Molecular targeted therapies in advanced or metastatic chordoma patients: Facts and hypotheses

Lebellec, Loïc; Aubert, Sébastien; Zaïri, Fahed; Ryckewaert, Thomas; Chauffert, Bruno; Penel, Nicolas

doi:10.1016/j.critrevonc.2015.01.010

Cited by 27 publications

(24 citation statements)

References 30 publications

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“…These results are again superimposable to what was observed in the Phase II trial. The difficulty in the assessment of activity and response to molecular-targeted therapies is an issue in chordoma, as highlighted also in a recent systematic review, and an important pitfall in the eventuality of future clinical trials [9]. It has been already underlined that RECIST [6,10] are not fully adequate to detect response in chordoma treated with imatinib.…”

Section: Discussionmentioning

confidence: 97%

Imatinib in advanced chordoma: A retrospective case series analysis

Hindi

Casali

Morosi

et al. 2015

European Journal of Cancer

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Section: Discussionmentioning

confidence: 97%

Imatinib in advanced chordoma: A retrospective case series analysis

Hindi

Casali

Morosi

et al. 2015

European Journal of Cancer

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“…Imatinib, an inhibitor of platelet-derived growth factor receptor (PDGFR), has demonstrated limited activity in a phase II study and when used in a compassionate programme [6,7]. However, there are encouraging results, in the form of anecdotal reports, on the response of chordoma to epidermal growth factor receptor (EGFR) [8][9][10][11][12][13] and vascular endothelial growth factor (VEGF) inhibitors [5,[12][13][14], although data from prospective randomized clinical trials are lacking [5,14].…”

Section: Introductionmentioning

confidence: 99%

EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen

et al. 2016

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Chordoma is a rare malignant bone tumour with a poor prognosis and limited therapeutic options. We undertook a focused compound screen (FCS) against 1097 compounds on three well‐characterized chordoma cell lines; 154 compounds were selected from the single concentration screen (1 µm), based on their growth‐inhibitory effect. Their half‐maximal effective concentration (EC50) values were determined in chordoma cells and normal fibroblasts. Twenty‐seven of these compounds displayed chordoma selective cell kill and 21/27 (78%) were found to be EGFR/ERBB family inhibitors. EGFR inhibitors in clinical development were then studied on an extended cell line panel of seven chordoma cell lines, four of which were sensitive to EGFR inhibition. Sapitinib (AstraZeneca) emerged as the lead compound, followed by gefitinib (AstraZeneca) and erlotinib (Roche/Genentech). The compounds were shown to induce apoptosis in the sensitive cell lines and suppressed phospho‐EGFR and its downstream pathways in a dose‐dependent manner. Analysis of substituent patterns suggested that EGFR‐inhibitors with small aniline substituents in the 4‐position of the quinazoline ring were more effective than inhibitors with large substituents in that position. Sapitinib showed significantly reduced tumour growth in two xenograft mouse models (U‐CH1 xenograft and a patient‐derived xenograft, SF8894). One of the resistant cell lines (U‐CH2) was shown to express high levels of phospho‐MET, a known bypass signalling pathway to EGFR. Neither amplifications (EGFR, ERBB2, MET) nor mutations in EGFR, ERBB2, ERBB4, PIK3CA, BRAF, NRAS, KRAS, PTEN, MET or other cancer gene hotspots were detected in the cell lines. Our findings are consistent with the reported (p‐)EGFR expression in the majority of clinical samples, and provide evidence for exploring the efficacy of EGFR inhibitors in the treatment of patients with chordoma and studying possible resistance mechanisms to these compounds in vitro and in vivo. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Natural history of chordoma is very slow and the gain of PFS described with molecular targeted therapy like sorafenib might be due to the indolent course of disease. Randomization is required to clearly identify the drug activity (predictive factor) and the natural history of the disease (prognostic) [5, 28]. The current phase II trial assessing regorafenib and conducted by the French Sarcoma Group is a randomized phase II trial placebo versus regorafenib (NCT02389244).…”

Section: Discussionmentioning

confidence: 99%

“…Up to now, there is no standard systemic therapy: conventional chemotherapy is regarded as an inappropriate option [1]; molecularly targeted therapies, particularly imatinib, are often used in first line, despite a low level of evidence based on several phase II trials [5]. As for other very rare cancers, few prospective series testing innovative treatment have been performed…”

Section: Introductionmentioning

confidence: 99%

Circulating vascular endothelial growth factor (VEGF) as predictive factor of progression-free survival in patients with advanced chordoma receiving sorafenib: an analysis from a phase II trial of the french sarcoma group (GSF/GETO)

et al. 2016

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BackgroundPatients with advanced chordoma are often treated with tyrosine kinase inhibitors without any predictive factor to guide decision. We report herein an ancillary analysis of the the Angionext phase II trial (NCT 00874874).ResultsFrom May 2011 to January 2014, 26 were sampled. The 9-month PFS rate was 72.9% (95%-CI: 45.9-87.9). During sorafenib treatment, a significant increase in PlGF (18.4 vs 43.8 pg/mL, p<0.001) was noted along with a non-significant increase in VEGF (0.7 vs 1.0 ng/mL, p=0.07). VEGF at D1 >1.04 ng/mL (HR=12.5, 95%-CI: 1.37-114, p=0.025) and VEGF at D7 >1.36 ng/mL (HR=10.7, 95%-CI: 1.16-98, p=0.037) were associated with shorter PFS. The 9-month PFS rate was 92.3% (95%-CI: 56.6-98.9) when VEGF at D1 was ≤1.04 ng/mL versus 23.3% (95%-CI: 1.0-63.2) when >1.04 ng/mL.Patients and MethodsChordoma patients were treated with sorafenib 800 mg/day for 9 months, unless earlier occurrence of progression or toxicities. Six biomarkers (sE-Selectin, VEGF, VEGF-C, placental growth factor (PlGF), Thrombospondin, Stem Cell Factor (SCF)) were measured at baseline (day 1: D1) and day 7 (D7).ConclusionHigh levels of VEGF was associated with poor outcome.

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Molecular targeted therapies in advanced or metastatic chordoma patients: Facts and hypotheses

Cited by 27 publications

References 30 publications

Imatinib in advanced chordoma: A retrospective case series analysis

Imatinib in advanced chordoma: A retrospective case series analysis

EGFR inhibitors identified as a potential treatment for chordoma in a focused compound screen

Circulating vascular endothelial growth factor (VEGF) as predictive factor of progression-free survival in patients with advanced chordoma receiving sorafenib: an analysis from a phase II trial of the french sarcoma group (GSF/GETO)

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