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Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.

ABSTRACT: The Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) project aims to additionally explore the data of the two large, randomized, cooperative-group studies comparing two doses of imatinib (400 mg daily v twice daily) in 1,640 patients with advanced GIST.End points were progression-free survival (PFS) and overall survival (OS). Investigated cofactors included age, sex, performance status (PS), primary tumor site, time from diagnosis, prior therapies, baseline biology, and KIT/PDGFRalpha mutations for a subset of 772 patients. Univariate and multivariate models were used for the analysis.At a median follow-up of 45 months, a small but significant PFS advantage was documented for the high-dose arm. OS was identical in the two arms. The multivariate prognostic models included the following adverse factors: male sex, poor PS, and high baseline neutrophils counts (PFS and OS); low hemoglobin and GIST from small bowel origin (PFS); and advanced age, large tumor size, low albumin level, and prior chemotherapy (OS). In patients analyzed for mutations, patients with wild type, patients with KIT exon 9 mutations, and patients with other mutations had worse prognoses than patients with KIT exon 11 mutations for both end points. The mutation status was the only predictive factor for the PFS benefit attributed to high-dose treatment that resulted in significantly longer PFS (and higher objective response rate) for patients with KIT exon 9 mutations.This analysis confirms a small PFS advantage of high-dose imatinib, essentially among patients with KIT exon 9 mutations, but no OS advantage.

SUBMITTER: Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST)

PROVIDER: S-EPMC2834472 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20100201 7

<h4>Purpose</h4>The Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST) project aims to additionally explore the data of the two large, randomized, cooperative-group studies comparing two doses of imatinib (400 mg daily v twice daily) in 1,640 patients with advanced GIST.<h4>Methods</h4>End points were progression-free survival (PFS) and overall survival (OS). Investigated cofactors included age, sex, performance status (PS), primary tumor site, time from diagnosis, prior therapies, ba ...[more]

PMID: 20124181

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Project description:BackgroundAvapritinib, 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 methodsWe 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).ResultsOf 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.ConclusionTolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs.Implications for practiceEarly 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.

Project description:Despite having significant rationale, S0502 failed to accrue for a number of reasons.Vetting a trial first, with scientific experts and funding agencies, does not guarantee success, especially when dealing with a rare tumor and/or one with an existing highly effective therapy.In the present case, adding an intravenous drug to an oral medication as part of a regimen expected to be continued for many years likely decreased patient (and physician) convenience and, thus, interest in the study.Imatinib mesylate, a potent inhibitor of the KIT and PDGFR tyrosine kinases, is highly effective in the treatment of advanced gastrointestinal stromal tumors (GISTs). However, most imatinib-treated tumors eventually become resistant, accounting for a median progression-free survival of 19-23 months. Expression of vascular endothelial growth factor (VEGF) correlates with poor prognosis in GIST; bevacizumab, a monoclonal antibody against VEGF, is effective in a variety of solid tumors. We postulated combination therapy with imatinib plus bevacizumab would benefit patients with advanced GIST, particularly those reliant on VEGFA-dependent angiogenesis.Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial, S0502. At registration, patients were randomly assigned to either imatinib 400 mg (standard) or 800 mg (patients with exon 9 KIT mutations), or imatinib plus bevacizumab, 7.5 mg/kg i.v. every 3 weeks. Patients were treated to progression, symptomatic deterioration, unacceptable toxicity, treatment delay greater than 4 weeks, or patient choice to withdraw from the study. The primary objective was to determine whether the addition of bevacizumab to imatinib would improve progression-free survival (PFS) in first-line treatment of incurable GIST.S0502 opened on April 15, 2008. As of fall 2009, only 12 patients from at least 178 eligible SWOG centers plus those participating through Cancer Trials Support Unit had been entered in the study. Despite an aggressive promotion scheme involving the other cooperative groups and a major GIST patient advocacy group, accrual remained slow. The trial was closed on October 1, 2009, having accrued only 2% of the 572 patients planned. No scientific conclusions were forthcoming because of the small number of patients entered in the study. Two patients of the 6 in the combination arm reported grade 3 toxicities, 1 with proteinuria and 1 with fatigue, upper gastrointestinal hemorrhage, and anemia.No conclusions may be drawn from this trial and, thus, the combination of imatinib plus bevacizumab cannot be recommended for use.

Project description:Few treatment options remain for patients with metastatic or unresectable gastrointestinal stromal tumours (GIST) after objective progression on approved tyrosine-kinase inhibitors. We aimed to assess efficacy of imatinib rechallenge in these patients.In our prospective, randomised, double-blind trial, we enrolled adults (?18 years) who had previously benefited from first-line imatinib (initial response or stable disease for ?6 months) but whose metastatic or unresectable GIST had progressed on at least imatinib and sunitinib. We randomly allocated participants in a 1:1 ratio, with a centralised computer-generated allocation procedure (random permuted blocks of two, four, and six) and stratified by previous treatment and Eastern Cooperative Oncology Group performance status, to receive best supportive care with imatinib 400 mg per day or matched placebo. Crossover to open-label imatinib was allowed after investigator-adjudicated disease progression. The primary endpoint was progression-free survival (PFS), as determined by a masked external radiological review. All analyses were done for all patients who received at least one dose of study drug.Between July 20, 2010, and Jan 17, 2013, we randomly allocated 41 patients to the imatinib group and 40 patients to the placebo group. After a median follow-up of 5·2 months (IQR 3·4-9·4), median PFS was 1·8 months (95% CI 1·7-3·6) with imatinib compared with 0·9 months (0·9-1·7) with placebo (hazard ratio for progression or death 0·46, 95% CI 0·27-0·78; p=0·005). 37 (93%) patients in the placebo group crossed over to open-label imatinib after progression. The most common grade 3 or worse adverse events were anaemia (12 [29%] of 41 patients in the imatinib group vs three [8%] of 40 in the placebo group), fatigue (four [10%] vs none), and hyperbilirubinaemia (three [7%] vs one [3%]).In patients with GIST that is refractory to treatment with all standard tyrosine-kinase inhibitors, the disease continues to harbour many clones that are sensitive to kinase inhibitors. Continued kinase suppression might slow, although not halt, disease progression.

Project description:Nilotinib inhibits the tyrosine kinase activity of ABL1/BCR-ABL1 and KIT, platelet-derived growth factor receptors (PDGFRs), and the discoidin domain receptor. Gain-of-function mutations in KIT or PDGFR? are key drivers in most gastrointestinal stromal tumours (GISTs). This trial was designed to test the efficacy and safety of nilotinib versus imatinib as first-line therapy for patients with advanced GISTs.In this randomised, open-label, multicentre, phase 3 trial (ENESTg1), participants from academic centres were aged 18 years or older and had previously untreated, histologically confirmed, metastatic or unresectable GISTs. Patients were stratified by previous adjuvant therapy and randomly assigned (1:1) via a randomisation list to receive oral imatinib 400 mg once daily or oral nilotinib 400 mg twice daily. The primary endpoint was centrally reviewed progression-free survival. Efficacy endpoints were assessed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT00785785.Because the futility boundary was crossed at a preplanned interim analysis, trial accrual terminated in April, 2011. Between March 16, 2009, and April 21, 2011, 647 patients were enrolled; of whom 324 were allocated nilotinib and 320 were allocated imatinib. At final analysis of the core study (data cutoff, October, 2012), 2-year progression-free survival was higher in the imatinib group (59·2% [95% CI 50·9-66·5]) than in the nilotinib group (51·6% [43·0-59·5]; hazard ratio 1·47 [95% CI 1·10-1·95]). In the imatinib group, the most common grade 3-4 adverse events were hypophosphataemia (19 [6%]), anaemia (17 [5%]), abdominal pain (13; 4%), and elevated lipase level (15; 5%), and in the nilotinib group were anaemia (18; 6%), elevated lipase level (15; 5%), elevated alanine aminotransferase concentration (12; 4%), and abdominal pain (11; 3%). The most common serious adverse event in both groups was abdominal pain (11 [4%] in the imatinib group, 14 [4%] in the nilotinib group).Nilotinib cannot be recommended for broad use to treat first-line GIST. However, future studies might identify patient subsets for whom first-line nilotinib could be of clinical benefit.Novartis Pharmaceuticals.

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Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.

Publications

Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients.

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