Abstract OT1-1-05: Pernetta: A randomized phase II trial of pertuzumab + trastuzumab with or without chemotherapy, both followed by T-DM1 at progression, in patients with HER2-positive metastatic breast cancer - SAKK 22/10 / UNICANCER UC-0140/1207
Authors: Huober J , Weder P , Boven E , Oehlschlegel C , Mac Grogan G , Thuerlimann B , Li Q , Hawle H , Brauchli P , Ribi K , Gerard M-A , Lemonnier J , van Giesen J , Bonnefoi H 
Published: August 2014

Abstract
Background: The dual blockade of HER2 signaling with trastuzumab (T) + pertuzumab (P) has been shown to be highly active with low toxicity in patients (pts) with HER2 positive breast cancer both in the neoadjuvant and metastatic setting even in the absence of chemotherapy. Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate combining the antitumor properties of trastuzumab with the cytotoxic agent DM1 via a stable linker. T-DM1 was more efficacious and less toxic than a combination of docetaxel and T in pts with metastatic breast cancer (MBC). Based on these data we decided to evaluate a potentially less toxic strategy of T+P without chemotherapy followed by T-DM1 in the context of a randomized phase 2 trial. It would be a major advantage for patients in terms of toxicity if the regimen of T+P followed by T-DM1 was equally effective with regard to overall survival to a strategy using a traditional chemotherapy-based regimen with T+P upfront followed by T-DM1.
Trial design: In this multicenter, randomized, open-label phase 2 trial, pts with HER2 positive disease will be randomized to T + P alone or to T + P combined with chemotherapy (paclitaxel weekly or vinorelbine) for at least 4 months followed by maintenance treatment with T+P until progression. Pts with hormone receptor positive disease will receive endocrine treatment when treated without chemotherapy or after completion of chemotherapy. In case of progression pts of both treatment arms will receive T-DM1 as second line treatment.
Eligibility: Eligibility criteria for the first-line part of the trial include a histologically confirmed BC with distant metastases, no prior chemotherapy, no anti-HER2 treatment for MBC. A biopsy from the primary tumor or a metastasis may be used for diagnosis. HER2 positive status must be confirmed by central testing. Prior neoadjuvant/adjuvant anti-HER2 treatment with T and/or lapatinib is allowed. Previous treatment with P is not allowed. For second-line treatment pts must have had at least one dose of trial therapy in the first-line phase and proven disease progression on first-line therapy.
Objectives: The primary endpoint is to evaluate the efficacy in terms of overall survival (OS) at 24 months in both treatment arms. Secondary endpoints include progression-free survival (PFS) of first-line treatment ignoring first CNS lesion, PFS of second-line treatment and of both treatment lines, OS, adverse events of first- and second -line treatment, quality of life and duration of chemotherapy-free time.
Statistical methods: For sample size calculation we estimated a median OS of 32 months corresponding to an expected survival proportion of 59.5% at 24 months under an exponential distribution. The two arms will be analyzed separately. Statistical comparisons by hypothesis tests between treatment arms are not planned. The hazard ratio for OS will be estimated with 95% confidence interval. Time-to-event endpoints are described by Kaplan-Meier plots and medians (with 95% confidence interval).
Accrual: Target accrual is 104 pts per arm, first patient was enrolled in May 2013.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-1-05.