Micromanagement of drug-resistant advanced gastrointestinal stromal tumors: regorafenib-new ammunition in battling exon 17 mutations.
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ABSTRACT:
SUBMITTER: Eckardt AJ
PROVIDER: S-EPMC5847923 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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Micromanagement of drug-resistant advanced gastrointestinal stromal tumors: regorafenib-new ammunition in battling exon 17 mutations.
Eckardt Alexander J AJ Klein Ortwin O
Translational gastroenterology and hepatology 20180228
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Project description:Gastrointestinal stromal tumors (GISTs) are rare malignancies, and historically had a poor prognosis, with little benefit from traditional anticancer therapies. The management of GISTs has undergone a paradigm change in recent years with the detection of activating mutations in the majority of these tumors. This knowledge has led to the development of targeted treatments which have dramatically improved benefit rates and survival. The tyrosine kinase inhibitor, imatinib, has become the standard of care for both those with high-risk resected GIST, and as first-line therapy in metastatic GIST. However, some patients demonstrate innate resistance to imatinib or, for many, resistance develops despite an initial response. Other tyrosine kinase inhibitors with a broader spectrum of action, such as sunitinib and sorafenib, have been investigated and show some benefit after the use of imatinib. Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity against a number of solid tumors and further studies have proven it to be effective in GISTs following failure of standard therapy, with manageable toxicity profile. It has now received licensing approval in a number of countries both for the treatment of GISTs and for colorectal cancer, and further research is ongoing. With a number of potential agents now available to treat this disease, clinicians must now consider questions of timing and sequencing to maximize the benefit from these treatments, and the role that new agents such as regorafenib could play in further advancing changes.
| S-EPMC4206614 | biostudies-literature
Project description:Regorafenib is a multi-target tyrosine kinase inhibitor that has been approved for the treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors (GIST). Severe hepatobiliary toxicity has been reported in patients with colorectal cancer treated with regorafenib, but not in those with GIST. Therefore, the aim of the present study was to investigate the incidence and clinical course of regorafenib-associated hepatic toxicity (HT) in patients with GIST in a real-world setting. Patients with metastatic GIST treated with regorafenib between September 2012 and May 2014 at three German tertiary care centers were followed up until August 2017. Patient records were retrospectively analyzed and descriptive statistics were employed. HT was defined as alterations in the serum values of aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, alkaline phosphatase and bilirubin (according to the Common Terminology Criteria for Adverse Events, version 4.0), and/or corresponding clinical signs. The time to clinical progression and the overall survival were calculated by Kaplan-Meier curves. Overall, 21 patients were treated with regorafenib and 5 (23.5%) of those heavily pretreated patients suffered from severe HT during regorafenib treatment. In 4 (80%) of these cases, regorafenib treatment was continued, optimizing individual treatment benefit. Clinical monitoring and adequate therapy management are crucial for ensuring continuation of regorafenib treatment in order to achieve an optimal clinical outcome.
| S-EPMC7523284 | biostudies-literature
Project description:BackgroundGastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%-90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2-3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown.Patients and methodsDocumented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1-21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety.ResultsBetween June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%).ConclusionRegorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted.Trial registrationThis trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097.Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.
| S-EPMC5546467 | biostudies-literature
Project description:Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.
| S-EPMC10029090 | biostudies-literature
Project description:BackgroundRegorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting.MethodsPatients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS.ResultsBetween August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1.ConclusionThe outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified.Clinical trial registrationhttps://clinicaltrials.gov, identifier NCT01933958.
| S-EPMC11215966 | biostudies-literature
Project description:Imatinib is strongly positioned as the recommended first-line agent for most patients with advanced gastrointestinal stromal tumor (GIST) due to its good efficacy and tolerability. Imatinib-resistant advanced GIST continues to pose a therapeutic challenge, likely due to the frequent presence of multiple mutations that confer drug resistance. Sunitinib and regorafenib are approved as second- and third-line agents, respectively, for patients whose GIST does not respond to imatinib or who do not tolerate imatinib, and their use is supported by large randomized trials. ATP-mimetic tyrosine kinase inhibitors provide clinical benefit even in heavily pretreated GIST suggesting that oncogenic dependency on KIT frequently persists. Several potentially useful tyrosine kinase inhibitors with distinct inhibitory profiles against both KIT ATP-binding domain and activation loop mutations have not yet been fully evaluated. Agents that have been found promising in preclinical models and early clinical trials include small molecule KIT and PDGFRA mutation-specific inhibitors, heat shock protein inhibitors, histone deacetylase inhibitors, allosteric KIT inhibitors, KIT and PDGFRA signaling pathway inhibitors, and immunological approaches including antibody-drug conjugates. Concomitant or sequential administration of tyrosine kinase inhibitors with KIT signaling pathway inhibitors require further evaluation, as well as rotation of tyrosine kinase inhibitors as a means to suppress drug-resistant cell clones.
| S-EPMC4532715 | biostudies-literature
Project description:ImportanceGastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients.ObjectiveTo evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib.Design, setting, and participantsThis single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor α (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017.InterventionsDasatinib, 70 mg orally twice daily.Main outcomes and measuresThe primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment.ResultsIn this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18.Conclusions and relevanceDasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.
| S-EPMC6145709 | biostudies-literature
Project description:BackgroundThe randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p < 0.0001].MethodsA subgroup analysis of Japanese patients in the GRID study was performed to compare the efficacy and safety of oral regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs).ResultsSeventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively).ConclusionRegorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.
| S-EPMC4527951 | biostudies-literature
Project description:Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal tract of humans and dogs. Little is known about the pathogenesis of these tumors. This study evaluated the role of c-KIT in canine GISTs; specifically, we investigated activating mutations in exons 8, 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), all of which have been implicated in human GISTs.Seventeen canine GISTs all confirmed to be positive for KIT immunostaining were studied. Exons 8, 9, 11, 13 and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA, were amplified from DNA isolated from formalin-fixed paraffin-embedded samples.Of these seventeen cases, six amplicons of exon 11 of c-KIT showed aberrant bands on gel electrophoresis. Sequencing of these amplicons revealed heterozygous in-frame deletions in six cases. The mutations include two different but overlapping six base pair deletions. Exons 8, 9, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA had no abnormalities detected by electrophoresis and sequencing did not reveal any mutations, other than synonymous single nucleotide polymorphisms (SNPs) found in exon 11 of c-KIT and exons 12 and 14 of PDGFRA.The deletion mutations detected in canine GISTs are similar to those previously found in the juxtamembrane domain of c-KIT in canine cutaneous mast cell tumors in our laboratory as well as to those reported in human GISTs. Interestingly, none of the other c-KIT or PDGFRA exons showed any abnormalities in our cases. This finding underlines the critical importance of c-KIT in the pathophysiology of canine GISTs. The expression of KIT and the identification of these activating mutations in c-KIT implicate KIT in the pathogenesis of these tumors. Our results indicate that mutations in c-KIT may be of prognostic significance and that targeting KIT may be a rational approach to treatment of these malignant tumors. This study further demonstrates that spontaneously occurring canine GISTs share molecular features with human GISTs and are an appropriate model for human GISTs.
| S-EPMC2970610 | biostudies-literature
Project description:BackgroundDespite its proven activity as third-line treatment in gastrointestinal stromal tumors (GIST), regorafenib can present a poor tolerability profile which often leads to treatment modifications and transient or permanent discontinuation; thus, in clinical practice physicians usually adopt various dosing and interval schedules to counteract regorafenib-related adverse events and avoid treatment interruption. The aim of this real-world study was to investigate the efficacy and safety of personalized schedules of regorafenib in patients with metastatic GIST, in comparison with the standard schedule (160 mg daily, 3-weeks-on, 1-week-off).Patients and methodsInstitutional registries across seven Italian reference centers were retrospectively reviewed and data of interest retrieved to identify patients with GIST who had received regorafenib from February 2013 to January 2021. The Kaplan-Meier method was used to estimate survival and the log-rank test to make comparisons.ResultsOf a total of 152 patients with GIST, 49 were treated with standard dose, while 103 received personalized schedules. At a median follow-up of 36.5 months, median progression-free survival was 5.6 months [95% confidence interval (CI) 3.73-11.0 months] versus 9.7 months (95% CI 7.9-14.5 months) in the standard-dose and the personalized schedule groups, respectively [hazard ratio (HR) 0.51; 95% CI 0.34-0.75; P = 0.00052]. Median overall survival was 16.6 months (95% CI 14.1-21.8 months) versus 20.5 months (95% CI 15.0-25.4 months), respectively (HR 0.75; 95% CI 0.49-1.22; P = 0.16).ConclusionsRegorafenib-personalized schedules are commonly adopted in daily clinical practice of high-volume GIST expert centers and correlate with significant improvement of therapeutic outcomes. Therefore, regorafenib treatment optimization in patients with GIST may represent the best strategy to maximize long-term therapy.
| S-EPMC8350191 | biostudies-literature