Abstract PD1-6: A randomized phase II neoadjuvant study of cisplatin, paclitaxel with or without everolimus (an mTOR inhibitor) in patients with stage II/III triple-negative breast cancer (TNBC)
Authors: Mayer IA , Jovanovic B , Abramson VG , Mayer EL , Sanders ME , Bardia A , Dillon PM , Kuba MG , Carpenter JT , Chang JC , Lehmann BD , Meszoely IM , Grau A , Shyr Y , Arteaga CL , Chen X(S) , Pietenpol JA 
Published: August 2014

Abstract
Background: mTOR inhibitors can activate p73, a pro-apoptotic member of the p53 family, and enhance the sensitivity of breast cancer cells to cisplatin and paclitaxel. Thus, we hypothesized that combined use of the mTOR inhibitor everolimus, cisplatin, and paclitaxel would have synergistic anti-tumor effects in TNBC.
Methods: Patients with clinical stage II/III TNBC were assigned (2:1) to weekly cisplatin 25 mg/m2 + paclitaxel 80 mg/m2 ± daily everolimus 5 mg for 12 weeks, until definitive surgery. Biopsy specimens were obtained in 100% of patients at baseline, at day 5 of cycle 1 and at surgery. Primary endpoint was pathological complete response (pCR). The study design provided 90% power to detect a difference in pCR rate of 35% vs. 20% with a two-sided significance level equal to 0.1 (type I error) for each arm.
Results: A total of 145 patients were accrued between 2009 and 2013. To date, 14 patients have not yet completed surgery, and 11 patients were not evaluable (study discontinuation due to disease progression, toxicity or withdrawal). Baseline characteristics between arms were similar and well balanced: median age was 52 (28 – 81), median breast tumor size was 2 cm (0.1 – 7.6), 72% of tumors were histologic grade III, and 70% of patients had clinical stage III disease. Clinical outcomes are summarized in Table 1.
Clinical outcomesEvaluable patientsEverolimusN = 82PlaceboN = 38OverallN = 120Pathological responseN%N%N%pCR (pT0N0)293516424538Near pCR (pT1aN0)17215132218Residual disease364417455344Clinical ResponseN%N%N%CR465721556759PR232814373629SD1113381511PD220-21
Despite similar rates of pCR and clinical response in both arms, the combination of cisplatin/paclitaxel provided comparable pCR rates to anthracycline/cyclophosphamide/taxane containing regimens administered for longer periods of time. Most common adverse events are summarized in Table 2.
Adverse events(%)Grade 1 and 2Grade 3 and 4 EvePlacEvePlacNeutropenia26272611Thrombocytopenia409 Anemia5975 2Rash4927 2Fatigue61753 Nausea6064 2Diarrhea30292 Dyspepsia3035 Mucositis3920 Hyperglycemia5140 2Transaminase elevation60183 Pneumonitis1
TNBC subtyping (Lehmann et al. JCI 2009), DNA mutations and alterations, as well as markers of proliferation, apoptosis, PI3K/mTOR and DNA damage response signaling will be presented. Preliminary analysis of Ki67 in a subset of tumors suggest that a reduction in Ki67 (day 5 biopsy) is associated with increased pCR rate. Tumors with androgen receptor expression exhibited a very low pCR rate.
Conclusion: To our knowledge, this is the largest randomized neoadjuvant study in TNBC with a PI3K/mTOR pathway inhibitor. Results suggest that the paclitaxel/cisplatin combination is well tolerated and active in TNBC. The addition of Everolimus was associated with more adverse events and did not improve pCR or clinical response rates. A molecular signature or biomarker predictive of benefit from the paclitaxel/cisplatin combination is currently under investigation, and will be presented at the time of the meeting.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr PD1-6.