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Clinical Trial
. 2013 Jan 10;31(2):195-202.
doi: 10.1200/JCO.2011.38.3331. Epub 2012 Dec 10.

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

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Clinical Trial

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 et al. J Clin Oncol. .
Free PMC article

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.

Trial registration: ClinicalTrials.gov NCT00083993.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
CONSORT flow diagram. AE, adverse event.
Fig 2.
Fig 2.
Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival. HR, hazard ratio; LET, letrozole; TEMSR, temsirolimus.
Fig 3.
Fig 3.
Kaplan-Meier estimates of progression-free survival by patient's age: (A) ≤ 65 years and (B) older than 65 years. HR, hazard ratio; LET, letrozole; TEMSR, temsirolimus.
Fig 4.
Fig 4.
STEPP analysis of the treatment effect of letrozole plus temsirolimus versus letrozole plus placebo as measured by (A) 5-month progression-free survival (PFS) and (B) difference (letrozole plus temsirolimus) – (letrozole plus placebo) in 5-month PFS with corresponding 95% pointwise CIs (dashed blue lines). The values on the x-axis indicate the median age for patients in each of the overlapping subpopulations. Each subpopulation contains approximately 200 patients and approximately 100 overlapping patients. (B) Solid horizontal black line indicates overall treatment effect, and dotted horizontal black line indicates no effect. A difference in 5-month PFS greater than 0 suggested letrozole plus temsirolimus treatment was better; otherwise, letrozole plus placebo was better (P = .003 represents the P value from the interaction test).

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