Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.

George D. Demetri, Sant P. Chawla, Isabelle Ray-Coquard, Axel Le Cesne, Arthur P. Staddon, Mohammed M. Milhem, Nicolas Penel, Richard F. Riedel, Binh Bui-Nguyen, Lee D. Cranmer, Peter Reichardt, Emmanuelle Bompas, Thierry Alcindor, Daniel Rushing, Yang Song, Ruey Min Lee, Scot Ebbinghaus, Joseph E. Eid, John W. Loewy, Frank G. HaluskaPierre F. Dodion, Jean Yves Blay

Research output: Contribution to journalArticle

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Abstract

Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P <.001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Original languageEnglish (US)
Pages (from-to)2485-2492
Number of pages8
JournalJournal of Clinical Oncology
Volume31
Issue number19
DOIs
StatePublished - Jul 1 2013
Externally publishedYes

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Sirolimus
Sarcoma
Placebos
Drug Therapy
Disease-Free Survival
ridaforolimus
Stomatitis
Survival
Exanthema
Drug-Related Side Effects and Adverse Reactions
Drug Resistance
Hyperglycemia
Thrombocytopenia
Fatigue
Neoplasms
Pneumonia
Maintenance
Safety
Bone and Bones
Infection

ASJC Scopus subject areas

  • Medicine(all)

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Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. / Demetri, George D.; Chawla, Sant P.; Ray-Coquard, Isabelle; Le Cesne, Axel; Staddon, Arthur P.; Milhem, Mohammed M.; Penel, Nicolas; Riedel, Richard F.; Bui-Nguyen, Binh; Cranmer, Lee D.; Reichardt, Peter; Bompas, Emmanuelle; Alcindor, Thierry; Rushing, Daniel; Song, Yang; Lee, Ruey Min; Ebbinghaus, Scot; Eid, Joseph E.; Loewy, John W.; Haluska, Frank G.; Dodion, Pierre F.; Blay, Jean Yves.

In: Journal of Clinical Oncology, Vol. 31, No. 19, 01.07.2013, p. 2485-2492.

Research output: Contribution to journalArticle

Demetri, GD, Chawla, SP, Ray-Coquard, I, Le Cesne, A, Staddon, AP, Milhem, MM, Penel, N, Riedel, RF, Bui-Nguyen, B, Cranmer, LD, Reichardt, P, Bompas, E, Alcindor, T, Rushing, D, Song, Y, Lee, RM, Ebbinghaus, S, Eid, JE, Loewy, JW, Haluska, FG, Dodion, PF & Blay, JY 2013, 'Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.', Journal of Clinical Oncology, vol. 31, no. 19, pp. 2485-2492. https://doi.org/10.1200/JCO.2012.45.5766
Demetri, George D. ; Chawla, Sant P. ; Ray-Coquard, Isabelle ; Le Cesne, Axel ; Staddon, Arthur P. ; Milhem, Mohammed M. ; Penel, Nicolas ; Riedel, Richard F. ; Bui-Nguyen, Binh ; Cranmer, Lee D. ; Reichardt, Peter ; Bompas, Emmanuelle ; Alcindor, Thierry ; Rushing, Daniel ; Song, Yang ; Lee, Ruey Min ; Ebbinghaus, Scot ; Eid, Joseph E. ; Loewy, John W. ; Haluska, Frank G. ; Dodion, Pierre F. ; Blay, Jean Yves. / Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. In: Journal of Clinical Oncology. 2013 ; Vol. 31, No. 19. pp. 2485-2492.
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abstract = "Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95{\%} CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3{\%} decrease in target lesion size versus a 10.3{\%} increase with placebo (P <.001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95{\%} CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1{\%} v 25.6{\%}). Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.",
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AU - Ebbinghaus, Scot

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