Abstract OT1-03-01: Chemotherapy-free trastuzumab and pertuzumab in HER2 [+] breast cancer: FDG-PET response-adapted strategy. The PHERGain study
Authors: Llombart-Cussac A , Curigliano G , Gebhart G , Gligorov J , Khaldoun K , Marmé F , Prat A , Schmid P , Cortes J , Perez J 
Published: February 2018

Abstract
BACKGROUND:
Several studies have confirmed that a significant subset of patients (pts) with early stage HER2[+]breast cancer (BC) achieve pathological complete response (pCR) with a dual HER2 neoadjuvant blockade without chemotherapy (chemo). Early metabolic evaluation using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) might help to recognize those pts with a higher likelihood of obtaining a pCR and an excellent outcome with a chemo-free strategy.
TRIAL DESIGN:
This is a randomized, multicenter, non-comparative phase II trial. Pts age ≥ 18 years with centrally-confirmed, treatment-naïve, HER2 [+] operable BC will be randomized, in a 1:4 ratio, and stratified by HR status, to receive docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) (cohort A), or trastuzumab and pertuzumab (HP) ± endocrine therapy (ET) according to HR status (cohort B). Centrally-reviewed 18F-FDG PET/CT scans will be performed prior to randomization and after 2 cycles of therapy. Pts allocated into cohort A will continue with the same therapy for a total of 6 cycles regardless of 18F-FDG PET/CT results. Pts enrolled into cohort B showing at least a 40% reduction of the SUVmax on 18F-FDG PET/CT respect to baseline (PET responders) will continue with the same therapy for a total of 8 cycles. PET non-responders pts will receive 6 cycles of TCHP. After surgery, cohort B/PET responders pts who do not achieve a pCR will receive 6 cycles of TCHP. Moreover, all pts from cohorts A/B must complete 18 cycles of HP, along with adjuvant ET and radiotherapy (RT) according to HR status and institutional practices, respectively. Pts with subclinic metastases will be assigned to cohort C to receive 6 cycles of TCHP. Surgery and RT will be evaluated on a case-by-case basis on cohort C, and all pts will continue with HP for at least 12 additional cycles ± ET according to HR status.
The first co-primary endpoint is to evaluate the rate of pCR defined as the absence of invasive disease in the breast and axilla (ypT0/isN0) achieved with HP ± ET in PET responders pts (cohort B/PET responders).The second co-primary endpoint is to evaluate 3-year (3-y) invasive disease-free survival (iDFS) rate defined as time from the first date of no disease to invasive recurrence, new invasive disease, or death by any cause in cohort B.
Total accrual will be 400 pts. Considering a 10% and 25% of drop-out rates at the time of first and second co-primary analysis, the study will be positive if ≥41 pts achieved a pCR in cohort B/PET responders; or if we observe ≤14 events of 3-y iDFS in cohort B. Decisions will be based on one-sided, exact binomial test. With a 2.5% type I error rate (H0: pCR ≤20% and 3-y iDFS ≤89%) and 80% power (HA: pCR ≥30% and 3-y iDFS ≥95%).
The secondary objectives are to evaluate other definitions of pCR, rates of breast-conserving surgery, tumor response by magnetic resonance imaging, optimal 18F-FDG PET cut-off for pCR and other 18F-FDG PET quantification parameters for pCR prediction, DFS, distant-DFS, overall survival, progression-free survival, and health-related quality of life. Translational sub-studies will analyze biomarkers that may be predictive of response to dual HER2 blockade with HP.
Citation Format: Llombart-Cussac A, Curigliano G, Gebhart G, Gligorov J, Khaldoun K, Marmé F, Prat A, Schmid P, Cortes J, Perez J. Chemotherapy-free trastuzumab and pertuzumab in HER2 [+] breast cancer: FDG-PET response-adapted strategy. The PHERGain study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-03-01.