e11058 Background: The PI3K/Akt/mTOR pathway, a key regulator of cellular proliferation, cellular metabolism, and angiogenesis, is constitutively activated in aromatase inhibitor-resistant breast cancer. Everolimus (EVE), an inhibitor of the PI3K/Akt/mTOR pathway, has single-agent activity and provides additional efficacy to long-term estrogen deprivation when combined with letrozole in the neoadjuvant setting. Combination of EVE and exemestane may improve outcomes for patients ER breast cancer refractory to nonsteroidal aromatase inhibitors (NSAI).
METHODS: In this multinational, double-blind, placebo-controlled phase III study, postmenopausal women ≥18 years old with ER locally advanced or metastatic breast cancer whose disease was refractory to NSAI and documented recurrence or progression were stratified by sensitivity to prior hormonal therapy and the presence of visceral metastasis and then randomized (2:1) to EVE (10 mg daily) or matching placebo orally once daily, with both arms receiving exemestane (25 mg daily). Treatment was continued until disease progression or unacceptable toxicity. The primary outcome was progression-free survival (PFS) assessed by the investigators. Secondary outcomes included overall survival, overall response rate, time to deterioration of ECOG performance status, safety, and change in QoL scores over time. Between June 2009 and January 2011, 723 patients were randomized from 24 countries; 84% had hormone sensitive-disease and 56% had visceral disease. An interim analysis based on safety and efficacy reviewed by the independent data monitoring committee will be performed when 317 PFS events have occurred. The IDMC meeting is planned for May 2011.
RESULTS: Accrual was from 11/1998 to 04/2009. 169 pts were assigned BEP and 168 T-BEP. 13 pts on both arms were ineligible, mainly due to good prognosis GCC (8 on BEP, 6 on T-BEP). Of 5 pts ineligible due to poor risk GCC, 4 had been allocated T-BEP. Relative dose-intensity was > 97.7% for all drugs. T-BEP was well tolerated; 31 episodes of neutropenic fevers were reported on T-BEP (compared to 18 on BEP), but there were only 2 toxic deaths. After a median follow-up of 5.3 years, a total of 84 events occurred. PFS at 3-years (ITT) was 79.4% on T-BEP versus 71.1% on BEP, HR= 0.73 (CI: 0.47-1.13), logrank P = 0.153. PFS at 3-years in all eligible pts was 82.7% versus 70.1%, respectively, HR=0.60 (CI: 0.37-0.97) and statistically significant, logrank P = 0.03. Overall survival was not statistically different.
CONCLUSIONS: The PFS intent-to-treat (primary efficacy) analysis is not statistically significant, but is negatively influenced by the uneven distribution of ineligible pts amongst the 2 treatment arms. The analysis of all eligible pts, however, shows a 12% superior 3-year PFS with T-BEP, which is statistically significant. This study demonstrates superior efficacy of T-BEP in the management of the intended intermediate prognosis GCC risk group. This is the first study to show superiority over standard BEP in this population.
CONCLUSION: As shown by the significant influence of metastatic sites, some P die from their advanced systemic disease situation before they would experience cerebral progression, in part explaining the influence of systemic treatment. In other individuals however, intensified local treatment and systemic treatment appear to influence both cTTP and OS significantly, implicating a direct influence of systemic therapy on BM. This might result from an impaired blood brain barrier around metastatic sites, making sufficient tissue concentrations of cytotoxic agents possible. No significant financial relationships to disclose.
TREATMENT: Rx 375 mg/m(2) IV at day 1; concomitant therapy: Rasburicase, steroids only for anaphylaxis, intrathecal (IT) triple drug at days 1, 3 for CNS pts only. Begin of chemotherapy at day 5. Response evaluation: product of 2 perpendicular diameters of 1 - 3 index lesions/% blasts in BM/PB within 24 h prior to Rx and at day 5: responder (RP): at least 1 lesion with at least objective effect (decrease of ≥25%) and no progress (increase of ≥25 %) at other sites. Study plan: Simon 2-stage phase II with α and β = 5%. Response rate (RR) for poor activity was set to 45%, for good activity 65%. 33 pts entered the first stage, final evaluation after 79 pts.