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Introduction Avapritinib (formerly known as BLU-285) is an orally available type I tyrosine kinase inhibitor that, in 2020, obtained regulatory approval for the treatment of patients with gastrointestinal stromal tumors (GISTs) harboring a primary mutation in PDGFRA exon 18, including the PDGFRA D842V mutation. Areas covered Herein, we comprehensively review the available efficacy and safety data on avapritinib, with the final goal of providing practical knowledge to both sarcoma and community-based oncologists for the correct management of this rare GIST subpopulation with this novel therapy. Expert opinion The approval of avapritinib in GIST is a milestone in precision oncology, as this is the first agent ever demonstrating unequivocal antitumoral activity in GIST driven by the multi-resistant PDGFRA D842V mutation. The safety profile is manageable and tolerability-guided dose adjustment is recommended to manage treatment-related adverse events without compromising efficacy. Based on its unprecedented activity, avapritinib should be considered as first-line therapy for GIST patients harboring this mutation. We strongly recommend to determine KIT/PDGFRA genotype in order to identify the different GIST molecular subtypes and guide treatment decision.

Avapritinib is a tyrosine kinase inhibitor currently being investigated on clinical trials for the treatment of unresectable or metastatic gastrointestinal stromal tumour (GIST). It has been recently approved by the Food and Drug Administration and the European Medicines Agency for the treatment of unresectable or metastatic GIST harbouring PDGFRa Exon 18 mutation and by the European Medicines Agency for the treatments of unresectable or metastatic GIST harbouring the PDGFRa D842V mutation. We report a clinical case of a 76-year-old female, diagnosed with a stage IV GIST, treated with avapritinib 300 mg once daily. through compassionate use who experienced an intraocular side effect not previously reported avapritinib. She developed preseptal cellulitis on her right eye following 2 months of treatment with avapritinib and, subsequently evolved to an intraocular inflammatory reaction and persistent corneal epithelial defect. The treatment with avapritinib was stopped and the patient received corticosteroid and corneal regenerating agents. The symptoms resolved within 1 month and the patient has remained on stable disease at two subsequent adjusted avapritinib doses (100 mg once daily) for over 1 year.

Objective The aim of the study was to study the clinicopathological and immunohistochemical features of gastrointestinal stromal tumours and correlation with KIT/PDGFRA mutations. Material and method Eighty consecutive resected cases were genotyped for KIT exons 11, 9, 13, 17 and PDGFRA exons 18, 14, 12 and correlated with histomorphology by nonparametric tests. Results Forty-seven cases (58.8%) were in the high-risk group. Males had higher rates of KIT exon 11 and PDGFRA exon 18 mutations than females (p=0.03). KIT and PDGFRA mutation frequencies were lower (58.8%) than western data showing KIT exon 11 mutation in 63.8%, KIT exon 9 mutation in 19% and PDGFRA exon 18 mutation in 17% of the cases. Extragastrointestinal stromal tumours (n=6) showed 100% mutation. KIT exon 11 deletion was associated with gastric location (60%) (p=0.04), spindle cells (63.3%), and high-risk stratification (66.6%) (p=0.01) while KIT exon 9 mutation was common in small intestine (66.7%) (p=0.04), in higher risk groups (66.7%) (p=0.01) and 75% of codon 502-503 duplications (p=0.03). PDGFRA 18 mutation was common in males (p=0.03), in gastric location (62.5%) (p=0.04), in cases showing mild to moderate atypia (62.5%) (p=0.01) and lower risk stratification (62.5%) (p=0.01). KIT/PDGFRA mutations were significantly associated with gender (p=0.03), location (p=0.04), nuclear atypia (p=0.01) and risk stratification (p=0.01). Conclusion Morphological features and anatomic location may be useful in deciding molecular testing strategy, particularly in resource-limited settings, when a plethora of targetable mutations are present. An algorithm may be derived for genotyping with KIT exon 11 and PDGFRA exon 18 heading the list of targetable mutations. This approach may reduce financial burden on patients as well as workload on hospital staff.

Importance With the approval of avapritinib for adults with unresectable or metastatic gastrointestinal stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 variant, including PDGFRA D842V variants, and National Comprehensive Cancer Network guideline recommendations as an option for patients with GIST after third-line treatment, it is important to estimate the potential financial implications of avapritinib on a payer's budget. Objective To estimate the budget impact associated with the introduction of avapritinib to a formulary for metastatic or unresectable GISTs in patients with a PDGFRA exon 18 variant or after 3 or more previous treatments from the perspective of a US health plan. Design, setting, and participants For this economic evaluation, a 3-year budget impact model was developed in March 2020, incorporating costs for drug acquisition, testing, monitoring, adverse events, and postprogression treatment. The model assumed that avapritinib introduction would be associated with increased PDGFRA testing rates from the current 49% to 69%. The health plan population was assumed to be mixed 69% commercial, 22% Medicare, and 9% Medicaid. Base case assumptions included a GIST incidence rate of 9.6 diagnoses per million people, a metastatic PDGFRA exon 18 mutation rate of 1.9%, and progression rate from first-line to fourth-line treatment of 17%. Exposures The model compared scenarios with and without avapritinib in a formulary. Main outcomes and measures Annual, total, and per member per month (PMPM) budget impact. Results In a hypothetical 1-million member plan, fewer than 0.1 new patients with a PDGFRA exon 18 variant per year and 1.2 patients receiving fourth-line therapy per year were eligible for treatment. With avapritinib available, the total increase in costs in year 3 for all eligible adult patients with a PDGFRA exon 18 variant was $46 875, or $0.004 PMPM. For patients undergoing fourth-line treatment, the total increase in costs in year 3 was $69 182, or $0.006 PMPM. The combined total budget impact in year 3 was $115 604, or $0.010 PMPM, including an offset of $3607 in postprogression costs avoided or delayed. The higher rates of molecular testing resulted in a minimal incremental testing cost of $453 in year 3. Conclusions and relevance These results suggest that adoption of avapritinib as a treatment option would have a minimal budget impact to a hypothetical US health plan. This would be primarily attributable to the small eligible patient population and cost offsets from reduced or delayed postprogression costs.

Gastrointestinal stromal tumors (GISTs) represent a spectrum of tumors characterized by variable behaviors and activating mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT) or platelet derived growth factor receptor α (PDGFRA) genes. However, whether genotype analysis should be regarded as a prognostic indicator remains unclear. In the present study, clinicopathological data and the mutation phenotypes of KIT and PDGFRA genes were assessed in a series of 302 patients with GISTs at a single center. Univariate and multivariate Cox regression analyses were performed to identify the clinicopathological and mutational factors associated with relapse-free survival (RFS) in patients who had undergone complete primary GIST resection. KIT and PDGFRA mutations were identified in 233 (77.2%) and 30 (9.9%) cases, respectively. The following clinicopathological parameters were significantly associated with a shorter RFS: Male, non-gastric tumor origin, larger tumor size (>5 cm), high mitotic activity (>5/50 high-power fields), necrosis and epithelioid morphology. Tumors at non-gastric sites, with high National Institutes of Health risk classification, high World Health Organization (WHO) grade and KIT deletion involving codons 557/558/559 exhibited a significantly higher risk of progression. In the Cox regression model, KIT deletion involving codons 557/558/559, non-gastric origin and high WHO grade were independent indicators of RFS. The adverse prognosis associated with KIT deletions involving codons 557/558/559 was also observed for gastric GISTs. Conversely, spindle morphology, KIT exon 11 substitution and PDGFRA exon 18 mutation were associated with a longer RFS and lower rate of relapse. Furthermore, the coexistence of KIT exon 11 deletion and exon 13 duplication was observed in one tumor, with adverse prognostic features. Heterogeneity affecting morphology, immunostaining and genotype was identified in 4 cases. In addition, the presence of succinate dehydrogenase-deficient GIST was found in 5 cases (3.6%). In conclusion, the tumor genotype with regard to KIT and PDGFRA mutations exhibited prognostic significance for the risk of GIST progression and may be helpful for the optimization of tailored adjuvant therapy.

Avapritinib (AYVAKIT™) is a potent and selective tyrosine kinase inhibitor of platelet-derived growth factor receptor alpha (PDGFRA) and KIT activation loop mutants. It is being developed by Blueprint Medicines for the treatment of gastrointestinal stromal tumours (GIST), solid tumours and systemic mastocytosis. Avapritinib is approved in the USA for PDGFRA exon 18 (including D842V) mutant GIST and is undergoing regulatory assessment in the USA as a 4th-line treatment for GIST. Avapritinib is also undergoing regulatory assessment in the EU for PDGFRA D842V mutant GIST. This article summarizes the milestones in the development of avapritinib leading to this first approval for the treatment of adults with unresectable or metastatic GIST harbouring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. Clinical development of avapritinib is also underway for the treatment of systemic mastocytosis and late-stage solid tumours in several countries.

Purpose: Patients, platelet-derived growth factor receptor alpha (PDGFRA) D842V-mutated gastrointestinal stromal tumours (GISTs) are known for their insensitivity to imatinib. However, in clinical practice responses have been observed in some patients. We describe the natural history and treatment outcomes in a cohort of PDGFRA exon 18 mutated GIST patients.Patients and methods: A retrospective cohort study was conducted in PDGFRA exon 18 mutation GIST patients treated in six expert centres in the Netherlands and the United States. Two independent radiologists assessed radiological response to imatinib according to Choi's criteria in all patients with measurable disease treated with imatinib in neo-adjuvant or palliative intent.Results: Seventy-one patients with PDGFRA exon 18 mutation were identified of whom 48 patients (69%) had a D842V mutation. Twenty-two (45.8%) D842V-mutated GIST patients received imatinib treatment, 16 had measurable disease. Fourteen out of the 23 (60.9%) patients with non-D842V mutations received imatinib treatment, eight had measurable disease. Two out of 16 (12.5%) D842V-mutated GIST patients had partial response, 3 patients (18.8%) had stable disease and 9 patients (56.3%) had progressive disease as best response. Two patients did not have follow-up computed tomography scans to assess response. Six out of 8 (75%) patients with non-D842V exon 18 mutations had partial response and two (25%) had stable disease as best response.Conclusion: Patients with D842V-mutated GISTs can occasionally respond to imatinib. In the absence of better therapeutic options, imatinib should therefore not be universally withheld in patients with this mutation. (C) 2017 Elsevier Ltd. All rights reserved.

Pathological diagnosis of gastrointestinal stromal tumors (GISTs) is based on histological findings and immunohistochemical demonstration of the KIT protein. KIT-negative GISTs account for ∼5% of cases and cause diagnostic difficulties. In the era of imatinib therapy, a correct diagnosis of GISTs is important for therapeutic reasons regardless of KIT expression. Recently, DOG1 has been introduced as an important diagnostic marker with high sensitivity and specificity. In this study, immunohistochemical staining for DOG1 and protein kinase C-θ (PKC-θ) in whole tissue sections, and mutation analyses for KIT and PDGFRA were performed in 26 KIT-negative GISTs. Tissue microarrays of 112 KIT-positive GISTs were used as controls. Overall, 25 KIT-negative GISTs were located in the stomach, and 1 in the rectum. The histological subtype was spindle in 12, epithelioid in 11, and mixed in 3 cases. The expression of DOG1 and PKC-θ was positive in 24 (92%) and in 25 cases (96%), respectively. All 26 KIT-negative GISTs expressed either DOG1 or PKC-θ, and 23 cases (89%) were positive for both makers. PKC-θ was positive in two cases (8%), which lacked both KIT and DOG1 expressions. Mutation analysis showed PDGFRA exon 18 mutation in 15 cases (58%) and KIT exon 11 mutation in 1 case (4%), whereas the remaining 10 cases (39%) were wild type for both KIT and PDGFRA. The expression of DOG1 and PKC-θ showed no significant difference in KIT-negative and KIT-positive GISTs (P=1.000 and P=0.167, respectively). Our findings suggest that both DOG1 and PKC-θ can be used in the diagnosis of KIT-negative GISTs and they show positive staining even in KIT-negative tumors, which are wild type for KIT and PDGFRA on mutation analysis.

PDGFRA is mutated in 5%–10% of gastrointestinal stromal tumors (GISTs), the PDGFRA D842V mutation accounting for ∼60% of all PDGFRA mutations known in GISTs [1]. The DIMH842–845 and the IMH843–846 deletions represent ∼15% of all PDGFRA mutations. While the latter have been associated with sensitivity to imatinib, the PDGFRA D842V mutation confers primary resistance to imatinib [1–4], sunitinib [5], and nilotinib [6]. In vitro data suggested that dasatinib is a potent inhibitor of PDGFRA D842V [7]. Sorafenib also displayed some intermediate efficacy even if it was significantly lower than for PDGFRA ΔDIM842–844 [7]. Given the rarity of metastatic GIST with PDGFRA mutation, clinical data in this setting are almost nonexistent [8]. We report here a series of five patients with metastatic GIST bearing a mutation of the exon 18 of PDGFRA and treated with sorafenib (400 mg twice daily).

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Expression of CD117, DOG1 and PKCθ was investigated immunohistochemically in a series of 99 paraffin-embedded GISTs in order to determine the sensitivity and diagnostic value of these markers. KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were amplified by PCR and sequenced. A total of 94/99 (94%) GISTs stained positive for CD117, 81/99 (82%) for PKCθ and 90/99 (91%) for DOG-1. A significant correlation was noted between CD117 and DOG-1 expression (p=0.0001). All three markers were expressed in 74% (73/99) of GISTs. Of the five CD117-negative cases, two were PKCθ-negative/DOG1-negative and had mutations in KIT exon 11. Two were PKCθ-positive/DOG1-positive and had mutations in PDGFRA (one each in exons 12 and 18), and one was DOG1-negative/PKCθ-positive, with a PDGFRA exon 18 mutation. The most sensitive marker was CD117, followed by DOG-1 and PKCθ. Although PKCθ was less sensitive, and its staining is more challenging and difficult to interpret, the use of this marker is highly recommended, particularly in CD117-negative/DOG-1-negative GISTs.

Purpose: Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA. As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling. Experimental Design: Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells. Results: A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTs showed a distinct transcriptional signature, with overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT. Conclusions: Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTs show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.

Aims: To characterise KIT-negative gastrointestinal stromal tumours (GISTs) clinically, pathologically, immunohistochemically and genetically, and to establish the usefulness of protein kinase C theta (PKCθ) as a diagnostic marker in KIT-negative GIST. Methods: 252 consecutive cases of GIST were evaluated for clinicopathological characteristics and immunostained for various antibodies. Mutational analyses of KIT and platelet-derived growth factor receptor α ( PDGFRA ) were also performed in 62 cases. Results: 20 (7.9%) GISTs showed negative immunostaining for KIT. KIT-negative GISTs were more likely to originate from omentum or peritoneum, have an epithelioid histology, and be classified as high risk. The overall survival rate of patients with KIT-negative GISTs (5-year survival rate 68.7% (SD 10.7%)) was lower than that of patients with KIT-positive GISTs (5-year survival rate, 79.9% (3.0%)) (p = 0.042, log-rank test). Negative KIT expression was an independent prognostic factor in multivariate Cox regression analysis when the risk of aggressive behaviour and the status of imatinib treatment were adopted as covariates. KIT-negative GISTs also showed lower expression rates of CD34, Bcl-2, and PKCθ than KIT-positive GISTs; mutational analysis revealed that 30% of KIT-negative GISTs harboured a PDGFRA exon 18 mutation. Immunostaining on PKCθ showed that 93.9% of all GISTs expressed PKCθ protein. However, 21.9% of 64 mesenchymal tumours other than GIST also showed positivity on PKCθ. Conclusions: KIT-negative GISTs had characteristics that differ from those of KIT-positive GISTs, and negative KIT expression was an independent prognostic indicator for overall survival of patients. Although PKCθ is a sensitive diagnostic marker for GIST, its usefulness is limited because of low sensitivity and low specificity in KIT-negative GISTs.