Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial

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• 作者：Prof Fabrice André ; MD^a ; Prof Ruth O'Regan ; MD^b ; Prof Mustafa Ozguroglu ; MD^c ; Prof Masakazu Toi ; MD^d ; Prof Binghe Xu ; MD^e ; Prof Guy Jerusalem ; MD^f ; Norikazu Masuda ; MD^g ; Sharon Wilks ; MD^h ; Francis Arena ; MDⁱ ; Prof Claudine Isaacs ; MD^j ; Yoon-Sim Yap ; MD^k ; Zsuzsanna Papai ; MD^l ; Prof Istvan Lang ; MD^m ; Anne Armstrong ; MDⁿ ; Guillermo Lerzo ; MD^o ; Michelle White ; MD^p ; ^q ; Prof Kunwei Shen ; MD^r ; Jennifer Litton ; MD^s ; David Chen ; PhD^t ; Yufen Zhang ; PhD^t ; Shyanne Ali^t ; Tetiana Taran ; MD^t ; Dr Luca Gianni ; MD^u ; ^{gianni.luca@hsr.it" class="auth_mail}
• 刊名：Lancet Oncology
• 出版年：May 2014
• 年：2014
• 卷：15
• 期：6
• 页码：580-591
• 全文大小：413 K

文摘

Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway. We aimed to assess whether the addition of the mTOR inhibitor everolimus to trastuzumab might restore sensitivity to trastuzumab.

Methods

In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited women with HER2-positive, trastuzumab-resistant, advanced breast carcinoma who had previously received taxane therapy. Eligible patients were randomly assigned (1:1) using a central patient screening and randomisation system to daily everolimus (5 mg/day) plus weekly trastuzumab (2 mg/kg) and vinorelbine (25 mg/m²) or to placebo plus trastuzumab plus vinorelbine, in 3-week cycles, stratified by previous lapatinib use. The primary endpoint was progression-free survival (PFS) by local assessment in the intention-to-treat population. We report the final analysis for PFS; overall survival follow-up is still in progress. This trial is registered with ClinicalTrials.gov, number NCT01007942.

Findings

Between Oct 26, 2009, and May 23, 2012, 569 patients were randomly assigned to everolimus (n=284) or placebo (n=285). Median follow-up at the time of analysis was 20·2 months (IQR 15·0–27·1). Median PFS was 7·00 months (95% CI 6·74–8·18) with everolimus and 5·78 months (5·49–6·90) with placebo (hazard ratio 0·78 [95% CI 0·65–0·95]; p=0·0067). The most common grade 3–4 adverse events were neutropenia (204 [73%] of 280 patients in the everolimus group vs 175 [62%] of 282 patients in the placebo group), leucopenia (106 [38%] vs 82 [29%]), anaemia (53 [19%] vs 17 [6%]), febrile neutropenia (44 [16%] vs ten [4%]), stomatitis (37 [13%] vs four [1%]), and fatigue (34 [12%] vs 11 [4%]). Serious adverse events were reported in 117 (42%) patients in the everolimus group and 55 (20%) in the placebo group; two on-treatment deaths due to adverse events occurred in each group.

Interpretation

The addition of everolimus to trastuzumab plus vinorelbine significantly prolongs PFS in patients with trastuzumab-resistant and taxane-pretreated, HER2-positive, advanced breast cancer. The clinical benefit should be considered in the context of the adverse event profile in this population.

Funding

Novartis Pharmaceuticals Corporation.