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A B S T R A C T PurposeRecent 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 MethodsThis 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). ResultsPatients 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 ϭ .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients Յ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P ϭ .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P ϭ .003). ConclusionAdding 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.

Translational RelevancePre-/perimenopausal patients with hormone-receptor positive (HR+)/human epithelial growth factor 2 negative (HER2-) advanced breast cancer (ABC) typically have a poorer prognosis and are under-represented in clinical trials. MONALEESA-7 is a phase 3 trial that studied ribociclib plus endocrine therapy (ET) versus placebo plus ET and dedicated specifically to peri-/premenopausal patients with HR+/HER2-ABC. The final protocol-specified overall survival (OS) analysis of MONALEESA-7 demonstrated a statistically significant OS benefit with ribociclib, however, outcomes can change over time, requiring prolonged observation to account for this disease's long natural history.An exploratory OS analysis of MONALEESA-7 with an extended follow-up (median, 53.5 months) was conducted revealing a median OS of 58.7 months in the ribociclib group versus 48.0 months in the placebo group (hazard ratio, 0.76; 95% CI, 0.61-0.96) with no new safety signals observed. These results show that ribociclib + ET continued to demonstrate OS benefit in pre-/perimenopausal patients long term.Research.

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