A randomised phase II trial of selumetinib vs selumetinib plus temsirolimus for soft-tissue sarcomas.

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.

• Authors: Z Eroglu, H A Tawbi, J Hu, M Guan, P H Frankel, N H Ruel, S Wilczynski, S Christensen, D R Gandara, W A Chow
• Journal: British journal of cancer (Br J Cancer) Vol. 112 Issue 10 Pg. 1644-51 (May 12 2015) ISSN: 1532-1827 [Electronic] England
• PMID: 25897676 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural)

Chemical References

• AZD 6244
• Benzimidazoles
• temsirolimus
• Sirolimus

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Benzimidazoles (administration & dosage, adverse effects)
• Disease-Free Survival
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Sarcoma (drug therapy)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives)
• Treatment Outcome
• Young Adult