Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors following progression with imatinib, sunitinib and regorafenib

Vincenzi, Bruno; Nannini, Margherita; Badalamenti, Giuseppe; Grignani, Giovanni; Fumagalli, Elena; Gasperoni, Silvia; D’Ambrosio, Lorenzo; Incorvaia, Lorena; Stellato, Marco; Ceruso, Mariella Spalato; Napolitano, Andrea; Valeri, Sergio; Santini, Daniele; Tonini, Giuseppe; Casali, Paolo G.; Tos, Angelo Paolo Dei; Pantaleo, Maria Abbondanza

doi:10.1177/1758835918794623

Cited by 31 publications

(18 citation statements)

References 27 publications

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“…Rechallenge with imatinib or sunitinib only provides a short duration of clinical benefit in some patients. Previous trials reported median progression-free survival and median time of progression of 1.8 and 5.4 months in retreated patients, respectively [ 18 , 19 ]. Systemic treatment with chemotherapy based on non-TKI, cytotoxic agents have proven ineffective in GIST in the pre-imatinib era when not any effective, targeted therapy was known for unresectable or metastatic GIST.…”

Section: Introductionmentioning

confidence: 99%

Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors

Wang

Woźniak

Wellens

et al. 2020

Translational Oncology

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The majority of patients with gastrointestinal stromal tumors (GIST) eventually become resistant with time due to secondary mutations in the driver receptor tyrosine kinase. Novel treatments that do not target these receptors may therefore be preferable. For the first time, we evaluated a tubulin inhibitor, plocabulin, in patient-derived xenograft (PDX) models of GIST, a disease generally considered to be resistant to cytotoxic agents. Three PDX models of GIST with different KIT genotype were generated by implanting tumor fragments from patients directly into nude mice. We then used these well characterized models with distinct sensitivity to imatinib to evaluate the efficacy of the novel tubulin inhibitor. The efficacy of the drug was assessed by volumetric analysis of the tumors, histopathology, immunohistochemistry and Western blotting. Plocabulin treatment led to extensive necrosis in all three models and significant tumor shrinkage in two models. This histological response can be explained by the drug's vascular-disruptive properties, which resulted in a shutdown of tumor vasculature, reflected by a decreased total vascular area in the tumor tissue. Our results demonstrated the in vivo efficacy of the novel tubulin inhibitor plocabulin in PDX models of GIST and challenge the established view that GIST are resistant to cytotoxic agents in general and to tubulin inhibitors in particular. Our findings provide a convincing rationale for early clinical exploration of plocabulin in GIST and warrant further exploration of this class of drugs in the management of this common sarcoma subtype.

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Section: Introductionmentioning

confidence: 99%

Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors

Wang

Woźniak

Wellens

et al. 2020

Translational Oncology

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“…This can be an explanation for the better activity of sunitinib in patients with peritoneal metastasis. Many studies indicate that dual inhibition of PDGFR and VEGFR from sunitinib produces greater antiangiogenic effects than inhibition of only one such as for imatinib, and the lower dimension and the homogeneous vascularization typical of the peritoneal metastasis, may contribute to better activity from sunitinib [22,23,24].…”

Section: Discussionmentioning

confidence: 99%

Predictive Factors of Response to Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs): A Multi-Institutional Study

Badalamenti¹,

Incorvaia²,

Vincenzi³

et al. 2019

Preprint

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Imatinib 400 mg is the standard of care for medical treatment of advanced GISTs. In the majority of cases, however, GISTs eventually develop resistance to imatinib. The optimal second line treatment has not been established yet and imatinib dose escalation (800 mg) or sunitinib represent two feasible options. The objective of this retrospective, multi-institutional, study is to analyze the validity of several parameters as possible predictive factors of response to sunitinib after imatinib failure. We reviewed 128 metastatic GISTs treated with sunitinib between January 2007 to June 2017. Primary tumour site, metastatic site, c-KIT/PDGFR-α mutational status, PET-FDG status and type of disease progression to sunitinib were assessed as possible predictive factors of response. This study identifies the gastric site of primary tumor as a predictive factor to sunitinib efficacy in second line setting. The mutational status (GIST WT), the site of metastasis (peritoneum) and the FDG-PET status (negative), although not statistically significant, seem to be elements of increased activity for sunitinib treatment. These results provide the rationale to drive physician for sunitinib choice in second line setting for metastatic GISTs, to improve patients selection and to maximize the benefit from the treatment, on the basis of possible predictive factors of response.

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“…Indeed, we recently showed that rechallenge with imatinib after combined treatment with sunitinib and regorafenib in advanced GIST is associated with clinically significant disease control rates. 10 …”

Section: A Translational Frameworkmentioning

confidence: 99%

Secondary KIT mutations: the GIST of drug resistance and sensitivity

Napolitano

Vincenzi

2019

Br J Cancer

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Summary Pharmacological targeting of KIT in gastrointestinal stromal tumours has dramatically changed the clinical outcome of this disease. Tyrosine kinase inhibitors are the cornerstone of this improvement, but resistance occurs through secondary KIT mutations. Studies aimed at improving our understanding of the molecular basis of sensitivity and resistance will soon allow us to further tailor our therapeutic strategies.

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Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors following progression with imatinib, sunitinib and regorafenib

Cited by 31 publications

References 27 publications

Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors

Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors

Predictive Factors of Response to Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumors (GISTs): A Multi-Institutional Study

Secondary KIT mutations: the GIST of drug resistance and sensitivity

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