Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial

Mir, Olivier; Cropet, Claire; Toulmonde, Maud; Cesne, Axel Le; Molimard, Mathiéu; Bompas, Emmanuelle; Cassier, Philippe; Ray‐Coquard, Isabelle; Rios, María; Adenis, Antoine; Italiano, Antoîne; Bouché, Olivier; Chauzit, Emmanuelle; Duffaud, Florence; Bertucci, François; Isambert, Nicolás; Gautier, Julien; Blay, Jean‐Yves; Pérol, David

doi:10.1016/s1470-2045(16)00075-9

Cited by 101 publications

(74 citation statements)

References 22 publications

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“…In a phase II French trial, Mir et al[34] showed that pazopanib plus best supportive care improves progression-free survival compared with best supportive care alone in patients with advanced GISTs resistant to imatinib and sunitinib. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for this group of patients.…”

Section: Tkis and Biological Therapy In Gistsmentioning

confidence: 99%

Current research and treatment for gastrointestinal stromal tumors

Lim

Tan

2017

WJG

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and have gained considerable research and treatment interest, especially in the last two decades. GISTs are driven by mutations commonly found in the KIT gene and less commonly in the platelet-derived growth factor receptor alpha gene, BRAF gene and succinate dehydrogenase gene. GISTs behave in a spectrum of malignant potential, and both the tumor size and mitotic index are the most commonly used prognostic criteria. Whilst surgical resection can offer the best cure, targeted therapy in the form of tyrosine kinase inhibitors (TKIs) has revolutionized the management options. As the first-line TKI, imatinib offers treatment for advanced and metastatic GISTs, adjuvant therapy in high-risk GISTs and as a neoadjuvant agent to downsize large tumors prior to resection. The emergence of drug resistance has altered some treatment options, including prolonging the first-line TKI from 1 to 3 years, increasing the dose of TKI or switching to second-line TKI. Other newer TKIs, such as sunitinib and regorafenib, may offer some treatment options for imatinib-resistant GISTs. New molecular targeted therapies are being evaluated, such as inhibitors of BRAF, heat shock protein 90, glutamine and mitogen-activated protein kinase signaling, as well as inhibitors of apoptosis proteins antagonist and even immunotherapy. This editorial review summarizes the recent research trials and potential treatment targets that may influence our future patient-specific management of GISTs. The current guidelines in GIST management from Europe, North America and Asia are highlighted.

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Section: Tkis and Biological Therapy In Gistsmentioning

confidence: 99%

Current research and treatment for gastrointestinal stromal tumors

Lim

Tan

2017

WJG

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“…6,8 Even though sunitinib and other new targeted drugs can sometimes be effective in recurrent GIST, clinical progression and drug resistance, such as insensitivity to sunitinib, subsequently evolve within 1 year. 9,10 Another potential strategy to increase the efficacy of imatinib is to combine imatinib with immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

PD‐1/PD‐L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway

et al. 2019

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Objectives:Although targeted therapy has revolutionized the treatment of gastrointestinal stromal tumours (GIST), it is almost never curative in GIST, and resistance commonly develops. One potential strategy is to combine targeted therapy with immunotherapy. Materials and methods:We first studied Programmed cell death 1 ligand 1 (PD-L1) expression and tumour-infiltrating T cells (TILs) in GIST. IFN-γ was used to induce the upregulation of PD-L1 expression in GIST-882 cells, a well-known GIST cell line.CD8+ T-cell apoptosis was determined by flow cytometry. The PI3K/Akt/mTOR levels in CD8+ T cells were examined by Western blotting.Results: PD-L1 expression was an independent factor of poor prognosis in GIST and resulted in exhausted T cells in the TILs population or the blood. Then, we found that PD-L1 blockade alone could not increase tumour cell apoptosis in GIST. The apoptosis rate of CD8+ T cells was higher when T cells were cultured with PD-L1+ GIST-882 cells (GIST-882 cells with high PD-L1 expression) than when T cells were cultured with control GIST-882 cells. However, when the PD-L1 blockade was used, the apoptosis rates of the CD8+ T cells in the two groups became similar. Then, Western blotting showed the PI3K/Akt/mTOR levels of the CD8+ T cells rescued by the PD-1/ PD-L1 blockade were higher than those of the CD8+ T cells not treated with the PD-1/PD-L1 blockade.Conclusions: PD-L1 expression was an independent poor prognosis factor in GIST.PD-1/PD-L1 blockade rescued exhausted CD8+ T cells in GIST via the PI3K/Akt/ mTOR signalling pathway. In GIST, PD-1/PD-L1 not only function as predictive biomarkers but also improve current therapies as treatment targets.

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“…Basic and clinical data indicate that imatinib, a KIT/PDGFRA-targeting agent, is not considered to have antitumor activities for "true" wild-type GISTs (18). Recent small cohort studies and sub-analysis of clinical trials indicate that inhibitors for vascular endothelial growth factor receptor, such as sunitinib, regorafenib, and pazopanib, may have significant activities on SDH-deficient GISTs (16)(17)(18). GISTs with typical BRAF mutations (V600E) were indicated to be sensitive to BRAF and/or MEK inhibitors (15).…”

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confidence: 99%

Therapeutic strategies for wild-type gastrointestinal stromal tumor: is it different from KIT or PDGFRA-mutated GISTs?

Nishida¹

2017

Transl. Gastroenterol. Hepatol.

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Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial

Cited by 101 publications

References 22 publications

Current research and treatment for gastrointestinal stromal tumors

Current research and treatment for gastrointestinal stromal tumors

PD‐1/PD‐L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway

Therapeutic strategies for wild-type gastrointestinal stromal tumor: is it different from KIT or PDGFRA-mutated GISTs?

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