A phase II trial of a mammalian target of rapamycin inhibitor, temsirolimus, in patients with metastatic breast cancer.

Abstract #407

Introduction:
 The PI3K/Akt/mTOR pathway is often constitutively activated in BC, making inhibition of this pathway an attractive treatment strategy. Temsirolimus (TEM) is an inhibitor of mammalian target of rapamycin (mTOR) inhibitor. A phase II trial of TEM was conducted to determine its activity in MBC and TEM's activity in tumors with PIK3CA mutations.
 Methods:
 An open-label, single-arm, phase II study in patients (pts) with metastatic breast cancer (MBC) was performed at two institutions. TEM (25mg) was intravenously administered weekly. Eligible pts had ECOG performance status (PS) 0 or 1, and albumin > 3.0 mg/dL. Tumor expression of ER, PR, and/or Her2 was required. Prior therapy was not limited. Pts were evaluated for response every 8 weeks of TEM. The primary endpoint was overall response rate, defined as a complete or partial response or stable disease (SD) for ≥ 24 weeks by RECIST. Tumor PIK3CA mutations and immunohistochemical (IHC) expression of PI3K/Akt/mTOR pathway components were evaluated.
 Results:
 Thirty-one pts were enrolled (median age 59; range: 37-80). Pts received a median of 4 prior chemotherapy regimens (range 1-8); pts had ECOG PS 0 (n=14), 1 (n=14), and unknown (n=3). A total of 111 cycles were administered. (median: 2 cycles; range 1-16). Three pts (9.7 %) had prolonged SD for ≥ 24 weeks. Two pts with SD at ≥ 24 weeks had ER+ tumor; all three pts were Her2/neu negative. Seven additional pts had a best response of SD at 16 weeks. One patient achieving SD remains on treatment after 16 cycles.
 The most common adverse events (grades 1-4) include fatigue (n=21), mucositis (n=18), anemia (n=14), increased LFTs (n=14), thrombocytopenia (n=13), rash (n=12), leukopenia (n=12), hypertriglyceridemia (n=11), and hyperglycemia (n=11). Twenty-three pts required a dose reduction or interruption; 3 pts discontinued therapy due to drug toxicity.
 Twenty-three tumors were available for sequencing of PIK3CA helical (HD) and kinase (KD) domains and 24 tumors underwent IHC analysis. Of the three pts with prolonged SD, two pts had tumor with a wildtype PIK3CA sequence in both domains (sequencing on 3rd pt is pending). Four pts had tumor PIK3CA mutations ( 2 pts with HD mutation; 1 with KD; 1 with both HD and KD); these 4 pts had a trend towards decreased progression-free survival versus pts with tumors with wild type PIK3CA (5.3 vs 7.8 weeks). IHC included analysis of pan and phosphorylated: AKT1, S6K1, mTOR, PTEN, and Cyclin D1. Nuclear pAKT308 expression was weakly associated with prolonged PFS (p=0.03).
 Conclusions:
 TEM has limited activity as a single agent in pts with pretreated MBC, and the study did not progress to the planned second stage. Preliminary data suggest that tumors with a mutation in hotspot domains of PIK3CA do not have enhanced sensitivity to TEM.
 This trial was supported by the Avon Foundation and NCI (P30 CA 1459931 S1).

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 407.