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

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.

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116TiP MONALEESA-7: a phase III, randomized, double-blind, placebo-controlled study of ribociclib (LEE011) combined with standard first-line endocrine therapy (ET) for the treatment of premenopausal women with HR +, HER2– advanced breast cancer (aBC)

Annals of Oncology ◽

10.1093/annonc/mdv519.65 ◽

2015 ◽

Vol 26 ◽

pp. ix16 ◽

Cited By ~ 1

Author(s):

S.-A. Im ◽

L. Chow ◽

Z. Shao ◽

D. Tripathy ◽

A. Bardia ◽

...

Keyword(s):

Breast Cancer ◽

Advanced Breast Cancer ◽

Endocrine Therapy ◽

Premenopausal Women ◽

Advanced Breast ◽

Phase Iii ◽

Controlled Study ◽

First Line ◽

Double Blind ◽

Double Blind Placebo

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Phase III Study of Letrozole Versus Tamoxifen as First-Line Therapy of Advanced Breast Cancer in Postmenopausal Women: Analysis of Survival and Update of Efficacy From the International Letrozole Breast Cancer Group

Journal of Clinical Oncology ◽

10.1200/jco.2003.04.194 ◽

2003 ◽

Vol 21 (11) ◽

pp. 2101-2109 ◽

Cited By ~ 531

Author(s):

Henning Mouridsen ◽

Mikhail Gershanovich ◽

Yan Sun ◽

Ramón Pérez-Carrión ◽

Corrado Boni ◽

...

Keyword(s):

Breast Cancer ◽

Advanced Breast Cancer ◽

Postmenopausal Women ◽

Endocrine Therapy ◽

Advanced Breast ◽

Phase Iii ◽

Karnofsky Performance Score ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Purpose: To analyze overall survival (OS) and update efficacy data for letrozole versus tamoxifen as first-line therapy in postmenopausal women with locally advanced or metastatic breast cancer. Patients and Methods: This multicenter phase III trial randomly assigned 916 patients with hormone receptor–positive or unknown tumors letrozole 2.5 mg (n = 458) or tamoxifen 20 mg (n = 458) daily until disease progression. Optional cross-over was permitted at the treating physician’s discretion. This report updates efficacy at a median follow-up of 32 months. Results: The superiority of letrozole to tamoxifen was confirmed for time to progression (median, 9.4 v 6.0 months, respectively; P < .0001), time to treatment failure (median, 9 v 5.7 months, respectively; P < .0001), overall objective response rate (32% v 21%, respectively; P = .0002), and overall clinical benefit. Median OS was slightly prolonged for the randomized letrozole arm (34 v 30 months, respectively). Although this difference in OS is not significant, survival was improved in the randomized letrozole arm over the first 2 years of the study. Approximately one half of the patients in each arm crossed over. Total duration of endocrine therapy (“time to chemotherapy”) was significantly longer (P = .005) for patients initially on letrozole (median, 16 months) than for patients initially on tamoxifen (median, 9 months). Time to worsening of Karnofsky performance score was significantly delayed with letrozole compared with tamoxifen (P = .001). Conclusion: This study documents the superiority of letrozole over tamoxifen in first-line endocrine therapy in postmenopausal women with advanced breast cancer.

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Phase III, randomized study of first-line trastuzumab emtansine (T-DM1) ± pertuzumab (P) vs. trastuzumab + taxane (HT) treatment of HER2-positive MBC: Final overall survival (OS) and safety from MARIANNE.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.1003 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 1003-1003 ◽

Cited By ~ 4

Author(s):

Edith A. Perez ◽

Carlos H. Barrios ◽

Wolfgang Eiermann ◽

Masakazu Toi ◽

Young-Hyuck Im ◽

...

Keyword(s):

Breast Cancer ◽

Advanced Breast Cancer ◽

Locally Advanced ◽

Advanced Breast ◽

Phase Iii ◽

First Line ◽

Primary Analysis ◽

Her2 Positive ◽

Grade 3

1003 Background: In MARIANNE (NCT01120184), patients with HER2-positive advanced breast cancer were randomized to trastuzumab + docetaxel or paclitaxel (HT; n=365), T-DM1 + placebo (T-DM1; n=367), or T-DM1 + P (T-DM1 + P; n=363) as first-line therapy. In the primary analysis, T-DM1–based treatment exhibited noninferior, but not superior, progression-free survival relative to HT (Perez EA, et al. J Clin Oncol 2016). OS was similar between treatments in the first interim analysis. Here we report OS from the final descriptive analysis. Methods: Enrolled patients had centrally assessed HER2-positive (IHC3+ or ISH+) progressive/recurrent locally advanced breast cancer or previously untreated MBC with a ≥6-month interval since (neo)adjuvant treatment with taxanes or vinca alkaloids. Results: At the clinical cutoff date of May 15, 2016, median follow-up was 54 months and 512 patients had died. Median OS was 50.9, 53.7, and 51.8 months with HT, T-DM1, and T-DM1 + P, respectively (Table). A sensitivity analysis in which HT-treated patients who received T-DM1 and/or P after disease progression (n=85) were censored prior to treatment switch found similar results. There were numerically fewer grade ≥3 adverse events (AEs) with T-DM1. Conclusions: With this longer follow-up, the T-DM1 safety profile was consistent with the primary analysis and prior experience. While OS was similar across treatment arms, a median OS of 53.7 months and fewer grade ≥3 AEs (vs other arms) supports T-DM1 as an effective and tolerable alternative first-line treatment for HER2-positive MBC patients. Clinical trial information: NCT01120184. [Table: see text]

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