CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study

Cassier, Philippe; Italiano, Antoîne; Gomez‐Roca, Carlos; Tourneau, Christophe Le; Toulmonde, Maud; Cannarile, Michael A.; Ries, Carola H.; Brillouet, Anne; Müller, Claudia; Jegg, Anna-Maria; Bröske, Ann-Marie; Dembowski, Markus; Bray‐French, Katharine; Freilinger, Christine; Meneses-Lorente, Georgina; Baehner, Monika; Harding, Ross; Ratnayake, Jayantha; Abiraj, K.; Gass, Nathalie; Noh, Karen; Christen, Randolph D.; Ukarma, Lidia; Bompas, Emmanuelle; Delord, Jean‐Pierre; Blay, Jean‐Yves; Rüttinger, Dominik

doi:10.1016/s1470-2045(15)00132-1

Cited by 309 publications

(258 citation statements)

References 26 publications

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“…A number of clinical trials are currently investigating the use of CSF1R inhibitors in patients with TGCT, including tyrosine kinase inhibitors such as nilotinib [13,51] or PLX3397 [14], or monoclonal antibodies such as emactuzumab (also known as RG7155) [12]. An inhibitor of the CSF1 ligand, MSC110, is also under investigation.…”

Section: Targeted Therapymentioning

confidence: 99%

“…A phase II study of MSC110 in patients with TGCT (NCT01643850) is still recruiting patients, and efficacy and safety data have not yet been reported [15]. Data from phase I studies with PLX3397 (NCT01004861) and emactuzumab have been recently published, demonstrating impressive activity in TGCT, with 12/23 and 24/28 patients achieving an objective response, respectively, and only one patient progressing in each series [12,14]. The toxicity of these targeted agents is usually mild.…”

Section: Targeted Therapymentioning

confidence: 99%

“…The toxicity of these targeted agents is usually mild. Adverse events included facial oedema, asthenia, change in hair colour, nausea, dysgeusia, and periorbital oedema [12,14].…”

Section: Targeted Therapymentioning

confidence: 99%

“…Patients who complete part 1 will be eligible to advance to part 2, a long-term treatment phase in which all patients will receive open-label PLX3397 [52]. Future studies with emactuzumab, such as an international collaboration with cooperative groups to ensure appropriate recruitment in D-TGCT, are currently under development [12].…”

Section: Targeted Therapymentioning

confidence: 99%

See 3 more Smart Citations

Diffuse-type tenosynovial giant cell tumour: Current treatment concepts and future perspectives

Staals

Ferrari

Donati

et al. 2016

European Journal of Cancer

105

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Section: Targeted Therapymentioning

confidence: 99%

Section: Targeted Therapymentioning

confidence: 99%

“…The toxicity of these targeted agents is usually mild. Adverse events included facial oedema, asthenia, change in hair colour, nausea, dysgeusia, and periorbital oedema [12,14].…”

Section: Targeted Therapymentioning

confidence: 99%

Section: Targeted Therapymentioning

confidence: 99%

See 2 more Smart Citations

Diffuse-type tenosynovial giant cell tumour: Current treatment concepts and future perspectives

Staals

Ferrari

Donati

et al. 2016

European Journal of Cancer

105

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“…Currently, the most advanced approaches rely on TAM depletion via the inhibition of CSF-1/CSF-1R signaling, based on evidence that this axis is essential for macrophage survival. Recently, a phase I clinical trial using a CSF-1R-blocking mAb (RG7155) in patients with diffuse-type giant cell tumors (DT-GCT), a proliferative disease caused by overexpression of CSF-1 (20), yielded measurable clinical responses. These effects correlated with the depletion of TAM and an increase in CD8 þ T-cell infiltration.…”

Section: Macrophages As Therapeutic Targetsmentioning

confidence: 99%

A Milestone Review on How Macrophages Affect Tumor Growth

et al. 2016

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learning how macrophages exert distinct effects on tumor pathophysiology based on their response to the specific microenvironment of tumors that they rove. This review also helped popularize the nomenclature of tumor-associated macrophages, or TAM, now a widely understood moniker used broadly in the field. Key Messages from the ReviewTAM infiltration was already shown to correlate with poor prognosis of cancer patients. The central message of this seminal review from Drs. Lewis and Pollard was that different TAM populations coexist in tumor, in distinct microenvironments, including areas of invasion, where TAMs promote cancer cell motility, stromal and perivascular areas, where TAMs promote metastasis, and avascular and perinecrotic areas, where hypoxic TAM stimulate angiogenesis. In terms of phenotype and diversity, this review provided a highlight complementing the M1/M2 polarization model proposed by Mantovani and colleagues (2), where exposure to IL4 and IL10 in tumors induced type II polarized TAM (alternatively activated) or M2 macrophage development. Here, distinct TAM populations were described according to their localization in different zones of the tumors and associated functions. An important aspect of the work of Pollard's team was the use of the MMTV-PyMT-induced spontaneous mammary tumor model, allowing longitudinal analyses of TAM at different stages of tumor development, a model that is now used very widely in cancer biology, physiology, and pharmacology studies. Distinct contributions of TAM to malignant development discussed in the review are noted below. InvasionTAMs present in areas of basement membrane breakdown and invasion during early-stage lesion development produce upregulated levels of proteolytic enzymes (cathepsin B and matrix metalloproteinases) and promote directional movement and invasion of the tumor cells.

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