Abstract
Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ≤2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1644-1651 |
| Number of pages | 8 |
| Journal | British Journal of Cancer |
| Volume | 112 |
| Issue number | 10 |
| DOIs | |
| State | Published - May 12 2015 |
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Keywords
- leiomyosarcoma
- selumetinib
- soft-tissue sarcomas
- temsirolimus
ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas. / Eroglu, Z.; Tawbi, H. A.; Hu, J.; Guan, M.; Frankel, P. H.; Ruel, N. H.; Wilczynski, S.; Christensen, Scott D; Gandara, David R; Chow, W. A.
In: British Journal of Cancer, Vol. 112, No. 10, 12.05.2015, p. 1644-1651.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas
AU - Eroglu, Z.
AU - Tawbi, H. A.
AU - Hu, J.
AU - Guan, M.
AU - Frankel, P. H.
AU - Ruel, N. H.
AU - Wilczynski, S.
AU - Christensen, Scott D
AU - Gandara, David R
AU - Chow, W. A.
PY - 2015/5/12
Y1 - 2015/5/12
N2 - Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ≤2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
AB - Background:The MEK inhibitor, selumetinib, suppresses soft-tissue sarcoma (STS) cell proliferation in vitro. Mammalian target of rapamycin inhibitors possess modest activity against STS; however, resistance develops via MAPK pathway feedback activation. The combination of selumetinib and temsirolimus synergistically inhibits STS cell line growth. Therefore, a randomized phase II trial of selumetinib vs selumetinib plus temsirolimus was conducted.Methods:Seventy-one adults with advanced STS who received ≤2 prior chemotherapeutics were randomized to selumetinib 75 mg p.o. bid and allowed to crossover upon progression, or to selumetinib 50 mg p.o. bid plus temsirolimus 20 mg i.v. weekly, with primary endpoint of progression-free survival (PFS).Results:There was no difference in PFS between the two arms for the overall cohort (median 1.9 vs 2.1 months); an improved median PFS was observed in the combination arm (N=11) over single agent (N=10) in the prespecified leiomyosarcoma stratum (median 3.7 vs 1.8 months; P=0.01). Four-month PFS rate was 50% (95% confidence interval 0.19-0.81) with the combination vs 0% with selumetinib alone in the leiomyosarcoma cohort. Most common grade 3/4 adverse events with the combination were mucositis (29%), lymphopenia (26%), neutropenia and anaemia (20% each).Conclusions:While single-agent selumetinib has no significant activity in STS, the combination may be active for leiomyosarcomas.
KW - leiomyosarcoma
KW - selumetinib
KW - soft-tissue sarcomas
KW - temsirolimus
UR - http://www.scopus.com/inward/record.url?scp=84929274022&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929274022&partnerID=8YFLogxK
U2 - 10.1038/bjc.2015.126
DO - 10.1038/bjc.2015.126
M3 - Article
C2 - 25897676
AN - SCOPUS:84929274022
VL - 112
SP - 1644
EP - 1651
JO - British Journal of Cancer
JF - British Journal of Cancer
SN - 0007-0920
IS - 10
ER -