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Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis.

ABSTRACT: Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38-0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45-0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31-0.51 and HR = 0.50; 95 % CrI 0.37-0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38-0.58 and HR = 0.55; 95 % CrI 0.40-0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor.

SUBMITTER: Bachelot T

PROVIDER: S-EPMC3889833 | biostudies-other | 2014 Jan

REPOSITORIES: biostudies-other

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Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis.

Bachelot Thomas T McCool Rachael R Duffy Steven S Glanville Julie J Varley Danielle D Fleetwood Kelly K Zhang Jie J Jerusalem Guy G

Breast cancer research and treatment 20131124 1

Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestr ...[more]

PMID: 24272078

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Project description:BACKGROUND:The prognostic and predictive value of the two nonluminal (human epidermal growth factor receptor 2 [HER2]-enriched and basal-like) subtypes within advanced hormone receptor-positive (HR+) breast cancer is currently unknown. MATERIALS AND METHODS:This study retrospectively analyzed 261 tumors (80.7% primary; 19.3% metastatic) from the BOLERO-2 study; BOLERO-2 randomized 724 patients with advanced HR+/HER2-negative breast cancer to everolimus plus exemestane or placebo plus exemestane. Tumors were classified using a PAM50 subtype predictor. Multivariable Cox regression analyses tested the independent prognostic significance of PAM50, and associations between PAM50 subtypes and treatment upon progression-free survival (PFS) were evaluated. RESULTS:Subtype distribution was 46.7% luminal A (n = 122), 21.5% HER2-enriched (n = 56), 15.7% luminal B (n = 41), 14.2% normal-like (n = 37), and 1.9% basal-like (n = 5); HER2-enriched subtypes were more common in metastatic versus primary tumors (32.0% vs. 18.7%; p = .038). Median PFS differences between luminal and nonluminal (6.7 vs. 5.2 months; adjusted hazard ratio, 0.66; 95% confidence interval [CI], 0.47-0.94; p = .020) and HER2-enriched and non-HER2-enriched subtypes (5.2 vs. 6.2 months; adjusted hazard ratio, 1.53; 95% CI, 1.07-2.19; p = .019) were significant. Everolimus plus exemestane significantly improved median PFS versus placebo plus exemestane among patients with HER2-enriched tumors (5.8 vs. 4.1 months; adjusted hazard ratio, 0.49; 95% CI, 0.26-0.90; p = .034); however, the association between HER2-enriched tumors and everolimus benefit was nonsignificant (p = .433). CONCLUSION:The HER2-enriched subtype was identified in a substantial proportion of advanced HR+/HER2-negative breast tumors, and was a consistent biomarker of poor prognosis. Tailored therapies are therefore needed for HER2-enriched tumors in the advanced HR+/HER2-negative breast cancer setting. IMPLICATIONS FOR PRACTICE:Using 261 tumor samples from the BOLERO-2 phase III clinical trial, this study shows that a substantial proportion (20%-30%) of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancers do not have a luminal A or B gene expression profile. This group of patients with nonluminal disease has a poor survival outcome regardless of the addition of everolimus to exemestane. This is the second study that confirms the prognostic value of this biomarker. Overall, these findings indicate a necessity to design novel clinical trials targeting nonluminal disease within HR+/HER2-negative breast cancer.

Project description:ImportanceRandomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.ObjectiveTo evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer.Design, setting, and participantsThe MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis.InterventionsFulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus.Main outcomes and measuresThe primary end point was progression-free survival (PFS).ResultsAmong the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16).Conclusions and relevanceThe combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant.Trial registrationClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.

Project description:BackgroundIn the FLIPPER trial, palbociclib/fulvestrant significantly improved progression-free survival (PFS) compared with placebo/fulvestrant in postmenopausal women with HR+/HER2- advanced breast cancer (ABC).ObjectiveWe assessed health-related quality of life (QoL) using patient-reported outcomes (PROs).Design and methodsIn this phase II double-blinded study, PROs were assessed at baseline after every three cycles and at the end of the treatment using the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23. Time to deterioration (TTD) in global health status (GHS)/QoL was defined as a decrease of ⩾10 points. Changes from baseline (CFB) and TTD were analysed using linear mixed-effect and Cox regression models, respectively.ResultsOf the 189 randomised (1:1) patients, 178 (94%) completed ⩾1 post-baseline assessment; 50% received ⩾22 cycles of study treatment, with a questionnaire compliance >90%. Mean baseline scores were comparable between arms. GHS/QoL scores were maintained throughout the palbociclib/fulvestrant treatment. CFB showed significant differences for GHS/QoL, appetite loss, constipation and systemic therapy side effect scores favouring placebo/fulvestrant. TTD in GHS/QoL was delayed in placebo/fulvestrant versus palbociclib/fulvestrant [30.3 versus 11.1 months; adjusted hazard ratio (aHR): 1.57, 95% CI: 1.03-2.39, p = 0.036]; this difference was not significant in patients with progressive disease (aHR: 1.2, 95% CI: 0.6-2.2, p = 0.658). No statistically significant differences in TTD were found for the other QLQ-C30 and QLQ-BR23 scales.ConclusionsAlthough TTD in GHS/QoL was prolonged with placebo/fulvestrant, no differences were observed on other functional or symptom scales. This finding and the improvement in PFS support the combination of palbociclib/fulvestrant as a beneficial therapeutic option for HR+/HER2- ABC.Trial registration numberSponsor Study Code: GEICAM/2014-12EudraCT Number: 2015-002437-21ClinTrials.gov reference: NCT02690480.

Dataset Information

Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis.

Publications

Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis.

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