Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial

Heinrich, Michael C.; Jones, Robin L.; Mehren, Margaret von; Schöffski, Patrick; Serrano, César; Kang, Yoon Koo; Cassier, Philippe; Mir, Olivier; Eskens, Ferry A.L.M.; Tap, William D.; Rutkowski, Piotr; Chawla, Sant P.; Trent, Jonathan C.; Tugnait, Meera; Evans, Erica; Lauz, Tamieka; Zhou, Teresa; Roche, Maria; Wolf, Beni B.; Bauer, Sebastian; George, Suzanne

doi:10.1016/s1470-2045(20)30269-2

Cited by 215 publications

(194 citation statements)

References 24 publications

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“…An increased understanding of GIST biology has revealed clear heterogeneity among the molecular subtypes and a corresponding need for novel therapeutics to target subtypespecific GIST. Recently, this has been borne out with the success of avapritinib in the treatment of PDGFRA D842V-mutant GIST, prompting FDA approval of avapritinib as front-line therapy for this subtype in the unresectable or metastatic setting (12). While the application of inhibitors targeting the primary mutant isoforms of KIT and PDGFRA has revolutionized the treatment of GIST, acquired resistance remains a significant clinical challenge.…”

Section: Discussionmentioning

confidence: 99%

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Sharipova

Kozinova

et al. 2020

Preprint

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Gastrointestinal stromal tumor (GIST) management has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of receptor tyrosine kinase (RTK) inhibitors in advanced disease. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GIST, resistance remains a significant clinical obstacle.Development of effective strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from the three most common molecular subtypes to identify novel kinase targets. Kinome profiling revealed distinct signatures in GIST subtypes.PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT and PDGFRA-mutant GIST cell lines, and notable efficacy of MK-1775 as a monotherapy in the PDGFRA-mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

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Section: Discussionmentioning

confidence: 99%

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Sharipova

Kozinova

et al. 2020

Preprint

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“…It is considered the gold-standard treatment for advanced GIST with D842V mutation. Different doses of daily avapritinib (300 mg and 400 mg) were tested in the phase I trial NAVIGATOR, which included 56 patients with advanced D842V-mutated GIST [ 223 ]. The reported response rate was 88% and the 2-years OS rate was 81%.…”

Section: Tyrosine Kinase Receptor Inhibitors Developed For Cancer mentioning

confidence: 99%

Tyrosine Kinase Receptors in Oncology

Esteban-Villarrubia

Castillo

Pozas

et al. 2020

IJMS

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Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

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“…In a phase 1 trial [64], 56 patients with a PDGFRA D842V mutation received avapritinib at a starting dose of 400 mg daily, which eventually because of toxicity, was reduced to 300 mg daily. The efficacy results are impressive, with the primary endpoint overall response rate being met in 87.5% of the patients.…”

Section: Avapritinibmentioning

confidence: 99%

Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib

Mohammadi

Gelderblom

2020

Expert Opinion on Investigational Drugs

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Introduction: Discovery of oncogenic mutations in the KIT and PDGFRA tyrosine kinase receptor was a crucial step for the development of tyrosine kinase inhibitors (TKIs). Since then, GIST became a model for the development of molecular-targeted therapy, which led to dramatically improved median overall survival of advanced GIST. Still, further progress is needed after third-line or for TKI resistant mutations. Areas covered: In this review, after a brief introduction on imatinib, sunitinib, and regorafenib, an overview of TKIs that was evaluated beyond these drugs is provided, with a main focus on the novel approved TKIs. Expert opinion: Combination therapies have thus far not fulfilled their promise in GIST, nor did immunotherapy. Increased understanding of GIST and advances in the development of moleculartargeted drugs led to the introduction of ripretinib and avapritinib. Furthermore, NTRK inhibitors became available for ultrarare NTRK fusions. Solutions for NF1 and BRAF mutated and SDH-deficient GIST are still to be awaited. This all underlines the need for adequate molecular profiling of high-risk GISTs before treatment is started. Possibly by using circulating tumor DNA in the future, targeting resistance mutations with specific drugs along the course of the disease would be easier, avoiding multiple tumor biopsies.

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Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial

Cited by 215 publications

References 24 publications

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Identification of Wee1 as Target in Combination with Avapritinib for the Treatment of Gastrointestinal Stromal Tumor

Tyrosine Kinase Receptors in Oncology

Systemic therapy of advanced/metastatic gastrointestinal stromal tumors: an update on progress beyond imatinib, sunitinib, and regorafenib

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