Abstract P4-22-13: Everolimus plus trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: Overall survival results from BOLERO-1

Abstract

Background Everolimus (EVE), an mTOR inhibitor has shown activity in HER2+ advanced breast cancer (ABC) in both preclinical and clinical studies. In the pivotal BOLERO-1 trial (NCT00876395), the progression-free survival (PFS) was not significantly different between the EVE + trastuzumab (TRAS) + paclitaxel (PAC) combination and placebo (PBO) + TRAS + PAC in the full HER2+ population (EVE, 15.0 mo vs PBO, 14.5 mo; HR=0.89; 95% CI: 0.73-1.08; p=0.1166). Although not reaching protocol defined level for statistical significance, the hormone receptor negative (HR-) subpopulation appeared to benefit from EVE, with a 7.2 mo PFS benefit vs PBO arm (EVE, 20.3 mo vs PBO, 13.1 mo; HR=0.66; 95% CI: 0.48-0.91; p=0.0049). The final exploratory overall survival (OS) analysis from the study is presented here. Methods In this phase 3 randomized trial, 719 women with HER2+ ABC without prior TRAS or chemotherapy in the metastatic setting were randomized 2:1 to receive either EVE (10 mg/d) or placebo (PBO) and weekly PAC+TRAS, stratified by visceral metastasis (lung, liver, peritoneal or pleural: yes vs no) and prior adjuvant or neo-adjuvant treatment with TRAS (yes vs no). As the primary objectives (PFS on full population and on HR- subpopulation) of BOLERO-1 were not met, the key secondary endpoint of OS was not formally statistically tested. However, given the results of PFS, in particular in the HR- subpopulation, a change to the OS analysis plan was made by introducing one final exploratory OS analysis at the time of study termination. Results At data cutoff (Dec 31, 2015), the median duration of exposure was 40.8 weeks (range: 0.6-320.4) in the EVE arm and 48.1 weeks (range: 1.1-308.0) in the PBO arm. After a median follow-up of 60.3 mo, 350 deaths were recorded in the full population, 238 (49.6%) in the EVE arm and 112 (46.9%) pts in the PBO arm. In the full population, the median OS was comparable in the EVE vs PBO arms (48.6 mo vs 50.0 mo respectively; HR = 1.13; 95% CI: 0.90-1.42). In the HR- subpopulation, 138 deaths were recorded; 88 (42.3%) pts in the EVE arm and 50 (48.5%) pts in the PBO arm. In the HR- subpopulation, the median OS in the EVE arm was longer compared to PBO arm (57.0 mo vs 41.6 mo respectively; HR = 0.83; 95% CI: 0.59-1.18). Stomatitis, diarrhea, alopecia, cough, rash, pyrexia, neutropenia, and fatigue were the most frequent adverse events (AEs) reported in EVE arm (≥35%). AEs leading to dose interruption and/or change were reported in 441 (93.4%) pts in EVE arm and 165 (69.3%) pts in the PBO arm respectively. Overall, AEs leading to treatment discontinuation were reported in 262 (55.5%) pts in EVE arm and 98 (41.2%) pts in PBO arm. Serious AEs were reported in 171 (36.2%) pts in the EVE arm and 40 (16.8%) pts in the PBO arm respectively. On treatment AE related deaths were reported for 3.6% pts in the EVE arm and 0% pts in the PBO arm. Conclusions The median OS was similar in the EVE vs PBO arms for overall population. However, a prolongation of 15.4 mo in median OS of HR- subpopulation was observed in the EVE arm vs PBO arm in this exploratory analysis. Pts in the EVE arm had a manageable safety, consistent with the safety profile of EVE and no new safety signals were identified. Citation Format: Yardley D, Hurvitz S, Jiang Z-f, Toi M, Burris H, Buyse M, Slamon D, Makhson A, Elsaid A, Lerzo G, Hellerstedt B, Nuzzo F, Sohn J, Manzyuk L, Cabaribere D, Lincy J, Weimann A, Noel-Baron F, Pacaud L, Andre F. Everolimus plus trastuzumab and paclitaxel as first-line therapy in women with HER2+ advanced breast cancer: Overall survival results from BOLERO-1 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-13.

<p>Efficacy and safety of targeted therapy for metastatic HER2-positive breast cancer in the first-line treatment: a Bayesian network meta-analysis</p>

“…The MARIANNE trial, a three-arm study, reported the PFS or OS,27,28 while the other trials were two-arm studies. Seven publications have explicitly reported the data both PFS and OS in one study,8,13,15,29–32 and the other six publications only mention one of the two indicators 9–12,27,28. The ORR and common AEs (hematologic toxicity and cardiac safety) were abstracted from the publications included.…”

“…Other dual anti-HER2 regimens, ETP and T-DM1+Pzmb, were also used to treat MBC but with no satisfactory result. There were no statistical differences in the PFS, OS, and ORR regarding the standard TP regimen (trastuzumab and taxane) for MBC, although the hormone receptor status of patients had an effect 12. T-DM1 is recommended as a second-line or further-line treatment 37…”

“…CLEOPATRA9,10 indicated that trastuzumab plus docetaxel in addition to pertuzumab compared with trastuzumab plus docetaxel improved the median progression-free survival (PFS) by 6.1 months and the median OS. In another dual target therapy trial BOLERO, the addition of everolimus was based on trastuzumab and docetaxel not prolonging the PFS or OS 11,12. Unsatisfied with the present outcome of the mono and dual target HER2 regimens, other anti-HER2 agents trials were designed, including trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab that significantly improved PFS with a similar OS and favorable safety among the patients with HER-2 positive metastatic breast cancer (MBC), compared with trastuzumab plus docetaxel 13.…”

“…Unsatisfied with the present outcome of the mono and dual target HER2 regimens, other anti-HER2 agents trials were designed, including trastuzumab emtansine (T-DM1), an antibody–drug conjugate of trastuzumab that significantly improved PFS with a similar OS and favorable safety among the patients with HER-2 positive metastatic breast cancer (MBC), compared with trastuzumab plus docetaxel 13. A semblable meta-analysis showed that trastuzumab and docetaxel plus pertuzumab (TDP) may be the preferred regimen for HER-2-positive MBC14 but was not included in the NEfERT-T15 and the BOLERO-1 trials 11,12. Neratinib, an oral small-molecule tyrosine kinase inhibitor of ERBB1, ERBB2, and ERBB4,16 plus paclitaxel compared with trastuzumab–paclitaxel showed the similar outcomes in the PFS (12.9 vs 12.9 months) and OS.…”

Current Therapies for Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Patients

“…However, it showed less encouraging results in two large phase III trials in HER2-positive MBC (BOLERO-1 and BOLERO-3). BOLERO-1, which studied addition of everolimus to trastuzumab + taxanes in first line metastatic treatment, reported that everolimus was associated with increased toxicity without any improvement in either PFS or OS ( 129 , 130 ). BOLERO-3 tested addition of everolimus to trastuzumab + vinorelbine in second line metastatic treatment for patients previously exposed to trastuzumab and taxanes.…”