0000000000430073
AUTHOR
Peter Reichardt
Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations : Results from a Multi-institutional European Retrospective Study
[Purpose] The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9–mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathologic variables with survival was evaluated in a large multi-institutional European cohort.
Randomized Phase 3 Trial of Regorafenib in Patients (Patients) with Metastatic and/or Unresectable Gastrointestinal Stromal Tumor (GIST) Progressing Despite Prior Treatment with at Least Imatinib (IM) and Sunitinib (SU) : Grid Trial
LBA10008 Background: Oral multikinase inhibitor regorafenib (REG) demonstrated substantial activity in a phase II trial in pts with GIST after failure of both IM and SU (J Clin Oncol. 2011; 29:606s; abstr 10007). This phase III, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of REG for this unmet clinical need. Methods: Eligible pts had metastatic and/or unresectable GIST, objective failure of both prior IM and SU (progressive disease [PD] on, or intolerance to, IM and PD on SU), ≥1 measurable lesion, ECOG performance status 0 or 1. Pts were randomized 2:1 to receive best supportive care plus either REG 160 mg po once daily (3 wks on/1 wk off) or placeb…
Results from a phase III trial (GRID) evaluating regorafenib (REG) in metastatic gastrointestinal stromal tumour (GIST): Subgroup analysis of outcomes based on pretreatment characteristics
10551 Background: REG, an oral receptor kinase inhibitor with activity against KIT, PDGFR, VEGFR, FGFRs, and other oncologic targets, demonstrated significant improvement in progression-free survival (PFS) over placebo (PL) in a phase III study (GRID) of patients (pts) with advanced GIST following failure of at least imatinib (IM) and sunitinib (SU). To understand the impact of pts’ baseline characteristics on outcome, we performed an exploratory analysis of REG effects across pt subgroups based on sex, age, and mitotic index of primary GIST tissue, as well as duration and number of lines of previous therapies. Methods: Adult pts with metastatic GIST (n=199) progressing after at least IM a…
TCR signalling network organization at the immunological synapses of murine regulatory T cells.
Regulatory T (Treg) cells require T-cell receptor (TCR) signalling to exert their immunosuppressive activity, but the precise organization of the TCR signalling network compared to conventional T (Tconv) cells remains elusive. By using accurate mass spectrometry and multi-epitope ligand cartography (MELC) we characterized TCR signalling and recruitment of TCR signalling components to the immunological synapse (IS) in Treg cells and Tconv cells. With the exception of Themis which we detected in lower amounts in Treg cells, other major TCR signalling components were found equally abundant, however, their phosphorylation-status notably discriminates Treg cells from Tconv cells. Overall, this s…
Selinexor in Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial
PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of st…
Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of regorafenib (REC) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes
10503 Background: The phase III GRID study showed that REG provides a significant improvement in progression-free survival (PFS) compared with PL in pts with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib (IM) and sunitinib (SU; HR 0.27, p<0.0001). Determining GIST genotype in TKI-refractory disease has proven challenging due to inter-tumoral heterogeneity and pt preference to avoid serial biopsies. To overcome this, we analysed circulating DNA in plasma as a source of tumor DNA and studied the correlation between mutational status and clinical outcome. Methods: DNA was isolated from both archival tumor tissue (n=102) and plasma at baseline (n=163…
Translational study associated to a phase II study evaluating the activity of pazopanib in patients (pts) with advanced/metastatic liposarcoma (LPS): A joint Spanish Sarcoma Group (GEIS) and German Interdisciplinary Sarcoma Group (GISG) study.
11067 Background: GEIS 30 was a phase II study showing moderate activity of pazopanib in well-differentiated/dedifferentiated LPS (cohort A:37 pts, Progression free Survival (PFS) at 12 weeks (w) 43.2%) and no activity in Myxoid/round cell LPS (cohort B: 15 pts, PFS at 12w 13.3%). The present study aims to identify tumor and plasma biomarkers that are differently expressed in long responders (LRs) PFS > 24 w. Methods: Serum samples and paraffin-blocks at diagnosis were collected for 28 pts in cohort A and 11 in B. A total of 13 pts were LRs. Serum samples were obtained at baseline, after 3 w of treatment and at progression. A panel of 15 cytokines and growth factors were evaluated using…
Abstract LB-295: Detection of oncogenic kinase mutations in circulating plasma DNA and correlation with clinical benefit in the phase III GRID study of regorafenib vs placebo in TKI-refractory metastatic GIST.
Abstract Background: GRID is a phase III study for patients with advanced gastrointestinal stromal tumors (GIST) following failure of imatinib (I) and sunitinib (S) who were randomized to receive either the multikinase inhibitor regorafenib (R) or placebo (P). R demonstrated a highly significant improvement in progression-free survival compared with P (HR 0.27, p&lt;0.0001). A preplanned retrospective biomarker analysis was conducted to assess GIST genotypes in GRID patients and to explore the possible impact of different driver oncogene mutations on clinical outcomes. Methods: DNA was isolated from archival tumor tissue and analyzed for KIT mutations via Sanger sequencing. The expectat…