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Neuropsychiatric adverse events (AEs) significantly impact the quality of life of patients using avapritinib. However, the majority of current data comes from pre-marketing, with limited real-world studies. Our research aimed to explore post-marketing data of avapritinib. We evaluated the signals of avapritinib-related neuropsychiatric AEs by data mining using the FDA Adverse Event Reporting System (FAERS). Reporting odds ratio (ROR) and information component (IC) were employed to quantify the signals from the first quarter of 2020 through the fourth quarter of 2023. Subsequently, stratified analyses were conducted to further explore the effect of different stratification schemes on the association between avapritinib and neuropsychiatric AEs. Finally, a combination medication analysis was conducted to explore the impact of the co-administration of neuropsychiatric AEs. A total of 2029 neuropsychiatric AEs were reported, and 49 signals were detected, of which 5 were determined to be new signals. Avapritinib was significantly associated with the occurrence of neuropsychiatric AEs (ROR: 1.52, 95% CI: 1.44–1.61; IC: 0.43, IC025: 0.35). The stratified analysis found that gender, age and eight preferred terms (PTs), including cerebral haemorrhage, may affect the severity of AEs. Combination medication analysis showed that combining avapritinib with 19 other medications, including prochlorperazine, may increase the risk of neuropsychiatric AEs. The median time-to-onset (TTO) of avapritinib-related neuropsychiatric AEs was 32 (interquartile range [IQR] 2-200) days, with about 65% of cases occurring within the first three months of treatment. An increase in the signal for neuropsychiatric AEs was identified in post-marketing studies of avapritinib. Clinicians are advised to remain vigilant for such events, particularly during the initial stages of treatment with avapritinib. [ABSTRACT FROM AUTHOR]

Systemic mastocytosis (SM) is a rare hematologic disorder characterized by clonal proliferation of mast cells in the bone marrow and/or other organs. SM‐associated hematologic neoplasm (SM‐AHN) is one of the advanced SM variants that usually confer a poor prognosis. We present a case of a 75‐year‐old female patient with SM‐AHN, specifically myelodysplastic syndrome (MDS), that harbored a unique KIT mutation KIT V560D, not previously described in the literature in this setting. We describe the clinical course and the outcome with the use of avapritinib, midostaurin, and decitabine‐cedazuridine. Trial Registration: ClinicalTrials.gov identifier: NCT00782067 [ABSTRACT FROM AUTHOR]

Purpose of Review: Since identification of Systemic mastocytosis (SM) as a distinct disease entity by the World Health Organisation (WHO), there has been a wealth of new research in therapeutic targeting of the pathogenic C-KIT D816V mutation. Recent findings: Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions. Studies have shown improved survival and symptomatic control in patients with SM. Of great triumph, this has been achieved in an outpatient setting with apparent tolerable and minimal toxicity. The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. Summary: This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages. [ABSTRACT FROM AUTHOR]

Douglas Tremblay,1 Nicole E Wagner,2 John Mascarenhas1 1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; 2Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USACorrespondence: John Mascarenhas, Myeloproliferative Disorders Program, Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Place, Box 1079, New York, NY, 10029, USA, Tel +1 212 241 3417, Fax +12128765276, Email john.mascarenhas@mssm.eduAbstract: Advanced systemic mastocytosis (AdvSM) is a rare hematologic malignancy with organ damage and compromised life expectancy arising from organ accumulation of neoplastic mast cells. Identification of the gain-of-function KITD816V in the majority of cases has accelerated pharmaceutical development culminating with the development of selective KIT inhibitors such as avapritinib. While the advent of these therapies has improved the quality and quantity of life in patients with AdvSM, current challenges remain in the management of this disease. In this review, we summarize the present and future therapeutics landscape of AdvSM, highlighting the development of novel KIT inhibitors including elenestinib and bezuclastinib. We also explore the continued role of additional treatment modalities including allogeneic stem cell transplantation before discussing unresolved clinical challenges in the management of AdvSM.Keywords: systemic mastocytosis, KITD816V, avapritinib, midostaurin

Acute myeloid leukemia (AML) with t(8;21) (q22;q22), which forms RUNX1::RUNX1T1 fusion gene, is classified as a favorable-risk group. However, the presence of mutations in KIT exon 17 results in an adverse prognosis in this group. Avapritinib, a novel tyrosine kinase inhibitor, was designed to target KIT mutation. We report a retrospective study of four pediatric patients with AML with t(8:21) and KIT exon 17 mutation who were treated with avapritinib, three of them failed to demethylate drugs and donor lymphocyte infusion targeting RUNX1::RUNX1T1-positivity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, all patients with RUNX1::RUNX1T1 positivity had turned negative after 1, 9, 7, 2 months of avapritinib treatment. The common adverse effect of avapritinib is neutropenia, which is well-tolerated. This case series indicates that avapritinib may be effective and safe for preemptive treatment of children with AML with t(8;21) and KIT mutation after allo-HSCT, providing a treatment option for preventing relapse after allo-HSCT. [ABSTRACT FROM AUTHOR]

Desmoid tumors (DTs) are rare and locally aggressive with a high rate of local recurrence even with optimal surgical resection. Systemic treatments are often utilized for desmoid cases with high risk of surgical morbidity or for local and symptomatic control of recurrent disease. However, the systemic treatment options for DTs are limited with limited responses. Avapritinib is a tyrosine kinase inhibitor (TKI) approved in 2020 for adults with unresectable or metastatic gastrointestinal (GI) stromal tumors (GISTs) harboring a platelet‐derived growth factor receptor alpha (PDGFRA) Exon 18 mutation, including D842V mutations. In this case report, we describe a 55‐year‐old man with a history of D842V‐mutant gastric GIST who presented several years after complete resection of the GIST with an enlarging soft tissue mass in the small intestine. After a nondiagnostic biopsy, the patient was started on avapritinib due to concerns for recurrent D842V‐mutant GIST. The tumor had a partial response to treatment by RECIST 1.1 criteria, and the patient underwent surgical resection. The final pathology report revealed a sporadic DT. To our knowledge, this is the first known description of the activity of avapritinib in the treatment of a sporadic mesenteric DT, which is relevant given the limited treatment options for patients with this diagnosis. This clinical finding may be worth exploring in a dedicated clinical trial. [ABSTRACT FROM AUTHOR]

Aims: Avapritinib was first approved by the FDA in January 2020 and represents the first precision‐targeted drug for gastrointestinal stromal tumours. However, there is a lack of large‐scale data relating to adverse events (AEs) related to its use. We aimed to explore the avapritinib‐related AEs in real‐world practice based on the post‐marketing data. Methods: We extracted all avapritinib‐related reports submitted to the FDA Adverse Event Reporting System (FAERS) by June 2022. Based on disproportionality analysis and Bayesian analysis, we then calculated the reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC) and empirical Bayes geometric mean (EBGM) to evaluate whether there is a significant association between avapritinib and AEs. Gender, age and time to onset were comparable between haemorrhage/non‐haemorrhage, serious/non‐serious, death/non‐death AEs, respectively. Results: In total, 3120 cases related to avapritinib were documented in the FAERS database, and 44% were reported within 30 days of commencing avapritinib. A total of 331 different AE signals were detected, and no significant differences between males and females was identified. Although the number of AEs associated with an abnormal skin texture and executive dysfunction was small, the signal intensity is high, suggesting that these events are strongly correlated with avapritinib. Subgroup analysis showed that elderly male patients were more likely to suffer from serious AEs compared to females (P <.01), but there was no significant difference between the haemorrhage group and the non‐haemorrhage group. Analysis of fatalities due to avapritinib‐related AEs indicated that sex, age and time‐to‐onset were all significantly related to death (P <.05). Conclusion: Our study provides a more precise description of the incidence and characteristics of AEs after using avapritinib, clinicians should be particularly careful when prescribing avapritinib to elderly male patients, especially within the 30 days. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST. [ABSTRACT FROM AUTHOR]

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This study aimed to assess the bioequivalence of 2 avapritinib tablets formulations. A randomized, open‐label, single‐center trial was conducted on fasting, healthy Chinese participants. The study utilized a partial replicated design with 3 sequences and 3 periods. Participants were assigned to 1 of 3 sequences, with each sequence receiving the reference formulation twice and the test formulation once. Plasma samples were collected and analyzed to determine pharmacokinetic parameters. The bioequivalence of the 2 avapritinib formulations was assessed using reference‐scaled average bioequivalence for the maximum plasma concentration (Cmax) and the average bioequivalence analysis for the area under the concentration‐time curve (AUC). Out of 39 participants, 38 completed the study. For Cmax, the 1‐sided 95% upper confidence interval (CI) bound from the scaled approach was −0.035 (<0) and the point estimate value was 0.958, falling inside the acceptance range of 0.8‐1.25. For both the AUC over all concentrations measured (AUC0‐t) and the AUC from time 0 to infinity (AUC0‐inf), the 90% CIs of geometric mean ratios (0.87‐1.01) also met the bioequivalence criteria of 0.8‐1.25. Consequently, the study demonstrated that the 2 avapritinib formulations were bioequivalent under fasting conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Ripretinib, with reported broad activity against KIT-mutated gastrointestinal stomal tumors (GISTs), has been approved in the fourth-line setting, while avapritinib, which has robust activity against PDGFRA D842V and KIT activation loop (AL) mutations, has been approved for tumors with PDGFRA exon 18 mutations in any line of treatment. Avapritinib has fair activity against tumors with KIT exon 17 AL mutations or primary exon 9 mutations, as reported in the NAVIGATOR trial. That finding led to the National Comprehensive Cancer Network guidelines' inclusion of avapritinib as an available option after progression of disease on other FDA-approved tyrosine kinase inhibitors. As ripretinib and avapritinib have shown overlapping activity against KIT secondary mutations, we investigated whether the benefit of trying one of these drugs remains after exposure to the other. This study reports no significant difference in efficacy of these drugs regarding the sequence in which they were administered to the patient. Ripretinib and avapritinib have demonstrated activity in the late-line treatment of gastrointestinal stomal tumors (GISTs). We investigated whether patients previously treated with ripretinib benefit from avapritinib, and vice versa. Patients diagnosed with metastatic/unresectable GIST and treated with both drugs at two institutions in 2000–2021 were included. Patients were grouped by drug sequence: ripretinib–avapritinib (RA) or avapritinib–ripretinib (AR). Radiographic response was evaluated using RECIST 1.1. Kaplan–Meier and log-rank tests were used to compare time-to-progression (TTP) and overall survival (OS). Thirty-four patients (17 per group) were identified, with a median age of 48 years. The most common primary site was the small bowel (17/34, 50%), followed by the stomach (10/34, 29.4%). Baseline characteristics and tumor mutations were not significantly different between groups. Response rates (RRs) for ripretinib were 18% for RA and 12% for AR; RRs for avapritinib were 12% for AR and 18% for RA. Median TTPs for ripretinib were 3.65 months (95%CI 2–5.95) for RA and 4.73 months (1.87–15.84) for AR. Median TTPs for avapritinib were 5.39 months (2.86–18.99) for AR and 4.11 months (1.91–11.4) for RA. Median OS rates following RA or AR initiation were 29.63 (95%CI 13.8–50.53) and 33.7 (20.03–50.57) months, respectively. Both ripretinib and avapritinib were efficacious in the late-line treatment of GIST, with no evidence that efficacy depended on sequencing. [ABSTRACT FROM AUTHOR]

Summary: Mastocytosis constitutes the neoplastic proliferation of mast cells and is broadly classified into systemic mastocytosis (SM), cutaneous mastocytosis and mast cell sarcoma. SM is further partitioned into advanced (AdvSM) and non‐advanced (SM‐non‐Adv) subcategories. AdvSM includes aggressive SM (ASM), SM with an associated haematological neoplasm (SM‐AHN) and mast cell leukaemia (MCL). In 2022, two separate expert committees representing the 5th edition of the World Health Organization (WHO5) and the International Consensus (ICC) classification systems submitted revised classification criteria for SM, highlighted by the ICC‐proposed incorporation of mast cell cytomorphology in the diagnostic criteria for MCL and myeloid‐lineage restriction for the AHN component in SM‐AHN. Recent developments in SM also include the introduction of KIT‐targeting tyrosine kinase inhibitors (KITi), including midostaurin and avapritinib, both drugs have shown potent activity in reducing mast cell and mutant KIT burden and alleviating mast cell‐associated organopathy and mediator symptoms; however, their overall impact on survival or superiority over pre‐KITi era treatment options (e.g. cladribine) has not been studied in a controlled setting. In the current review, we provide a summary of recent changes in disease classification and an analysis of recent clinical trials and their impact on our current treatment approach in AdvSM. [ABSTRACT FROM AUTHOR]

Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in organ dysfunction and reduced life expectancy. The subtypes include aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). The gain of function KIT D816V mutation is present in most cases. The availability of tyrosine kinase inhibitors (TKIs) has revolutionised the treatment landscape for patients with this life-limiting disease. Patients are now able to achieve molecular remission, improved quality of life and improved overall survival. This review focuses on the targeted therapies currently available in clinical practice and within the clinical trial setting for AdvSM. This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease. [ABSTRACT FROM AUTHOR]

Key Clinical Message Low dose Avapritinib is a new medication that is a potential treatment option not just for advanced systemic mastocytosis, but also for the indolent form.

Systemic mastocytosis (SM) is a complex and heterogeneous disease, characterized by the clonal accumulation of mast cells in one or more organs. In 2022 both the World Health Organization (WHO) and the International Consensus Classification (ICC) modified the diagnostic and classification criteria of SM. Moreover, the identification of new clinical and molecular variables has improved prognostic tools and led to increasingly individualized therapeutic strategies. The aim of this review is to present the updates introduced by the International Consensus Classification in diagnostic criteria of SM. In addition, we report the latest data available from the most important clinical trials in patients both with non-advanced and advanced disease, including elenestinib and bezuclastinib. Diagnosis and classification of SM has evolved over years. The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future. [ABSTRACT FROM AUTHOR]

Copyright of Best Practice Onkologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Exon 18 D842V, which is a point mutation from aspartic acid to valine at codon 842, is the most frequent mutation in Platelet-Derived Growth Factor Receptor alpha (PDGFRA)-mutated gastrointestinal stromal tumor (GIST). In the Japanese GIST guidelines, no standard systematic therapy is available for this type of GIST, which is refractory after recurrence. Recently, pimitespib (PIMI), a novel heat shock protein 90 (HSP90) inhibitor, was approved for the treatment of advanced GIST in a phase III study. This report presents a case of a long-term response to PIMI in GIST with PDGFRA D842V mutation. Case presentation A 55-year-old woman was diagnosed with primary GIST of the stomach and underwent partial gastrectomy. Eight years after the operation, recurrent GISTs were identified as multiple recurrent peritoneal GISTs in the upper right abdomen and pelvic cavity. We administered tyrosine kinase inhibitors, but they achieved poor effects. After failure of the standard treatment, PIMI was administered and achieved a partial response in the patient. The highest reduction rate was 32.7%. After PIMI failed, we performed multiplex gene panel testing, which revealed the PDGFRA D842V mutation. Conclusions We report the first case of long-term response to PIMI in PDGFRA D842V mutant GIST. Pimitespib may be effective for treating GIST harboring this mutation by inhibiting HSP90.

Abstract Background Systemic mastocytosis (SM), a rare myeloid neoplasm, is defined as a clonal and neoplastic proliferation of mast cells in at least one extracutaneous organ(s). The pathologic diagnosis and treatment of SM are challenging. Case presentation We presented a 44-year-old male patient who had endured abdomen discomfort for 4 years and diarrhea for 5 months. Colonoscopy and PET/CT found a protuberant lesion in the cecum with adjacent lymphadenopathy. Histopathology of the cecum biopsy showed diffuse infiltration of medium-sized round/oval cells in lamina propria with immunohistochemical expressions of CD45, CD117, CD25, CD68, CD123, CD56, CD4, and CD35, mimicking blastic plasmacytoid dendritic cell neoplasm. Sanger sequencing revealed missense mutation (D816V) in the exon 17 of KIT gene. Serum tryptase level was 38.56 ng/ml. No abnormality was found in skin examination and bone marrow biopsy. No primitive cells were observed in bone marrow smear and peripheral blood smear. The diagnosis of aggressive SM with intestinal tract involvement was established. The patient received avapritinib treatment at an initial dosage of 200 mg once daily and exhibited dramatic clinical improvement but memory impairment within 1 month. No recurrence was observed in 1-year follow-up at the adjusted avapritinib dose (75 mg once daily). Conclusions SM is very rare and should be considered in patients with long-term diarrhea symptoms and hematopoietic/lymphoid-appearing tumors. KIT D816V mutation contributes to the differentiation of CD123, CD4, and CD56 immunoreactive SM from blastic plasmacytoid dendritic cell neoplasm. The rare side-effect of memory impairment in this case helps to accumulate the experience of avapritinib in treating KIT D816V-mutant SM.

Avapritinib (AVP) was the first precision drug to be approved by the US Food and Drug Administration (FDA) in 2020 for patients suffering from metastatic gastrointestinal stromal tumors (GISTs) and progressive systemic mastocytosis. The analysis of AVP in pharmaceutical tablets and human plasma was then carried out using a fast, efficient, sensitive, and simple fluorimetric method using a fluorescamine reagent. The procedure is based on the interaction between fluorescamine as a fluorogenic reagent and the primary aliphatic amine moiety in AVP using borate buffer solution at pH 8.8. The produced fluorescence was measured at 465 nm (Excitation at 395 nm). The calibration graph's linearity range was discovered to be 45.00–500.0 ng mL−1. Utilizing the International Council for Harmonization (ICH) and US‐FDA recommendations, the research technique was validated and bioanalytically validated. The proposed approach was effectively employed for determining the stated pharmaceuticals in plasma with a high percentage of recovery ranging from 96.87 to 98.09 and pharmaceutical formulations with a percentage of recovery equal to 102.11% ± 1.05%. In addition, the study was extended to a pharmacokinetic study of AVP with 20 human volunteers as a step for AVP management in therapeutic cancer centers. [ABSTRACT FROM AUTHOR]

Avapritinib is a highly selective inhibitor of mutated KIT and PDGFRA kinases, approved in 2020 for the treatment of patients with gastrointestinal stromal tumors (GIST). It has particular activity against GIST with the PDGFRA D842V mutation associated with imatinib resistance. The safety and efficacy of avapritinib have been evaluated in two clinical trials, NAVIGATOR and VOYAGER, which showed particularly favorable results in patients with the PDGFRA D842V mutation. In the NAVIGATOR study, the objective response rate (ORR) in patients with the mutation was 91%. In the VOYAGER study, the ORR was 17.1% in all patients receiving avapritinib and 42.9% in the group of patients with the PDGFRA D842V mutation. While the efficacy in the subgroup of patients with the mutation was significantly superior to regorafenib, this benefit was not demonstrated for the overall population. In both studies, adverse events were reported in more than 90% of patients, with more than 50% of patients experiencing Grade 3 or higher reactions. The most commonly reported treatment-related adverse events were nausea, fatigue, anemia, diarrhea, periorbital edema, and cognitive impairment. Based on the preliminary study results, avapritinib was approved in the United States and the European Union for treating patients with metastatic or unresectable GIST with the PDGRA D842V mutation. It is the first inhibitor showing activity against this mutation. In this review, we summarize the current data on the efficacy and safety of avapritinib and present its place in the diagnostic and therapeutic guidelines. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin, and a paradigmatic model for a successful rational development of targeted therapies in cancer. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. These guidelines are elaborated by the conjoint effort of the Spanish Society of Medical Oncology (SEOM) and the Spanish Sarcoma Research Group (GEIS) and provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up. [ABSTRACT FROM AUTHOR]

Simple Summary: This review summarises the systemic treatment options available for patients with gastrointestinal stromal tumours (GIST). While surgical treatment is recommended for most localised GIST, pre- or post-operative therapy with imatinib is indicated in patients with a high risk of disease recurrence. For most patients with inoperable or metastatic GIST, imatinib is the first-line therapy. Sunitinib, regorafenib, and ripretinib are licensed as second-, third-, and fourth-line therapy, respectively. However, patients with GIST harbouring specific mutations could be imatinib-resistant and follow different therapeutic schemes. This review evaluates potential medication options for each line of systemic treatment and examines the possibility of personalised treatment. The focus is placed on the tumour mutational profile, treatment-related adverse effects, and patient characteristics. Finally, a multidisciplinary approach is crucial, as combining systemic therapy with surgery, radiotherapy, interventional radiology, and radionuclide therapy can improve outcome. Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival. [ABSTRACT FROM AUTHOR]

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work. [ABSTRACT FROM AUTHOR]

The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT / PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutant GIST that is indicated for avapritinib treatment. Here, circulating tumor DNA (ctDNA) sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT / PDGFRA mutational landscape contributes to tyrosine kinase inhibitor (TKI) resistance and to determine its clinical validity and utility. VOYAGER (N = 476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and one or two additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end of treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes. A total of 386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib. ctDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment. • This study comprehensively documents the landscape of KIT and PDGFRA mutations in metastatic, imatinib-resistant GIST. • Selective pressure exerted with prior lines promotes a shift toward increased resistant subpopulations in the KIT A-loop. • Individual mutations in KIT / PDGFRA determine TKI sensitivity and resistance in metastatic GIST. • ctDNA-detected KIT/PDGFRA mutations in imatinib-resistant GIST prognosticate third- or fourth-line TKI treatment outcomes. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Low dose Avapritinib is a new medication that is a potential treatment option not just for advanced systemic mastocytosis, but also for the indolent form. [ABSTRACT FROM AUTHOR]

Copyright of Wiener Medizinische Wochenschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Exon 18 D842V, which is a point mutation from aspartic acid to valine at codon 842, is the most frequent mutation in Platelet-Derived Growth Factor Receptor alpha (PDGFRA)-mutated gastrointestinal stromal tumor (GIST). In the Japanese GIST guidelines, no standard systematic therapy is available for this type of GIST, which is refractory after recurrence. Recently, pimitespib (PIMI), a novel heat shock protein 90 (HSP90) inhibitor, was approved for the treatment of advanced GIST in a phase III study. This report presents a case of a long-term response to PIMI in GIST with PDGFRA D842V mutation. Case presentation: A 55-year-old woman was diagnosed with primary GIST of the stomach and underwent partial gastrectomy. Eight years after the operation, recurrent GISTs were identified as multiple recurrent peritoneal GISTs in the upper right abdomen and pelvic cavity. We administered tyrosine kinase inhibitors, but they achieved poor effects. After failure of the standard treatment, PIMI was administered and achieved a partial response in the patient. The highest reduction rate was 32.7%. After PIMI failed, we performed multiplex gene panel testing, which revealed the PDGFRA D842V mutation. Conclusions: We report the first case of long-term response to PIMI in PDGFRA D842V mutant GIST. Pimitespib may be effective for treating GIST harboring this mutation by inhibiting HSP90. [ABSTRACT FROM AUTHOR]

Background: Systemic mastocytosis (SM), a rare myeloid neoplasm, is defined as a clonal and neoplastic proliferation of mast cells in at least one extracutaneous organ(s). The pathologic diagnosis and treatment of SM are challenging. Case presentation: We presented a 44-year-old male patient who had endured abdomen discomfort for 4 years and diarrhea for 5 months. Colonoscopy and PET/CT found a protuberant lesion in the cecum with adjacent lymphadenopathy. Histopathology of the cecum biopsy showed diffuse infiltration of medium-sized round/oval cells in lamina propria with immunohistochemical expressions of CD45, CD117, CD25, CD68, CD123, CD56, CD4, and CD35, mimicking blastic plasmacytoid dendritic cell neoplasm. Sanger sequencing revealed missense mutation (D816V) in the exon 17 of KIT gene. Serum tryptase level was 38.56 ng/ml. No abnormality was found in skin examination and bone marrow biopsy. No primitive cells were observed in bone marrow smear and peripheral blood smear. The diagnosis of aggressive SM with intestinal tract involvement was established. The patient received avapritinib treatment at an initial dosage of 200 mg once daily and exhibited dramatic clinical improvement but memory impairment within 1 month. No recurrence was observed in 1-year follow-up at the adjusted avapritinib dose (75 mg once daily). Conclusions: SM is very rare and should be considered in patients with long-term diarrhea symptoms and hematopoietic/lymphoid-appearing tumors. KIT D816V mutation contributes to the differentiation of CD123, CD4, and CD56 immunoreactive SM from blastic plasmacytoid dendritic cell neoplasm. The rare side-effect of memory impairment in this case helps to accumulate the experience of avapritinib in treating KIT D816V-mutant SM. [ABSTRACT FROM AUTHOR]

Background: Avapritinib is a type 1 kinase inhibitor designed to potently and selectively inhibit oncogenic KIT/PDGFRA mutants by targeting the kinase active conformation. This multicenter, single-arm, open-label, phase I/II bridging study of NAVIGATOR in Chinese patients evaluated the safety and the antineoplastic activity of avapritinib in Chinese patients with unresectable/metastatic gastrointestinal stromal tumors (GIST). Methods: Phase I comprised dose escalation for safety and phase II dose determination. Phase II comprised dose expansion for safety/efficacy evaluations in patients with PDGFRA D842V mutations or patients having received at least 3 lines of therapy without PDGFRA D842V mutations. The primary endpoints were recommended phase II dose, safety, and Independent Radiology Review Committee (IRRC)-assessed objective response rate (ORR). Results: No dose-limiting toxicities occurred (n = 10); the recommended phase II dose was avapritinib 300 mg once daily orally. Fifty-nine patients initially received avapritinib 300 mg. Common grade ≥3 treatment-related adverse events were anemia, decreased white blood cell count, increased blood bilirubin levels, and decreased neutrophil count. In patients with PDGFRA D842V mutations, IRRC- and investigator-assessed ORRs were 75% and 79%, respectively; clinical benefit rates were both 86%. Median duration of response/progression-free survival were not reached. IRCC- and investigator-assessed ORRs in patients in the fourth- or later-line setting were 22% and 35%, respectively. Median progression-free survivals were 5.6 months for both. Overall survival data were immature and not calculated. Conclusion: Avapritinib was generally well tolerated and showed marked anti-tumor activity in Chinese patients with GIST bearing PDGFRA D842V mutations and notable efficacy as fourth- or later-line monotherapy (ClinicalTrials.gov Identifier: NCT04254939). This article evaluates the safety and the antineoplastic activity of avapritinib in Chinese patients with unresectable/metastatic gastrointestinal stromal tumors. [ABSTRACT FROM AUTHOR]

Over 90% of gastrointestinal stromal tumors (GISTs) harbor mutations in KIT or PDGFRA that can predict response to tyrosine kinase inhibitor (TKI) therapies, as recommended by NCCN (National Comprehensive Cancer Network) guidelines. However, gene sequencing for mutation testing is expensive and time-consuming and is susceptible to a variety of preanalytical factors. To overcome the challenges associated with genetic screening by sequencing, in the current study we developed an artificial intelligence-based deep-learning （DL） model that uses convolutional neural networks (CNN) to analyze digitized hematoxylin and eosin staining in tumor histological sections to predict potential response to imatinib or avapritinib treatment in GIST patients. Assessment with an independent testing set showed that our DL  model could predict imatinib sensitivity with an area under the curve (AUC) of 0.902 in case-wise analysis and 0.807 in slide-wise analysis. Case-level AUCs for predicting imatinib-dose-adjustment cases, avapritinib-sensitive cases, and wildtype GISTs were 0.920, 0.958, and 0.776, respectively, while slide-level AUCs for these respective groups were 0.714, 0.922, and 0.886, respectively. Our model showed comparable or better prediction of actual response to TKI than sequencing-based screening (accuracy 0.9286 versus 0.8929; DL model versus sequencing), while predictions of nonresponse to imatinib/avapritinib showed markedly higher accuracy than sequencing (0.7143 versus 0.4286). These results demonstrate the potential of a DL model to improve predictions of treatment response to TKI therapy from histology in GIST patients. © 2025 The Pathological Society of Great Britain and Ireland., (© 2025 The Pathological Society of Great Britain and Ireland.)

Mastocytosis is characterized by an abnormal accumulation of mast cells (MC) in various organs. In most patients, the disease is driven by the KIT D816V mutation, leading to activation of the KIT receptor and subsequent downstream signaling, including the JAK/STAT pathway. In recent years, KIT-targeting tyrosine kinase inhibitors (TKI) have emerged for the treatment of systemic mastocytosis; however, the overall response rate is often not sufficient. In this study, we investigated whether targeting the JAK/STAT pathway might be a novel treatment approach in mastocytosis. Using human MC lines carrying the KIT D816V mutation and human primary cord blood-derived MC, we examined the effects of different JAK inhibitors. Our findings revealed that the JAK inhibitors fedratinib and gandotinib decreased viability, reduced proliferation, and induced apoptosis in KIT D816V-positive MC lines (HMC-1.2 and ROSA KIT D816V ). In contrast, ruxolitinib, baricitinib, upadacitinib and abrocitinib failed to affect MC functions. Combinatorial treatment with fedratinib, gandotinib and the two TKI avapritinib and midostaurin was more effective than treatment with TKI alone. Fedratinib also induced apoptosis and enhanced the efficacy of TKI in primary cord blood-derived MC. These results indicate that fedratinib and gandotinib, but not the other JAK inhibitors used in this study, can suppress viability and induce apoptosis in KIT D816V-mutant and KIT WT MC and increase effects of TKI. These findings suggest to explore fedratinib and gandotinib as novel treatment option in mastocytosis., Competing Interests: MA has consulted for and received honoraria from AB Science, Blueprint Medicines and Thermo Fisher. KH has consulted for and received honoraria from ALK, Allergopharma, BioCryst, Blueprint, Cogent, Galderma, KalVista, Leo, Menarini, Novartis, Pfizer, Sanofi, Takeda and Thermo Fisher., (AJCR Copyright © 2025.)

Increased concentrations of the fibronectin glycoprotein can cause ectopic tissue growth patients with endometriosis and the formation of various cancerous tumors. Furthermore, fibronectin binding to its receptors from the EDA (Extra Domain A) region contributes to promote tumorigenesis, metastasis and vasculogenesis. Thus, the EDA region can be considered a unique target for therapeutic intervention. Therefore, the present study used computational methods to identify the best fibronectin inhibitor(s) among FDA-approved drugs. First, docking-based virtual screening was performed using PyRx 0.8. Next, FDA-approved drugs that obtained favorable results in the docking phase were selected for further studies and analysis using molecular dynamics (MD) simulation. The preliminary findings of the virtual screening showed that 17 FDA-approved drugs (from 2471) had more favorable energy with their binding energy less than -9 kcal/mol. The MD simulation results of these 17 drugs showed that Avapritinib had a lower RMSD value and higher binding energy and hydrogen bonding than the other complexes in the EDA domain. Also, analyses related to the second structure changes displayed that Avapritinib in the EDA domain led to more changes in the second structure. According to the results, the anticancer drug Avapritinib forms a more stable complex with fibronectin than other FDA-approved drugs. Furthermore, this drug leads to more changes in the second EDA structure, which may have more serious potential for inhibiting EDA fibronectin.Communicated by Ramaswamy H. Sarma.

Aims: Gastrointestinal stromal tumors (GISTs) account for about 80% of the mesenchymal tumors of the GI tract. About 5000-6000 patients are diagnosed in the United States (US) alone, and up to 14.5 cases per million discovered in Europe annually. Avapritinib (AVP) is a potent selective targeted medication that has been recently approved, by the US Food and Drug Administration, in 2020 for treatment of GISTs. AVP is currently considered the first-line treatment for mutant GIST, which is resistant to other medications. This in turn stimulates the need for fast, green, and efficient methods for routine AVP estimation in quality control and clinical studies., Materials and Methods: The proposed approach designs a spectrofluorimetric tool to estimate AVP in different matrices, based on a nucleophilic substitution reaction. A highly fluorescent product was measured at 535 nm following excitation at 470 nm. The research procedure was bioanalytically validated within AVP range between 80 and 900 ng mL -1 , where the limit of quantitation (LOQ) was 15.78 ng mL -1 ., Conclusion: The developed approach was successfully applied to investigate AVP in content uniformity testing of tablet dosage forms, and biological plasma in AVP pharmacokinetic study. The proposed approach could be recommended for AVP therapeutic drug monitoring.

Gastrointestinal stromal tumors (GISTs) are tumors of the digestive tract. To date, there have been no neurological paraneoplastic syndromes or symptoms associated with metastatic GISTs. Tyrosine kinase inhibitors (TKIs) are the typical class of agents used in management of this malignancy. Avapritinib, a new TKI, has been associated with myriad neurological adverse events with fairly rapid resolution in clinical trials. Herein, we present the case of a patient with metastatic GIST who, after starting treatment with avapritinib, developed rapidly progressive and persisting severe neuropsychiatric symptoms, including profound parkinsonism and encephalopathy, while concurrently receiving therapy with the antipsychotic olanzapine. We posit that the patient could be conceptualized as having a relative vulnerability to medication effects in the setting of metastatic GIST - possibly driven by an immune-mediated process - and that the addition of avapritinib triggered an overtly evident, clinically significant cascade of neurological deterioration.

Background: Atypical chronic myeloid leukemia (aCML) is a rare myelodysplastic/myeloproliferative neoplasm. There is no proven standard of care treatment and the only curative option available is hematopoietic stem cell transplant. In addition to traditional chemotherapy, targeted therapy has shown to be a promising. Avapritinib is a selective type 1 tyrosine kinase inhibitor with high potency for KIT D816V and was recently approved for treatment of systemic mastocytosis. Here we present a case of aCML with novel D816V mutation treated with avapritinib for 17 months leading to clonal extinction of the driver mutation. Case presentation: An 80 year old man initially presented for evaluation of aCML. A bone marrow biopsy was completed, and next generation sequencing was notable for a novel KIT D816V mutation. Patient was started on avapritinib leading to significant improvement in leukocytosis and extinction of the D816V mutation over 17 months of treatment. The extinction was followed with serial next generation sequencing. Conclusion: We present the first case of aCML with KIT D816V driver mutation. We also demonstrate two novel management strategies. First, we show that treatment with avapritinib does not need to be limited to cases of systemic mastocytosis and could be useful in other hematologic malignancies with this driver mutation. Furthermore, with the use of serial next generation sequencing we were able to identify new emerging clones. While none of the clones noted in this study were targetable, they could be in other patients with aCML and help guide treatment.

Copyright of Lijecnicki Vjesnik is the property of Croatian Medical Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Primary Hepatic Neuroendocrine Carcinoma (PHNEC) is a rare and aggressive tumor with high recurrence rates. Surgical resection remains the only therapeutic strategy. The effectiveness of tyrosine kinase inhibitors (TKIs) for PHNEC remains unclear due to limited research. We employed immunohistochemical staining to diagnose PHNEC and assess the expression of eight tyrosine kinase receptors in tumor tissues, including VEGFRs, PDGFRA, EGFR, FGFRs et al. A patient-derived xenograft (PDX) model was established using PHNEC tumor tissues to test the efficacy of TKIs. PDX mice bearing tumors were treated with Avapritinib, an FDA-approved PDGFRA-targeting drug, at a daily oral dose of 10 mg/kg for 2 weeks. Pathological analysis confirmed the diagnosis of PHNEC with positive expression of Neural cell adhesion molecule (NCAM/CD56), Synaptophysin (Syn), and Somatostatin receptor 2 (SSTR-2), and negative expression of Hep (Hepatocyte Paraffin 1), a biomarker for Hepatocellular carcinoma. Notably, PDGFRA was significantly overexpressed in PHNEC tumor tissues compared to other tyrosine kinases. Avapritinib treatment significantly reduced tumor growth in PDX mice by 73.9 % (p = 0.008). Additionally, Avapritinib treatment led to a marked decrease in PDGFRA and Ki-67 expression, suggesting that it inhibits tumor cell proliferation by suppressing PDGFRA. Our findings suggest that PDGFRA is a potential therapeutic target for PHNEC, and its inhibition with Avapritinib may offer clinical benefits to patients with this rare malignancy. • We initially identified the expressions of tyrosine kinase receptors in primary hepatic neuroendocrine carcinoma. • An patient-derived xenograft (PDX) model of PHNEC was constructed by us. • Avapritinib might be a safe and effective candidate for treating PHNEC based on the treatment of PHNEC in PDX model. [ABSTRACT FROM AUTHOR]

Proto-oncogene KIT is the gene encoding the receptor tyrosine kinase protein KIT. Activating mutations are found in 2.9% of neoplasms, with the highest prevalence in gastrointestinal stromal tumour. Exon 17 mutations typically alter the kinase activation loop and are relatively rare, representing 11.7% of all activating KIT mutations. Recently, KIT exon 17 mutants turned out to be a potential molecular target for the type 1 kinase inhibitor avapritinib (BLU-285). In this framework, we aimed at investigating the potential activity of avapritinib in mucosal melanoma and thymic carcinoma, two disease histologies with dismal prognosis, currently lacking evidence-based second line treatment options and in which KIT exon 17 activating mutations could represent a relevant therapeutic target. In this series, we report the only four cases of patients affected by exon 17 mutant mucosal melanoma and thymic carcinoma that have been treated in Italy with avapritinib within a Compassionate Use Program. Two patients harboured mucosal melanoma and the other two were diagnosed with thymic carcinoma. We describe a differential activity of avapritinib (3/4 patients responded, 1/4 did not respond), along with possible hypotheses to justify such differences and potential implications for precision oncology. Taken together, the inactivity of imatinib on KIT exon 17 mutations, the general low clinical efficacy of immunotherapy, as well as the consequent formal lack of standard available and active second line systemic treatments in both mucosal melanoma and thymic carcinoma, support the implementation of avapritinib in the therapeutic armamentarium, even though further prospective evidence is warranted. • Mucosal melanoma and thymic carcinoma are orphan diseases with dismal prognosis. • KIT exon 17 activating mutations are a relevant therapeutic target in both diseases. • Unlike imatinib, KIT exon 17 mutants are a target for kinase inhibitor avapritinib. • We describe activity of avapritinib in the only 4 patients treated within CU Program. • Hypotheses to justify different responses are provided, to serve precision oncology. [ABSTRACT FROM AUTHOR]

Opinion Statement: Gastrointestinal stromal tumor (GIST), though rare, is the most common mesenchymal tumors of the gastrointestinal tract. KIT or PDGFRα mutation plays as an oncogenic driver in the majority of GISTs. Surgical resection is the only curative treatment for localized disease. The discovery of imatinib with promising anti-tumor effect and successive tyrosine kinase inhibitors (TKI), including second-line sunitinib and third-line regorafenib, revolutionized the management of advanced and metastatic GIST over the past two decades. Recently, ripretinib and avapritinib were approved for the fourth line setting and for PDGFRA exon 18-mutant GIST in first-line setting, respectively. Despite multi-line TKIs exerted ability of disease control, drug resistance remained an obstacle for preventing rapid disease progression. Experimental TKIs or novel therapeutic targets may further improve treatment efficacy. Immune checkpoint inhibitors such as anti-programmed cell death protein-1 (PD1) and anti-CTL-associated antigen 4 (CTLA-4) showed moderate response in early phase trials composed of heavily pretreated patients. KIT/PDGFRα wild-type GISTs are generally less sensitive to imatinib and late-line TKIs. Recent studies demonstrated that targeting fibroblast growth factor receptor signaling may be a potential target for the wild-type GISTs. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10–15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60–70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Advanced systemic mastocytosis (AdvSM) is a rare malignant disease with a poor prognosis due to the drug resistance of neoplastic mast cells. We found that drugs targeting the cell cycle regulators CDK4 and CDK6 profoundly suppress the growth and survival of neoplastic mast cells. Furthermore, these drugs can overcome resistance against KIT D816V-targeting drugs, including midostaurin, in neoplastic mast cells. Finally, the CDK4/CDK6 inhibitors applied induced apoptosis in CD34+/CD38− stem cells in AdvSM. Based on these results, we believe that CDK4/CDK6 inhibition may be a new and interesting therapeutic approach with curative potential for AdvSM. Whether combinations of KIT D816-targeting drugs and CDK4/CDK6 inhibitors can induce long-term remission in patients with AdvSM remains to be determined in clinical trials. In most patients with advanced systemic mastocytosis (AdvSM), neoplastic mast cells (MC) express KIT D816V. However, despite their disease-modifying potential, KIT D816V-targeting drugs, including midostaurin and avapritinib, may not produce long-term remissions in all patients. Cyclin-dependent kinase (CDK) 4 and CDK6 are promising targets in oncology. We found that shRNA-mediated knockdown of CDK4 and CDK6 results in growth arrest in the KIT D816V+ MC line HMC-1.2. The CDK4/CDK6 inhibitors palbociclib, ribociclib, and abemaciclib suppressed the proliferation in primary neoplastic MC as well as in all HMC-1 and ROSA cell subclones that were examined. Abemaciclib was also found to block growth in the drug-resistant MC line MCPV-1, whereas no effects were seen with palbociclib and ribociclib. Anti-proliferative drug effects on MC were accompanied by cell cycle arrest. Furthermore, CDK4/CDK6 inhibitors were found to synergize with the KIT-targeting drugs midostaurin, avapritinib, and nintedanib in inducing growth inhibition and apoptosis in neoplastic MCs. Finally, we found that CDK4/CDK6 inhibitors induce apoptosis in CD34+/CD38− stem cells in AdvSM. Together, CDK4/CDK6 inhibition is a potent approach to suppress the growth of neoplastic cells in AdvSM. Whether CDK4/CDK6 inhibitors can improve clinical outcomes in patients with AdvSM remains to be determined in clinical trials. [ABSTRACT FROM AUTHOR]