Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer

Antonio C. Wolff, Ann A. Lazar, Igor Bondarenko, August M. Garin, Stephen Brincat, Louis Chow, Yan Sun, Zora Neskovic-Konstantinovic, Rodrigo C. Guimaraes, Pierre Fumoleau, Arlene Chan, Soulef Hachemi, Andrew Strahs, Maria Cincotta, Anna Berkenblit, Mizue Krygowski, Lih Lisa Kang, Laurence Moore, Daniel F. Hayes

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Abstract

Purpose: Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. Patients and Methods: This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor-positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). Results: Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). Conclusion: Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation.

Original languageEnglish (US)
Pages (from-to)196-202
Number of pages7
JournalJournal of Clinical Oncology
Volume31
Issue number2
DOIs
StatePublished - Jan 10 2013

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wolff, A. C., Lazar, A. A., Bondarenko, I., Garin, A. M., Brincat, S., Chow, L., Sun, Y., Neskovic-Konstantinovic, Z., Guimaraes, R. C., Fumoleau, P., Chan, A., Hachemi, S., Strahs, A., Cincotta, M., Berkenblit, A., Krygowski, M., Kang, L. L., Moore, L., & Hayes, D. F. (2013). Randomized phase III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in postmenopausal women with locally advanced or metastatic breast cancer. Journal of Clinical Oncology, 31(2), 196-202. https://doi.org/10.1200/JCO.2011.38.3331