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Background: The mTOR pathway is constitutively activated in hormone-resistant advanced breast cancer (ABC). In phase II trials, everolimus (EVE) showed promising efficacy both as monotherapy and in combination with endocrine therapy in patients with estrogen receptor-positive (ER+) ABC. This double-blind, placebo-controlled, phase III study evaluated EVE plus exemestane (EXE) in patients with ER+ ABC refractory to letrozole or anastrozole. Patients and Methods: Eligible patients were randomized (2:1) to EXE (25 mg/day) with EVE (10 mg/day) or with matching placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, quality of life (QoL), and safety. Results: 724 patients were randomized (485: EVE+EXE; 239: EXE). Baseline characteristics were well balanced; median age was 62 years, 56% had visceral involvement, and 84% had documented benefit from previous endocrine therapy, which included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy for advanced disease (25%). This analysis is based on 457 events and median follow-up of 12.5 months. PFS by investigator assessment showed a hazard ratio (HR) of 0.44 (95% CI: 0.36−0.53) and a median duration of 7.4 (EVE+EXE) vs 3.2 months (EXE) (P The most common grade 3/4 adverse events were stomatitis (8% vs 1%), anemia (7% vs 1%), hyperglycemia (5% vs < 1%), dyspnea (4% vs 1%), and fatigue (4% vs 1%) for the EVE+EXE and EXE groups, respectively. Grade 3 pneumonitis was observed in patients receiving EVE (3% vs 0%). No difference in time to deterioration of QoL was observed. EVE increased EXE steady-state Cmin and Cmax levels by 45% and 64%, respectively, with no difference in estradiol levels. Serum markers of bone resorption and bone formation increased in the EXE arm and generally decreased in the EVE+EXE arm. Conclusion: The addition of EVE to EXE is associated with significant and sustained prolongation of PFS. Adverse events were higher in the combination arm but manageable by dose interruption and/or reduction and did not affect QoL. EVE in combination with an aromatase inhibitor is a promising therapeutic option for women with hormone receptor-positive advanced breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-7.

Introduction: Treatment options for postmenopausal women with hormone receptor-positive (HR+) breast cancer (BC) who relapse or progress on a nonsteroidal aromatase inhibitor (NSAI) are limited. Interim analyses of the BOLERO-2 trial demonstrated that combining the oral mammalian target of rapamycin (mTOR) inhibitor, everolimus (EVE), with the steroidal aromatase inhibitor, exemestane (EXE), significantly prolonged progression-free survival (PFS) in this patient population. Protocol-specified final PFS analyses are presented. Methods: The phase III, double-blind, BOLERO-2 trial randomized postmenopausal women with HR+ BC progressing or recurring after NSAIs to EVE (10 mg once daily; n = 485) plus EXE (25 mg once daily) or placebo (PBO; n = 239) plus EXE. The primary endpoint was PFS. Secondary endpoints included overall survival, safety, bone turnover, and overall response rate. Results: At a median follow-up of 18 months, 510 PFS events were reported. The addition of EVE to EXE significantly prolonged median PFS versus EXE monotherapy as per local assessment (7.8 vs 3.2 mo, respectively; HR = 0.45 [95% CI, 0.38–0.54]; log-rank P < .0001). Furthermore, these data were consistent with results based on central assessment (11.0 mo for EVE + EXE vs 4.1 mo for EXE alone; HR = 0.38 [95% CI, 0.31–0.48]; log-rank P < .0001). Fewer deaths were reported with EVE + EXE (25.4%) vs PBO + EXE (32.2%). In addition to significantly improving PFS and delaying disease progression in bone, PFS benefits with EVE + EXE versus PBO + EXE were consistent in all prospectively defined subgroups, including subsets of patients with visceral metastases (n = 406), 3 or more sites of metastasis (n = 271), and Eastern Cooperative Oncology Group (ECOG) performance status 1 or 2 (n = 274). The safety profile of EVE + EXE was consistent with that reported at the interim analysis and with data for EVE from other oncology settings. Updated overall survival data will be presented. Conclusions: Adding EVE to EXE markedly prolonged PFS in the overall population and in all patient subsets, validating the rationale of targeting the mTOR pathway to improve clinical outcome in patients with HR+ advanced BC progressing during or after NSAI therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-02.

Background: Data for this analysis is provided by pooled data from 2 randomized phase III trials (046 and 048) comparing Ixa + Cape versus cape alone in women with MBC refractory to or pretreated with anthracyclines (A) and taxanes (T). Pre-specified sub-group analyses (SGA) were undertaken in MBC patients with PPF including triple negative phenotype (TN), symptomatic KPS 70-80 (KPS), and post adjuvant rapid relapse (PARR, recurrence ≤ 12 months after adjuvant A and T). For each SGA, a clinically meaningful PFS increase was seen with Ixa + Cape (Table 1), consistent with the overall population (OP). A significant overall survival (OS) improvement was not observed in the OP. In the SGA, the OS results were as follows: TN (10.3 vs 9.0 months, p=0.1802c), PARR (15.1 vs 12.5 months, p=0.2081c) and KPS (12.3 vs 9.5 months, p=0.0015c). Across SGA, treatment related adverse events (AEs) were more common for Ixa + Cape, but similar to the OP. A Q-TWiST analysis was undertaken for each SGA to evaluate the trade off between toxicity and PFS.Methods: The area under the OS curves for each SGA was partitioned into 3 health states: 1) Toxicity (TOX) - time the subject spent prior to progression with grade 3/4 treatment toxicity, 2) TWiST - time spent without grade 3/4 AEs prior to progression, 3) Relapse (REL) - time from progression to death or end of follow-up. Utility weights (UW) between 0 and 1 were assigned to the TOX and REL health states with the base case analysis using 0.5 for TOX and REL. The TWiST UW was assumed to equal 1.0 as the most favorable health state achievable. The utility weighted sum of the mean health state durations was derived and treatment comparisons were made. Sensitivity analyses were performed varying the UW of the TOX and REL states between 0 and 1 and calculating the differences in the weighted sum for all combinations.Results: For each SGA, all UW combinations for REL and TOX were associated with greater observed quality adjusted survival (QAS) durations for Ixa + Cape compared to Cape. The base case showed improvements in mean QAS in favor of Ixa + Cape (Table 1), with differences ranging from 4.9 to 9.6 weeks and the PARR group deriving the largest benefit.Median PFS and Mean QAS in Pooled PPF MBC Sub-Groups* Median PFSa, monthsMean QASb, weeksaPatient Sub-GroupsIxa + CapeCapeHR (95% CI)P value cIxa + CapeCapeP value cTN(N = 191) 4.2(N = 208) 1.70.63 (0.52 -0.77) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5051.

Abstract #6117 Background: Patients (pts) with breast cancer who progress within 1 year of adjuvant anthracycline (A) / taxane (T) therapy have limited options for first line treatment. Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046; JCO, 2007) or pretreated with A and T (study 048). In 048, ixa plus C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43 vs. 29%). A trend towards increased OS was seen in both 048 (HR 0.90 [0.78-1.03] and 046 (HR 0.90 [0.77-1.05]) which did not reach statistical significance. Here we present a pooled analysis of efficacy outcomes (ORR, PFS and OS) from the 2 studies of pts who recurred within 1 year of adjuvant A/T therapy and received no prior metastatic treatment. Methods: 1973 pts with MBC previously treated with A and T were randomized in open-label, multinational trials (046 and 048) to receive either ixa (40 mg/m2 IV over 3h Q3w) + C (1000 mg/m2 PO BID x 14d Q3w) or C alone (1250 mg/m2 PO BID x 14d Q3w). Due to the similarity of the study populations, individual patient data from both studies was pooled to better evaluate treatment effect within pre-planned patient subgroups. 293 pts were randomized to ixa + C or C alone in the first line setting. Results: ORR and PFS favored ixa + C in this pt population, and there was a trend towards increased OS, which did not reach statistical significance (see table). Conclusions: Pooled analysis of individual studies confirmed significant ORR and PFS benefit of ixa + C compared to C in pts whose disease relapsed within 12 months of adjuvant A/T. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6117.

Abstract #6140 Background: Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in combination with capecitabine (C) in 2 large clinical trials in metastatic breast cancer (MBC) pts whose tumors were resistant to (study 046, JCO, 2007) or pretreated with anthracycline (A) and taxanes (T) (study 048). In 048, ixa + C, compared to C alone, demonstrated significant increases in PFS (HR 0.79 [0.69-0.90]) and ORR (43% vs 29%). A trend toward increased OS was seen both in 048 (HR 0.90 [0.78-1.03]) and in 046 (HR 0.90 [0.77-1.05]), which did not reach statistical significance. Similar to taxanes, dose-limiting peripheral neuropathy (PN) is a side effect associated with ixa treatment. Here we present the incidence rates, management of ixa-induced PN from 3 registrational studies in pts with MBC and an analysis of resolution time. Also, data on potential risk factors for PN are presented. Methods: Incidence of PN is summarized from a 2000 pt program from 3 multi-center clinical trials. In this program, almost 1100 pts with MBC received ixa either as a monotherapy (40 mg/m2 IV over 3h Q3w, N=126) in a phase II study, or in combination with C (1000 mg/m2 PO BID x14d Q3w) in 2 large phase III studies (N = 369 and N = 595). PN was evaluated every 4 weeks after completion of treatment until toxicity was resolved. Resolution of PN was defined as the time from onset of worst grade to baseline or grade 1. A Cox regression analysis was also performed on a dataset of 945 pts with different tumor types across multiple studies, receiving ixa as a monotherapy or in combination with C, to identify the potential risk factors for grade 3/4 PN. Results: Incidence rates of grade 3/4 PN and resolution time observed in 1 phase III study (046) and the phase II (081) have been published before (081: JCO, 25; 3407). Here we present the data from the final confirmatory phase III study (048). PN was effectively managed with dose reduction. After dose reduction, symptoms improved or did not worsen in the majority of pts, and a median of 2-3 additional treatment cycles were delivered. Pts with diabetes were at a higher risk of grade 3/4 PN (HR: 1.67 [1.00-2.78], p-value = 0.049). Conclusions: Incidence of ixa-associated PN was similar to that observed in trials of other T based regiments. Ixa-induced PN has a predictable median time to resolution of 5-6 weeks over 3 large studies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6140.

Abstract #6114 Introduction: Symptomatic patients (pts) with performance status (KPS) 70-80 with locally advanced or metastatic breast cancer (MBC) have worse prognosis than pts with good performance status and are often excluded from clinical trials. Ixabepilone (ixa), the first in a new class of antineoplastic agents, showed clinical benefit in 2 large clinical trials in combination with capecitabine (C) in MBC pts with tumors resistant to (study 046; JCO; 2007) or pretreated with anthracycline (A) and taxane (T) (study 048). In 048, ixa + C, compared to C alone, showed significant increases in PFS (HR 0.79 [0.69-0.90] and ORR (43% vs 29%). A trend toward increased OS was seen in 048 (HR 0.90 [0.78-1.03]) and 046 (HR 0.90 [0.77-1.05]) which did not reach statistical significance. In 046 and 048 trials, a survival benefit was seen with ixa + C in a predefined analysis in a subset of symptomatic KPS 70-80 pts (HR: 0.75 [0.58-0.98], 0.76 [0.60-0.96], respectively). We present a predefined pooled analysis of clinical outcomes in symptomatic pts from both studies to better evaluate the treatment effect in this subset. Methods: 1973 pts with MBC previously treated with an A and T were randomized in phase III trials 046 and 048 to receive ixa (40mg/m2 IV over 3h Q3w) + C (1000mg/m2 PO BID x14d Q3w) or C alone (1250mg/m2 PO BID x14d Q3w). 606 pts from the 2 studies were KPS 70-80. Study outcomes included ORR, PFS and OS. Results: ORR, PFS and OS favored ixa + C in this pt population. In asymptomatic pts (KPS 90-100), similar improvement was observed in PFS and ORR; no benefit in OS was seen. Incidence of key treatment related grade 3/4 AEs for ixa + C in this subset of pts was similar to the overall population. Conclusions: In the pooled analysis, ixa + C demonstrates a survival benefit (2.8 mo) for symptomatic pts (KPS 70-80) failing A and T, which was consistently seen in this pt population in the individual studies as well, indicating that symptomatic pts can benefit from management of their disease and achieve overall clinical benefit with ixa combination. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6114.