RESUMO
PURPOSE OF REVIEW: This review explores the role of circulating tumor (ct)DNA as a biomarker for clinical decision-making and monitoring purposes in metastatic gastrointestinal stromal tumor (GIST) patients. We discuss key insights from recent clinical trials and anticipate the future perspectives of ctDNA profiling within the clinical landscape of GIST. RECENT FINDINGS: The identification and molecular characterization of KIT/platelet-derived growth factor receptor alpha (PDGFRA) mutations from ctDNA in metastatic GIST is feasible and reliable. Such identification through ctDNA serves as a predictor of clinical outcomes to tyrosine-kinase inhibitors (TKIs) in metastatic patients. Additionally, conjoined ctDNA analysis from clinical trials reveal the evolving mutational landscapes and increase in intratumoral heterogeneity across treatment lines. Together, this data positions ctDNA determination as a valuable tool for monitoring disease progression and guiding therapy in metastatic patients. These collective efforts culminated in the initiation of a ctDNA-based randomized clinical trial in GIST, marking a significant milestone in integrating ctDNA testing into the clinical care of GIST patients. SUMMARY: The dynamic field of ctDNA technologies is rapidly evolving and holds significant promise for research. Several trials have successfully validated the clinical utility of ctDNA in metastatic GIST, laying the foundations for its prospective integration into the routine clinical management of GIST patients.
Assuntos
DNA Tumoral Circulante , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Humanos , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/sangue , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/patologia , Neoplasias Gastrointestinais/tratamento farmacológico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Mutação , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
OBJECTIVE: To review the evidence of uncommon but fatal adverse event of hyperammonemic encephalopathy by tyrosine kinase inhibitors (TKI) and the possible mechanisms underlying this condition and to describe the case of a patient that developed drug-induced hyperammonemic encephalopathy related to TKI. DATA SOURCES: Literature search of different databases was performed for studies published from 1 January 1992 to 7 May 2023. The search terms utilized were hyperammonemic encephalopathy, TKI, apatinib, pazopanib, sunitinib, imatinib, sorafenib, regorafenib, trametinib, urea cycle regulation, sorafenib, carbamoyl-phosphate synthetase 1, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, arginase 1, Mitogen activated protein kinases (MAPK) pathway and mTOR pathway, were used individually search or combined. DATA SUMMARY: Thirty-seven articles were included. The articles primarily focused in hyperammonemic encephalopathy case reports, management of hyperammonemic encephalopathy, urea cycle regulation, autophagy, mTOR and MAPK pathways, and TKI. CONCLUSION: Eighteen cases of hyperammonemic encephalopathy were reported in the literature from various multitargeted TKI. The mechanism of this event is not well-understood but some authors have hypothesized vascular causes since some of TKI are antiangiogenic, however our literature review shows a possible relationship between the urea cycle and the molecular inhibition exerted by TKI. More preclinical evidence is required to unveil the biochemical mechanisms responsible involved in this process and clinical studies are necessary to shed light on the prevalence, risk factors, management and prevention of this adverse event. It is important to monitor neurological symptoms and to measure ammonia levels when manifestations are detected.
Assuntos
Hiperamonemia , Humanos , Masculino , Antineoplásicos/efeitos adversos , Encefalopatias/induzido quimicamente , Hiperamonemia/induzido quimicamente , /efeitos adversosRESUMO
BACKGROUND: Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. METHODS: Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. RESULTS: From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. CONCLUSIONS: Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02638766.
Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Sarcoma , Adulto , Humanos , Antineoplásicos/uso terapêutico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Sarcoma/tratamento farmacológicoRESUMO
Gastrointestinal stromal tumor (GIST), the most common sarcoma, is mainly caused by an oncogenic mutation in the KIT receptor tyrosine kinase. Targeting KIT using tyrosine kinase inhibitors, such as imatinib and sunitinib, provides substantial benefit; however, in most patients, the disease will eventually progress due to KIT secondary mutations leading to treatment failure. Understanding how GIST cells initially adapt to KIT inhibition should guide the selection of appropriate therapies to overcome the emergence of resistance. Several mechanisms have been broadly implicated in the resistance to imatinib anti-tumoral effects, including the reactivation of MAPK signaling upon KIT/PDGFRA targeted inhibition. This study provides evidence that LImb eXpression 1 (LIX1), a protein we identified as a regulator of the Hippo transducers YAP1 and TAZ, is upregulated upon imatinib or sunitinib treatment. LIX1 silencing in GIST-T1 cells impaired imatinib-induced MAPK signaling reactivation and enhanced imatinib anti-tumor effect. Our findings identified LIX1 as a key regulator of the early adaptative response of GIST cells to targeted therapies.
Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proteínas Relacionadas à Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib/farmacologia , Mesilato de Imatinib/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Sunitinibe/farmacologia , Sunitinibe/uso terapêutico , Sistema de Sinalização das MAP QuinasesRESUMO
Preclinical forms of gastrointestinal stromal tumor (GIST), small asymptomatic lesions, called microGIST, are detected in approximately 30% of the general population. Gastrointestinal stromal tumor driver mutation can be already detected in microGISTs, even if they do not progress into malignant cancer; these mutations are necessary, but insufficient events to foster tumor progression. Here we profiled the tissue microbiota of 60 gastrointestinal specimens in three different patient cohorts-micro, low-risk, and high-risk or metastatic GIST-exploring the compositional structure, predicted function, and microbial networks, with the aim of providing a complete overview of microbial ecology in GIST and its preclinical form. Comparing microGISTs and GISTs, both weighted and unweighted UniFrac and Bray-Curtis dissimilarities showed significant community-level separation between them and a pronounced difference in Proteobacteria, Firmicutes, and Bacteroidota was observed. Through the LEfSe tool, potential microbial biomarkers associated with a specific type of lesion were identified. In particular, GIST samples were significantly enriched in the phylum Proteobacteria compared to microGISTs. Several pathways involved in sugar metabolism were also highlighted in GISTs; this was expected as cancer usually displays high aerobic glycolysis in place of oxidative phosphorylation and rise of glucose flux to promote anabolic request. Our results highlight that specific differences do exist in the tissue microbiome community between GIST and benign lesions and that microbiome restructuration can drive the carcinogenesis process.
Assuntos
Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Microbiota , Transformação Celular Neoplásica , Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mutação , Proteínas Proto-Oncogênicas c-kit/genéticaRESUMO
BACKGROUND: Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. METHODS: In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. RESULTS: Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. CONCLUSION: PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017.
Assuntos
Tumores do Estroma Gastrointestinal , Humanos , Alopecia/induzido quimicamente , Medidas de Resultados Relatados pelo Paciente , Qualidade de VidaRESUMO
PURPOSE OF REVIEW: This article critically revisits novel data on tyrosine kinase inhibitors that have shown clinical activity in the treatment of gastrointestinal stromal tumor (GIST). RECENT FINDINGS: GIST therapeutic development exploits the oncogene addiction to KIT or PDGFRA receptor tyrosine kinases. Based on this principle, two new drugs were approved in 2020: ripretinib in GIST patients after progression to all standard treatments and avapritinib, the first agent ever active in the multiresistant PDGFRA D842V-mutant GIST. Additionally, cabozantinib has also shown encouraging activity in imatinib-resistant GIST patients. Finally, novel agents targeting NTRK-driven GIST have emerged as a breakthrough for the treatment of a subset of KIT/PDGFRA wild-type GIST patients. GIST is a paradigmatic tumor model for the rational and successful development of molecularly targeted agents directed against driver mutations in cancer.
Assuntos
Antineoplásicos , Neoplasias Gastrointestinais , Tumores do Estroma Gastrointestinal , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genéticaRESUMO
Gastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5-7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset.
Assuntos
Tumores do Estroma Gastrointestinal , MicroRNAs , Humanos , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/terapia , Tumores do Estroma Gastrointestinal/patologia , Mesilato de Imatinib , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , MicroRNAs/genética , Mutação , Receptores Proteína Tirosina Quinases/genética , Fatores Imunológicos , Imunoterapia , RNA Mensageiro , Proteínas Proto-Oncogênicas c-kit/genéticaRESUMO
BACKGROUND: Ripretinib 150 mg once daily (QD) is indicated for advanced gastrointestinal stromal tumors (GISTs) as at least fourth-line therapy. In INVICTUS, ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. was allowed after progressive disease (PD) on 150 mg QD by blinded independent central review using modified RECIST 1.1. We report the efficacy and safety of ripretinib IPDE to 150 mg b.i.d. after PD among patients randomized to ripretinib 150 mg QD in the INVICTUS study. MATERIALS AND METHODS: Tumor imaging was performed every 28-day cycle for the first four cycles in the ripretinib 150 mg QD period and then every other cycle, including the 150 mg b.i.d. PERIOD: Among the ripretinib IPDE patients, progression-free survival (PFS)1 was the time from randomization until PD; PFS2 was the time from the first dose of ripretinib 150 mg b.i.d. to PD or death. RESULTS: Among 43 ripretinib IPDE patients, median PFS1 was 4.6 months (95% confidence interval [CI], 2.7-6.4) and median PFS2 was 3.7 months (95% CI, 3.1-5.3). Median overall survival was 18.4 months (95% CI, 14.5-not estimable). Ripretinib 150 mg b.i.d. (median duration of treatment 3.7 months) was well tolerated with new or worsening grade 3-4 treatment-emergent adverse events (TEAEs) of anemia in six (14%) and abdominal pain in three (7%) patients. Ripretinib 150 mg b.i.d. was discontinued because of TEAEs in seven (16%) patients. CONCLUSION: Ripretinib 150 mg b.i.d. after PD on 150 mg QD may provide additional clinically meaningful benefit with an acceptable safety profile in patients with at least fourth-line GISTs. IMPLICATIONS FOR PRACTICE: Of the 85 patients with advanced gastrointestinal stromal tumor having received at least three prior anticancer therapies randomized to ripretinib 150 mg once daily (QD) in the phase III INVICTUS study, 43 underwent ripretinib intrapatient dose escalation (IPDE) to 150 mg b.i.d. after progressive disease (PD). Median progression-free survival was 4.6 months before and 3.7 months after ripretinib IPDE. The safety profile of ripretinib 150 mg b.i.d. was acceptable. These findings indicate ripretinib IPDE to 150 mg b.i.d. may provide additional clinical benefit in patients with PD on ripretinib 150 mg QD, for whom limited treatment options exist.
Assuntos
Tumores do Estroma Gastrointestinal , Progressão da Doença , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Humanos , Naftiridinas , Ureia/análogos & derivadosRESUMO
BACKGROUND: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding. MATERIALS AND METHODS: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose). RESULTS: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without. CONCLUSION: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs. IMPLICATIONS FOR PRACTICE: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.
Assuntos
Tumores do Estroma Gastrointestinal , Adulto , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Pirazóis , Pirróis , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , TriazinasRESUMO
BACKGROUND: Most gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST. MATERIALS AND METHODS: Eligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy. RESULTS: As of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6). CONCLUSION: Avapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations. IMPLICATIONS FOR PRACTICE: In the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.
Assuntos
Antineoplásicos , Tumores do Estroma Gastrointestinal , Antineoplásicos/efeitos adversos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Triazinas/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The current article revisits the most recent advances that occurred in the field of gastrointestinal stromal tumor (GIST) therapeutics. RECENT FINDINGS: GIST is driven by the oncogenic activation of KIT or PDGFRA receptor tyrosine kinases, and agents targeting these receptors lead to substantial benefit throughout the entire course of the disease. Two new drugs were approved in 2020. On one hand, ripretinib obtained the regulatory approval for the treatment of GIST patients after progression to all standard treatments. On the other hand, avapritinib became the first agent ever displaying activity in GIST driven by the multiresistant PDGFRA D842V mutation. The addition of both drugs to GIST therapeutics constitutes a remarkable milestone, particularly considering that the last agent approved was back in 2012. Similarly, the recent identification of neurotrophic tyrosine receptor kinase (NTRK) fusions in a subset of KIT/PDGFRA wild-type GISTs led to an open window for tailored treatment using specific NTRK inhibitors. Finally, multiple efforts have been made toward the clinical implementation of circulating tumor DNA evaluation to guide clinical decisions in GIST. SUMMARY: GIST has been consolidated over the years as a paradigmatic model in personalized medicine for the successful development of novel therapeutic strategies through targeted inhibition of oncogenic drivers.
Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Triazinas/uso terapêutico , Ureia/análogos & derivados , Antineoplásicos/uso terapêutico , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/metabolismo , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/metabolismo , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Ureia/uso terapêuticoRESUMO
INTRODUCTION: Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial event in gastrointestinal stromal tumor (GIST) biology. Seminal works during the past two decades have underscored, first, the continuous relevance of KIT/PDGFRA oncogenic signaling after progression to targeted inhibition; second, the heterogeneity of KIT/PDGFRA acquired mutations, that cannot be efficiently suppressed by any given tyrosine kinase inhibitor (TKI); and third, the presence of specific mutants highly resistant to all approved therapies. AREAS COVERED: This review discusses treatment options in advanced/metastatic GIST, including a detailed dissection of ripretinib and avapritinib, the two novel small molecule inhibitors approved by the Food and Drug Administration in 2020. EXPERT OPINION: The three only therapeutic options since 2012 for metastatic GIST patients were imatinib, sunitinib, and regorafenib. Although imatinib was highly effective in treatment-naïve GIST, the benefit of second- and third-line sunitinib and regorafenib was modest, thus emphasizing the medical need for new treatment options. Ripretinib, a switch control inhibitor with broad anti-KIT/PDGFRA activity, has been approved as ≥4th line in GIST after progression to all standard therapies. Avapritinib, a type I TKI highly specific against the multi-resistant PDGFRA D842V mutation, is approved in this specific subset of GIST patients.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mutação , Inibidores de Proteínas Quinases/farmacologiaRESUMO
OPINION STATEMENT: Gastrointestinal stromal tumor (GIST) constitutes a paradigm for clinically effective targeted inhibition of oncogenic driver mutations. Therefore, GIST has emerged as a compelling clinical and biological model to study oncogene addiction and to validate preclinical concepts for drug response and drug resistance. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the essential drivers of GIST progression throughout all stages of the disease. Interestingly, KIT/PDGFRA genotype predicts the response to first-line imatinib and to all tyrosine kinase inhibitors (TKIs) approved or in investigation after imatinib failure. Considering that TKIs are effective only against a subset of KIT or PDGFRA resistance mutations, close monitoring of tumor dynamics with non-invasive methods such as liquid biopsy emerges as a necessary step forward in the field. Liquid biopsy, in contrast to solid tumor biopsy, aims to characterize tumors irrespective of heterogeneity. Although there are several components in the peripheral blood, most recent studies have been focused on circulating tumor (ct)DNA, due to the technological feasibility, the stability of DNA itself and DNA alterations, and the therapeutic development in precision oncology largely based on the identification of genetic driver mutations. In the present review, we systematically dissect the current wealth of data of ctDNA in GIST. To do so, a critical understanding of the promises and limitations of the current technologies will be followed by an exposition of the knowledge gathered with such studies in GIST. Collectively, our goal is to establish clear premises that can be used as the foundations to build future studies towards the clinical implementation of ctDNA evaluation in GIST patients.
Assuntos
Biomarcadores Tumorais , Tumores do Estroma Gastrointestinal/diagnóstico , Biópsia Líquida , DNA Tumoral Circulante , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Tumores do Estroma Gastrointestinal/etiologia , Tumores do Estroma Gastrointestinal/terapia , Genômica/métodos , Genômica/normas , Humanos , Biópsia Líquida/métodos , Biópsia Líquida/normas , Técnicas de Diagnóstico Molecular , Oncogenes , Medicina de Precisão/métodos , Medicina de Precisão/normas , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor α (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours. METHODS: In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov, number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing. FINDINGS: Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6·3 months (IQR 3·2-8·2) in the ripretinib group and 1·6 months (1·1-2·7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6·3 months (95% CI 4·6-6·9) with ripretinib compared with 1·0 months (0·9-1·7) with placebo (hazard ratio 0·15, 95% CI 0·09-0·25; p<0·0001). The most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two (2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep). INTERPRETATION: Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. FUNDING: Deciphera Pharmaceuticals.
Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Seguimentos , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proto-Oncogene Mas , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Targeting of KIT and PDGFRA with imatinib revolutionised treatment in gastrointestinal stromal tumour; however, PDGFRA Asp842Val (D842V)-mutated gastrointestinal stromal tumour is highly resistant to tyrosine kinase inhibitors. We aimed to assess the safety, tolerability, and antitumour activity of avapritinib, a novel KIT and PDGFRA inhibitor that potently inhibits PDGFRA D842V, in patients with advanced gastrointestinal stromal tumours, including patients with KIT and PDGFRA D842V-mutant gastrointestinal stromal tumours (NAVIGATOR). METHODS: NAVIGATOR is a two-part, open-label, dose-escalation and dose-expansion, phase 1 study done at 17 sites across nine countries (Belgium, France, Germany, Poland, Netherlands, South Korea, Spain, the UK, and the USA). Patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 2 or less, and with adequate end-organ function were eligible to participate. The dose-escalation part of the study included patients with unresectable gastrointestinal stromal tumours. The dose-expansion part of the study included patients with an unresectable PDGFRA D842V-mutant gastrointestinal stromal tumour regardless of previous therapy or gastrointestinal stromal tumour with other mutations that either progressed on imatinib and one or more tyrosine kinase inhibitor, or only received imatinib previously. On the basis of enrolment trends, ongoing review of study data, and evolving knowledge regarding the gastrointestinal stromal tumour treatment paradigm, it was decided by the sponsor's medical director together with the investigators that patients with PDGFRA D842V mutations would be analysed separately; the results from this group of patients is reported in this Article. Oral avapritinib was administered once daily in the dose-escalation part (starting dose of 30 mg, with increasing dose levels once daily in continuous 28-day cycles until the maximum tolerated dose or recommended phase 2 dose was determined; in the dose-expansion part, the starting dose was the maximum tolerated dose from the dose-escalation part). Primary endpoints were maximum tolerated dose, recommended phase 2 dose, and safety in the dose-escalation part, and overall response and safety in the dose-expansion part. Safety was assessed in all patients from the dose-escalation part and all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour in the dose-expansion part, and activity was assessed in all patients with PDGFRA D842V-mutant gastrointestinal stromal tumour who received avapritinib and who had at least one target lesion and at least one post-baseline disease assessment by central radiology. This study is registered with ClinicalTrials.gov, NCT02508532. FINDINGS: Between Oct 26, 2015, and Nov 16, 2018 (data cutoff), 46 patients were enrolled in the dose-escalation part, including 20 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour, and 36 patients with a PDGFRA D842V-mutant gastrointestinal stromal tumour were enrolled in the dose-expansion part. At data cutoff (Nov 16, 2018), 38 (46%) of 82 patients in the safety population (median follow-up of 19·1 months [IQR 9·2-25·5]) and 37 (66%) of the 56 patients in the PDGFRA D842V population (median follow-up of 15·9 months [IQR 9·2-24·9]) remained on treatment. The maximum tolerated dose was 400 mg, and the recommended phase 2 dose was 300 mg. In the safety population (patients with PDGFRA D842V-mutant gastrointestinal stromal tumour from the dose-escalation and dose-expansion parts, all doses), treatment-related grade 3-4 events occurred in 47 (57%) of 82 patients, the most common being anaemia (14 [17%]); there were no treatment-related deaths. In the PDGFRA D842V-mutant population, 49 (88%; 95% CI 76-95) of 56 patients had an overall response, with five (9%) complete responses and 44 (79%) partial responses. No dose-limiting toxicities were observed at doses of 30-400 mg per day. At 600 mg, two patients had dose-limiting toxicities (grade 2 hypertension, dermatitis acneiform, and memory impairment in patient 1, and grade 2 hyperbilirubinaemia in patient 2). INTERPRETATION: Avapritinib has a manageable safety profile and has preliminary antitumour activity in patients with advanced PDGFRA D842V-mutant gastrointestinal stromal tumours. FUNDING: Blueprint Medicines.
Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Triazinas/uso terapêutico , Idoso , Feminino , Seguimentos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. METHODS: We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). RESULTS: We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. CONCLUSIONS: ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
Assuntos
Biomarcadores Tumorais , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Tumores do Estroma Gastrointestinal/genética , Adulto , Idoso , Éxons , Feminino , Tumores do Estroma Gastrointestinal/sangue , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Metástase Neoplásica , Reação em Cadeia da Polimerase , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Carga TumoralRESUMO
AIM: To assess the efficacy of treatment using a minimally invasive approach (selective removal of carious tissue, restoration and preventive strategies) in immature permanent molars with MIH. DESIGN: A total of 281 patients, aged 6-8 years, with carious lesions (ICDAS 5-6), severe MIH, and incomplete root formation (one tooth/patient) were included. After clinical and radiographic examinations, selective carious tissue removal was performed, and the teeth received interim restoration for 6 months and were then restored with composite resin. Clinical and radiographic follow-up was undertaken, 6, 12, 18, and 24 months. A protocol of preventive oral care measures was established and repeated at each follow-up, including diet counselling, oral hygiene instruction, dental plaque control, and topical application of fluoride varnish containing CPP-ACP. All clinical procedures and evaluations were done by a single operator. RESULTS: Clinical and radiographic success was observed 24 months after treatment in 96.8% of the cases. Failures were due to enamel fracture at restoration margins, resulting in pulpitis and absence of apex closure. CONCLUSION: Selective removal of carious tissue, interim, and subsequently definitive restoration, combined with home and professional preventive measures, maintained marginal integrity of restorations in immature permanent molars with severe MIH, confirmed by pulp vitality and occurrence of apexogenesis.
Assuntos
Hipoplasia do Esmalte Dentário , Restauração Dentária Permanente , Criança , Resinas Compostas , Humanos , Estudos Longitudinais , Dente MolarRESUMO
AIM: To compare the incidence of gestational diabetes mellitus (GDM) in women with three or more risk factor to developing GDM supplemented with myo-inositol plus probiotics versus women care without supplementation. METHODS: Retrospective cohort study, group 1, women with supplementation (myo-inositol 2g plus Bifidobacterium lactis and Lactobacillus rhamnosus 5x108 UFC, twice per day, from 12-14 to 28 weeks of gestation; group 2, women with prenatal care without supplementation, matched by age and body mass index (BMI). The primary outcome was the incidence of GDM using the International Association of Diabetes and Pregnancy Study Groups criteria. RESULTS: Group 1 n=48, group 2 n=96. There were no significant baseline differences between groups in age, BMI and number of risk factors. The incidence of GDM in group 1 was n=14 (29.2%), and for group 2 n=46 (47.9%); RR: 0.61 (95% CI: 0.37-0.99; p = 0.03). CONCLUSIONS: Supplementation from 12-14 weeks of gestation with myo-inositol plus probiotics decrease the incidence of GDM in Mexican women.
OBJETIVO: Comparar la incidencia de diabetes mellitus gestacional (DMG) en mujeres con tres o más factores de riesgo para desarrollar DMG suplementadas con mioinositol más probióticos versus mujeres sin suplementación.. MATERIAL Y MÉTODOS: Estudio de cohorte retrospectivo, grupo 1, mujeres con suplementación (mioinositol 2 g más Bifidobacterium lactis y Lactobacillus rhamnosus 5x108unidades formadoras de colonias, dos veces al día, de las 12-14 hasta las 28 semanas de gestación); grupo 2, mujeres con control prenatal habitual sin suplementación, pareadas por edad e índice de masa corporal (IMC). El resultado primario fue la incidencia de DMG utilizando los criterios de la Asociación Internacional de Grupos de Estudio de Diabetes y Embarazo. RESULTADOS: Grupo 1, n = 48, y grupo 2 n = 96. No hubo diferencias significativas en características basales como edad, IMC, y numero de factores de riesgo entre los grupos. La incidencia de DMG en el grupo 1 fue n = 14 (29.2%) y en el grupo 2 n = 46 (47.9%); RR: 0.61 (IC 95%: 0.37-0.99; p = 0.03). CONCLUSIONES: La suplementación desde las 12-14 semanas de gestación con mioinositol más probióticos disminuye la incidencia de DMG en mujeres mexicanas.
Assuntos
Bifidobacterium animalis , Diabetes Gestacional , Suplementos Nutricionais , Lacticaseibacillus rhamnosus , Probióticos , Adulto , Índice de Massa Corporal , Diabetes Gestacional/prevenção & controle , Feminino , Humanos , Gravidez , Cuidado Pré-Natal , Probióticos/uso terapêutico , Estudos RetrospectivosRESUMO
BACKGROUND: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. METHODS: We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. RESULTS: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. CONCLUSIONS: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.