Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 99-99 ◽  
Author(s):  
Francis P. Arena ◽  
Shinzaburo Noguchi ◽  
Kathleen I. Pritchard ◽  
Howard A. Burris ◽  
Hope S. Rugo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Aromatase Inhibitor ◽  
Postmenopausal Women ◽  
Survival Data ◽  
Safety Data ◽  
Phase Iii ◽  
Once Daily ◽  
Estrogen Receptor Positive

99 Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing EVE (10 mg once daily) + EXE (25 mg once daily) vs. placebo (PBO) + EXE in postmenopausal women with advanced estrogen-receptor–positive BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate. Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR], 0.43; P < .0001) and 7.4 mo (HR, 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced estrogen-receptor–positive BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.

Everolimus for postmenopausal women with advanced breast cancer: Updated results of the BOLERO-2 phase III trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 559-559 ◽  
Author(s):  
Martine J. Piccart-Gebhart ◽  
Shinzaburo Noguchi ◽  
Kathleen I. Pritchard ◽  
Howard A. Burris ◽  
Hope S. Rugo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitor ◽  
Postmenopausal Women ◽  
Survival Data ◽  
Treatment Options ◽  
Safety Data ◽  
Phase Iii ◽  
Double Blind ◽  
Once Daily

559 Background: Current treatment options for postmenopausal patients with estrogen-receptor–positive (ER+) breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. The BOLERO-2 trial supports the activity of everolimus (EVE; an oral mammalian target of rapamycin [mTOR] inhibitor) added to the steroidal aromatase inhibitor exemestane (EXE) to prolong progression-free survival (PFS) in this patient population. Long-term PFS and survival data are awaited. Methods: BOLERO-2 is a phase III double-blind, randomized, international trial comparing EVE (10 mg once daily) plus EXE (25 mg once daily) versus placebo (PBO) plus EXE in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs (letrozole or anastrozole). Patients were randomized (2:1) to EVE + EXE or PBO + EXE. The primary endpoint was PFS by local investigator assessment. Main secondary endpoints included centrally assessed PFS, overall survival (OS), safety, bone turnover, and overall response rate (ORR). Results: Baseline disease characteristics including tumor burden and prior cancer therapy were well balanced between treatment arms (N = 724). Median PFS was doubled and response rates were consistently improved with EVE + EXE (n = 485) vs PBO + EXE (n = 239) in interim analyses. Median PFS by local assessment was ~3 mo with PBO + EXE vs 6.9 mo (hazard ratio [HR] = 0.43; P < .0001) and 7.4 mo (HR = 0.44; P < .0001) with EVE + EXE at 7.5 mo and 12.5 mo follow-up, respectively. Fewer deaths were reported with EVE + EXE (17.2%) vs PBO + EXE (22.7%) at 12.5 mo follow-up. Safety profiles were consistent with previous reports for mTOR inhibitors. PFS data including 528 events (protocol-specified final analysis), and updated OS and safety data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in patients with NSAI-refractory advanced ER+ BC. There were fewer deaths among patients receiving EVE, and further follow-up will evaluate the effect of EVE on OS.

Safety of everolimus for women over age 65 with advanced breast cancer (BC): 12.5-month follow-up of BOLERO-2.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 104-104 ◽  
Author(s):  
Hope S. Rugo ◽  
Howard A. Burris ◽  
Michael Gnant ◽  
José Baselga ◽  
Martine J. Piccart-Gebhart ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Postmenopausal Women ◽  
Mammalian Target Of Rapamycin ◽  
Safety Data ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Tolerability Profile ◽  
Once Daily ◽  
Grade 3

104 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE), but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily), in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 months’ median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients <65 (HR, 0.37; p < .05) or ≥65 years of age (HR, 0.56; p < .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infection (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3-4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3-4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.

Safety of everolimus in estrogen receptor–positive advanced breast cancer.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 103-103
Author(s):  
Alejandra T. Perez
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Management Strategies ◽  
Disease Recurrence ◽  
Phase Iii ◽  
Antitumor Effects ◽  
Estrogen Receptor Positive ◽  
Oral Corticosteroids ◽  
Grade 3

103 Background: Despite advances in treatment of estrogen receptor–positive (ER+) breast cancer (BC), resistance to endocrine therapy remains a frequent cause of disease recurrence. The mTOR pathway has been identified as a point of deregulation in patients resistant to standard therapy. Everolimus (EVE), an oral mTOR inhibitor, was evaluated as a potential antitumor therapy. Treatment-emergent adverse events (AEs) and their management are presented. Methods: BOLERO-2 (NCT00863655), a phase III trial, evaluated EVE in postmenopausal women with ER+ advanced BC refractory to letrozole or anastrozole. Patients with documented recurrence or progression were randomized 2:1 to receive daily oral EVE (10 mg) or matching placebo, in addition to exemestane (EXE; 25 mg/d), stratified by sensitivity to prior hormonal therapy and the presence of visceral metastasis. Results: At 12.5 months’ follow-up, PFS was 7.4 months in the EVE + EXE arm (n = 485) vs 3.2 months in the EXE-only arm (n = 239) (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.36-0.53; p < 1 × 10-l6). Notable AEs (all grades) in the EVE + EXE vs EXE-only treated patients included stomatitis (59% vs 11%), rash (39% vs 6%), pneumonitis (15% vs 0), and hyperglycemia (14% vs 2%). Grade 3-4 AEs of interest in the EVE + EXE vs EXE-only treated patients were stomatitis (8% vs <1%), anemia (7% vs <1%), hyperglycemia (5% vs <1%), pneumonitis (3% vs 0), and rash (1% vs 0). EVE doses could be reduced or interrupted for the management of AEs. Exploratory analyses of antitumor effects of EVE in patients who received time-averaged EVE doses <7.5 mg/d compared with ≥7.5 mg/d were consistent (HR, 0.4 [95% CI, 0.31-0.52] vs HR, 0.45 [95% CI, 0.37-0.56], respectively). Stomatitis was managed with topical corticosteroids and/or mouthwashes containing nonsteroidal anti-inflammatories or anesthetics. Noninfectious pneumonitis was managed by a combination of radiographic imaging, oral corticosteroids, and temporary cessation of treatment. Conclusions: Addition of EVE to EXE significantly prolonged PFS and was generally well tolerated. AEs were manageable with appropriate care. Knowledge of AE management strategies is essential to optimize EVE tolerability and patient outcomes.

scholarly journals Randomized Phase II, Double-Blind, Placebo-Controlled Study of Exemestane With or Without Entinostat in Postmenopausal Women With Locally Recurrent or Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Treatment With a Nonsteroidal Aromatase Inhibitor

2013 ◽  
Vol 31 (17) ◽  
pp. 2128-2135 ◽  
Author(s):  
Denise A. Yardley ◽  
Roohi R. Ismail-Khan ◽  
Bohuslav Melichar ◽  
Mikhail Lichinitser ◽  
Pamela N. Munster ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Aromatase Inhibitor ◽  
Postmenopausal Women ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Advanced Breast ◽  
End Point ◽  
Estrogen Receptor Positive

Purpose Entinostat is an oral isoform selective histone deacetylase inhibitor that targets resistance to hormonal therapies in estrogen receptor–positive (ER+) breast cancer. This randomized, placebo-controlled, phase II study evaluated entinostat combined with the aromatase inhibitor exemestane versus exemestane alone. Patients and Methods Postmenopausal women with ER+ advanced breast cancer progressing on a nonsteroidal aromatase inhibitor were randomly assigned to exemestane 25 mg daily plus entinostat 5 mg once per week (EE) or exemestane plus placebo (EP). The primary end point was progression-free survival (PFS). Blood was collected in a subset of patients for evaluation of protein lysine acetylation as a biomarker of entinostat activity. Results One hundred thirty patients were randomly assigned (EE group, n = 64; EP group, n = 66). Based on intent-to-treat analysis, treatment with EE improved median PFS to 4.3 months versus 2.3 months with EP (hazard ratio [HR], 0.73; 95% CI, 0.50 to 1.07; one-sided P = .055; two-sided P = .11 [predefined significance level of .10, one-sided]). Median overall survival was an exploratory end point and improved to 28.1 months with EE versus 19.8 months with EP (HR, 0.59; 95% CI, 0.36 to 0.97; P = .036). Fatigue and neutropenia were the most frequent grade 3/4 toxicities. Treatment discontinuation because of adverse events was higher in the EE group versus the EP group (11% v 2%). Protein lysine hyperacetylation in the EE biomarker subset was associated with prolonged PFS. Conclusion Entinostat added to exemestane is generally well tolerated and demonstrated activity in patients with ER+ advanced breast cancer in this signal-finding phase II study. Acetylation changes may provide an opportunity to maximize clinical benefit with entinostat. Plans for a confirmatory study are underway.

Results of the CONFIRM Phase III Trial Comparing Fulvestrant 250 mg With Fulvestrant 500 mg in Postmenopausal Women With Estrogen Receptor–Positive Advanced Breast Cancer

2010 ◽  
Vol 28 (30) ◽  
pp. 4594-4600 ◽  
Author(s):  
Angelo Di Leo ◽  
Guy Jerusalem ◽  
Lubos Petruzelka ◽  
Roberto Torres ◽  
Igor N. Bondarenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Postmenopausal Women ◽  
Clinical Benefit ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Phase Iii ◽  
Estrogen Receptor Positive

Purpose We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per month for treatment of postmenopausal women with estrogen receptor–positive advanced breast cancer who experienced progression after prior endocrine therapy. Patients and Methods Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind, parallel-group, multicenter, phase III study. Patients were randomly assigned to fulvestrant 500 mg (500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days thereafter) or 250 mg every 28 days. Primary end point was progression-free survival (PFS). Secondary end points included objective response rate, clinical benefit rate (CBR), duration of clinical benefit (DoCB), overall survival (OS), and quality of life (QOL). Results PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio [HR] = 0.80; 95% CI, 0.68 to 0.94; P = .006), corresponding to a 20% reduction in risk of progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%, respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS were 16.6 and 25.1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and 22.8 months, respectively, in the 250-mg group. Fulvestrant 500 mg was well tolerated with no dose-dependent adverse events. QOL was similar for both arms. Conclusion Fulvestrant 500 mg was associated with a statistically significant increase in PFS and not associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit versus risk compared with fulvestrant 250 mg.

Safety of everolimus for women over 65 years of age with advanced breast cancer (BC): 12.5-mo follow-up of BOLERO-2.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 551-551 ◽  
Author(s):  
Kathleen I. Pritchard ◽  
Howard A. Burris ◽  
Hope S. Rugo ◽  
Michael Gnant ◽  
José Baselga ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Postmenopausal Women ◽  
Mammalian Target Of Rapamycin ◽  
Safety Data ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Tolerability Profile ◽  
Once Daily ◽  
Grade 3

551 Background: Postmenopausal women with estrogen-receptor–positive (ER+) BC who relapse/progress on a nonsteroidal aromatase inhibitor (NSAI) are usually treated with the steroidal AI exemestane (EXE); but there is no currently approved treatment for this indication. The BOLERO-2 trial showed that adding everolimus (EVE), an oral inhibitor of mammalian target of rapamycin (mTOR), to EXE significantly improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011, Abstract S3-7). As many women with advanced BC are elderly, the tolerability profile of EVE + EXE in this population is of interest. Methods: BOLERO-2 is a phase III, randomized, trial comparing EVE (10 mg once daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal women with advanced ER+ BC progressing or recurring after NSAIs. Safety data with a focus on elderly patients are reported at 12.5 mo median follow-up. Results: Baseline disease characteristics, age, and prior cancer therapy were well balanced between treatment arms (N = 724). At 12.5 months’ median follow-up, the addition of EVE to EXE significantly improved progression-free survival in patients <65 (HR = 0.37; P < .05) or ≥65 years of age (HR = 0.56; P < .05). Adverse events (AEs) of special interest (all grades) occurring more frequently with EVE vs PBO (overall study population) included stomatitis (66.6% vs 11.3%), infections (50.4% vs 25.2%), rash (44.0% vs 8.4%), pneumonitis (18.7% vs 0.4%), and hyperglycemia (15.4% vs 2.5%). Elderly EVE-treated patients (≥65 years) had similar or marginally lower incidence of stomatitis (52.1%), rash (32.3%), pneumonitis (14.6%), and hyperglycemia (12.5%) compared with the overall population. Grade 3/4 AEs in patients ≥70 years of age (n = 161) reported only among patients receiving EVE (n = 118) included fatigue (10.2%), anemia (10.2%), hyperglycemia (8.5%), stomatitis (7.6%), dyspnea (6.8%), pneumonitis (5.1%), neutropenia (3.4%), and hypertension (3.4%). Conclusions: Adding EVE to EXE was well tolerated in the overall population and in elderly patients with advanced BC; grade 3/4 AEs were uncommon and manageable. Overall, AEs were consistent with the known safety profile of EVE.

scholarly journals Ki67 Proliferation Index as a Tool for Chemotherapy Decisions During and After Neoadjuvant Aromatase Inhibitor Treatment of Breast Cancer: Results From the American College of Surgeons Oncology Group Z1031 Trial (Alliance)

2017 ◽  
Vol 35 (10) ◽  
pp. 1061-1069 ◽  
Author(s):  
Matthew J. Ellis ◽  
Vera J. Suman ◽  
Jeremy Hoog ◽  
Rodrigo Goncalves ◽  
Souzan Sanati ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Neoadjuvant Chemotherapy ◽  
Aromatase Inhibitor ◽  
Postmenopausal Women ◽  
Stage Ii ◽  
Phase Iii ◽  
Oncology Group ◽  
American College Of Surgeons ◽  
Er Positive

Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) –positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).

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