at the low dose. Both the US and the European Medicines Agency (FDA and EMA) have approved the use of Avapritinib in GISTs with PDGFRA exon 18 mutations due to its significant therapeutic effect on PDGFRA D842V mutations. In patients with KIT or non-D842V PDGFRA mutations treated more than three lines, the ORRs of atorvastatin were 17%, all were partial responses (PRs), the median DORs were 10.2 m (95% CI 7.% -10.2), the clinical benefit rate (CBRs) was 38%, the median PFSs were 3.7 m (95% CI 2.% -4.6), the median OSs were 11.6 m (95% CI 9.% -12.6), and there was no difference in efficacy between the 300 mg and 400 mg daily dose groups. The above studies showed that Avapritinib was effective in the treatment of PDGFRA D842V mutant GISTs, and some patients with KIT or non-D842V PDGFRA mutations were able to obtain tumor control from the treatment of Avapritinib, with a dose effect on the anti-tumor efficacy, but no significant difference in the high dose 300 mg or 400 mg efficacy. With respect to the safety of avapritinib, patients with \>99% reported at least one adverse event (Adverse events, AEs), with common AEs including nausea (59%), fatigue (50%), periorbital edema (42%), anemia (39%), diarrhea (36%), and vomiting (33%). The incidence of grade ≥3 AEs was 72% and higher in the 400 mg dose group than in the 300 mg dose group, 84% and 73%, respectively. Common AEs included anemia (30%), fatigue (8%), abdominal pain (6%) and hypophosphatemia (6%). The incidence and severity of AEs in elderly patients (≥65 y) was slightly higher than that in younger patients. The incidence of treatment-related adverse events leading to discontinuation of Avapritinib was 11.2%, the most common were cognitive effects (4.1%), intracranial hemorrhage (1.2%), fatigue (\<1%), and vomiting (\<1%), which were higher in the 400 mg group than in the 300 mg group. The incidence of downtitration of Avapritinib was (32%), and the incidence of AEs of each grade and grade ≥3 was significantly lower after downtitration than before downtitration. Preclinical studies with avapritinib suggest that the drug can penetrate the blood-brain barrier with a brain-to-plasma concentration ratio of 0.7 -1.0 3, leading to edema of the choroid plexus in dogs and intracranial hemorrhage at high doses. Therefore, central nervous system AEs, including cognitive effects and intracranial haemorrhage \[14\], are of particular interest in clinical studies. In the Phase I/II clinical study of Avapritinib (Navigator), the incidence of cognitive effects in patients receiving Avapritinib was 42% (104/250) and 40% in the 300 mg group, which was lower than that in the 400 mg dose group (50%). Memory impairment was the most common manifestation of cognitive effects, with an incidence of 27% in the 300 mg group and 40% in the 400 mg group, with a higher incidence in elderly patients (age ≥65 y). The cognitive effects were mostly Grade 1-2 in the Avapritinib 300 mg group and 7.5% in the Avapritinib 300 mg group. The cognitive effects were improved in most patients by discontinuation or dose adjustment, with a median adjusted dose of 233 mg. The incidence of intracranial hemorrhage was 2.4% in the Avapritinib 300 mg dose group, one case of grade 1 subdural hematoma, three cases of grade 1, 2 and 4 intracranial hemorrhage, and one case of grade 3 intracranial hemorrhage. Intracranial hemorrhage was improved by discontinuation or dose adjustment, and no patient died due to intracranial hemorrhage. Median PFSs were 11.4 m (95 %CI 8.% -20.3) in dose-reduced patients and 7.2 m (95 %CI 5.% -24.0) in dose-unadjusted patients, with similar trends for both non-D842V 4 + line therapy and D842V mutations. These studies indicate that the overall safety of Avapritinib is adequate, but special attention needs to be paid to central nervous system AEs, including cognitive abnormalities and cerebral haemorrhage, which have a dose effect, the incidence of high-dose cognitive abnormalities of Avapritinib is higher, the incidence of high-dose cognitive abnormalities of Avapritinib is higher after dose reduction, whether D842V mutations or non-D842V mutations, dose adjustment does not affect survival, and PFSs are longer in appropriately reduced-dose patients. Avapritinib is a small molecule oral TKI with a dose-proportional increase in Cmax and AUC over the 30-400 mg qd range with a mean accumulation rate of 2. -8.9 2 after repeat dosing. Protein binding was 98.8%, mainly metabolized by CYP3A in vivo, 70% excreted in feces, major metabolite, and plasma elimination half-life was 32-57 h. Pharmacokinetic inter-individual differences were large, with in vivo exposure varying up to 8-10-fold in the 300 mg qd dose group. Approximately 50% or more of the patients who started 300 mg qd had high drug exposures, and the incidence of cognitive abnormalities was associated with cumulative exposure to Avapritinib, i.e., there were large individual pharmacokinetic differences, with a tendency to increase the incidence of Grade III or IV AEs as patients' in vivo concentrations of Avapritinib increased. However, there are no lowest effective exposures and highest toxic exposures leading to central nervous AEs in the benefit populations of atorvastatin for the treatment of PDGFRA D842V mutations and PDGFRA mutations with KIT or non-D842V. Therefore, it is necessary to conduct a multicenter observational study on the pharmacokinetics, efficacy, and safety of Avapritinib in patients with metastatic or unresectable GIST, to explore the influencing factors on the pharmacokinetics of Avapritinib, to identify the treatment window of Avapritinib, so that the dose can be adjusted according to the in vivo exposure of Avapritinib, to reduce the risk or severity of AEs, to improve the treatment effect, and to conduct individualized administration.

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