S3-6: Neoadjuvant Chemotherapy of Paclitaxel with or without Rad001: Results of the Non-Responder Part of the GEPARQUINTO Study (GBG 44).
Authors: J Huober, C Hanusch, PA Fasching, M Rezai, H Eidtmann, K Kittel, K Schwedler, H Tesch, C Höß, C Mau, F Khandan, P Krabisch, S Loibl, V Nekljudova, M Untch, G von Minckwitz
Journal: Cancer Research (2011)

Abstract Background: The oral signal transduction inhibitor everolimus (RAD001 = R), binds selectively to mTOR (mammalian target of rapamycin), an intracellular protein kinase implicated in the control of cellular proliferation of activated T-lymphocytes and neoplastic cells. Phase II data suggested that R can enhance the clinical efficacy of endocrine treatment in the metastatic and neoadjuvant setting. The GeparQuinto phase III study had 3 settings (HER2−positive: trastuzumab vs lapatinib; HER2−negative: +/− bevacizumab (Bev); HER2−negative non-responder: +/− R). Primary aim of the last setting was to improve pathological complete response (pCR) for patients with HER2−negative breast cancer not responding to 4x epirubicin/cyclophosphamide (EC) +/− Bev by adding R to weekly paclitaxel as neoadjuvant chemotherapy. Patients and Methods: Patients with untreated HER2−negative breast cancer were eligible if their tumors were stage cT3/4a-d; or estrogen (ER) and progesterone (PgR) receptor-negative; or ER/PgR-positive tumors with clinically N+ (for cT2) or pNSLN+ (for cT1). Only patients without response (&amp;lt;50% tumor reduction) to 4x EC+/−Bev were eligible and were randomized to receive further paclitaxel (Pac: 80 mg/m2 q1w x12) chemotherapy with or without R. Treatment with R started 21 to 35 days after the last application of EC with a dose escalation from 2.5 mg every 2nd day to 5 mg every day over 14 days and maintained at 5 mg/day for additional 10 weeks. Dose of R could be decreased to 2.5 mg/day in case of toxicity. Treatment with Pac started within 7–14 days after the start of R. pCR was defined as no invasive and no non-invasive tumor residuals in breast and nodes. We assumed a pCR rate of 5% for Pac based on the GeparDuo study and expected a pCR of 12.1% for Pac+R (odds ratio 2.62). A two-sided Pearson's C2 with a=0.05 and β=0.20 calculated a sample size of 566 P. One interim futility analysis after 1/3 of patients completed therapy was planned. Randomisation was stratified by participating center, ER/PgR status, extend of disease (T4 or N3 vs. T1-3 and N0-2) and pre-treatment with Bev or not. Results: Between 11/07 and 15/06/11 402 P were randomized to Pac (N=201) and Pac+R (N=201). Median age was 51.0 and 50.0 [-R/+R] years. Median clinical tumor size was 40/40 mm; 62%/55% had cT2, 18% / 20% cT3, and 16.7% / 16.7% cT4a-d tumors; 88% / 89% had non-lobular; 35% / 33% grade 3; 55% / 57% node-positive; and 29% / 27% ER and PgR-negative (triple-negative) disease. The futility interim analysis was performed in 02/10, futility boundary was not reached and the trial was continued. After the other 2 settings completed accrual in 06/10, recruitment to the 3rd setting dropped such that it appeared not possible to recruit the full number of patients.. The trial will therefore close recruitment on June, 30th 2011 with an estimated statistical power of 65%. Results on histological response and surgical outcome will be reported. Conclusion: This will be the first report on efficacy data of neoadjuvant R + Pac for patients with early breast cancer. The results of the GeparQuinto study will have to be set into context with the results from the Bolero studies in metastatic disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-6.