Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study

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Abstract

BACKGROUND: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma.

METHODS: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response.

RESULTS: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively.

CONCLUSIONS: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

Original languageEnglish
Pages (from-to)4056-4063
Number of pages8
JournalCancer
Volume124
Issue number20
DOIs
Publication statusPublished - Oct 15 2018

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Chordoma
S 6
Disease-Free Survival
Phosphorylation
Platelet-Derived Growth Factor beta Receptor
Imatinib Mesylate
Everolimus
Clinical Studies
Survival
Sirolimus
Neoplasms
Western Blotting
Immunohistochemistry

Cite this

@article{e44b939b3b214769847204e2968f420f,
title = "Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study",
abstract = "BACKGROUND: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma.METHODS: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response.RESULTS: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9{\%}), 24 with stable disease (SD) (ORR, 55.8{\%}), and 7 with progressive disease (ORR, 16.3{\%}). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3{\%}), 37 stable disease (ORR, 86{\%}), and 4 progressive disease (ORR, 9.3{\%}). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8{\%} and 48.1{\%} of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5{\%} and 30.2{\%} of patients, respectively.CONCLUSIONS: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.",
author = "Silvia Stacchiotti and Carlo Morosi and {Lo Vullo}, Salvatore and Alessandra Casale and Elena Palassini and Frezza, {Anna Maria} and Gabriella Dinoi and Antonella Messina and Alessandro Gronchi and Adalberto Cavalleri and Elisabetta Venturelli and Daniele Morelli and Silvana Pilotti and Paola Collini and Silvia Brich and Elena Tamborini and Luigi Mariani and Casali, {Paolo G}",
note = "{\circledC} 2018 American Cancer Society.",
year = "2018",
month = "10",
day = "15",
doi = "10.1002/cncr.31685",
language = "English",
volume = "124",
pages = "4056--4063",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "20",

}

TY - JOUR

T1 - Imatinib and everolimus in patients with progressing advanced chordoma

T2 - A phase 2 clinical study

AU - Stacchiotti, Silvia

AU - Morosi, Carlo

AU - Lo Vullo, Salvatore

AU - Casale, Alessandra

AU - Palassini, Elena

AU - Frezza, Anna Maria

AU - Dinoi, Gabriella

AU - Messina, Antonella

AU - Gronchi, Alessandro

AU - Cavalleri, Adalberto

AU - Venturelli, Elisabetta

AU - Morelli, Daniele

AU - Pilotti, Silvana

AU - Collini, Paola

AU - Brich, Silvia

AU - Tamborini, Elena

AU - Mariani, Luigi

AU - Casali, Paolo G

N1 - © 2018 American Cancer Society.

PY - 2018/10/15

Y1 - 2018/10/15

N2 - BACKGROUND: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma.METHODS: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response.RESULTS: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively.CONCLUSIONS: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

AB - BACKGROUND: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma.METHODS: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response.RESULTS: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively.CONCLUSIONS: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

U2 - 10.1002/cncr.31685

DO - 10.1002/cncr.31685

M3 - Article

C2 - 30216418

VL - 124

SP - 4056

EP - 4063

JO - Cancer

JF - Cancer

SN - 0008-543X

IS - 20

ER -