Abstract OT1-12-07: A phase 2 study of chemotherapy de-escalation using a pathological response-guided strategy in patients with HER2-positive, low-risk early breast cancer: PHERGain-2
Authors: Pérez-García José Manuel , Guerrero-Zotano Ángel , Medioni Jacques , Schneeweiss Andreas , Colleoni Marco , Sampayo-Cordero Miguel , Malfettone Andrea , Cortés Javier , Llombart-Cussac Antonio 
Published: March 2022

Abstract
Background: The introduction of trastuzumab (H) and pertuzumab (P) and ado-trastuzumab emtansine (T-DM1) has drastically improved clinical outcomes in patients (pts) with HER2-positive early breast cancer, allowing to explore chemotherapy-sparing approaches in this population. PHERGain trial is evaluating the efficacy of dual HER2-blockade with HP as both neoadjuvant and adjuvant treatment using an 18F-fluorodeoxyglucose-PET-based and a pathological response-adapted strategy [Pérez-García JM et al., Lancet Oncol. 2021;22:858-871]. PHERGain-2 study is an additional step forward and aims to assess the feasibility of chemotherapy de-escalation with neoadjuvant HP followed by adjuvant HP or T-DM1 using a pathological response-adapted strategy in low-risk HER2-positive early breast cancer pts. Trial Design: PHERGain-2 is a multicenter, open-label, non-comparative, phase 2 trial. Eligible participants are patients aged ≥18 years with previously untreated, centrally confirmed, HER2-positive (immunohistochemical score 3+), invasive, node-negative breast cancer (&gt;0.5 and &lt;2.5 cm in tumor size). Eastern Cooperative Oncology Group performance status of 0 or 1, left ventricular ejection fraction of at least 55%, and adequate organ function are also required. Pts will receive the fixed-dose combination of HP for subcutaneous injection (1200 mg P plus 600 mg H loading dose, followed by 600 mg P plus 600 mg H maintenance doses) administered every 3 weeks for 8 cycles as neoadjuvant treatment. Hormone receptor-positive pts will be additionally given letrozole (2.5 mg/day orally) if postmenopausal or tamoxifen (20 mg/day orally) plus gonadotropin-releasing hormone analogue if pre-/peri-menopausal or men. Centrally reviewed MRI will be performed at screening and within 2 weeks prior to surgery. Surgery will be done within 4 weeks after the last dose of study treatment. After surgery, pts who achieve a pathologic complete response in breast and axilla (ypT0/is, ypN0) will continue HP for a total of 18 cycles; pts with residual invasive breast disease and/or ypN0(i+/mol+), ypN1mi will receive T-DM1 for 10 cycles; and pts with ypN1-3 will receive T-DM1 for 10 cycles and, at investigator’s discretion, chemotherapy before starting T-DM1. Adjuvant endocrine therapy and radiotherapy will be administered as per hormone receptor status and institutional practices. The primary efficacy and safety endpoints are 3-year recurrence-free interval (RFI) as per STEEP criteria and patient-reported outcomes after 1 year from neoadjuvant treatment initiation as measured by the EORTC-QLQ-C30 scale in the overall population. Key secondary endpoints include pathologic complete response, residual cancer burden, breast-conserving surgery rate; 3-year and 5-year event-free survival, relapse-free survival, distant relapse-free survival, disease-free survival, invasive disease-free survival, breast cancer-specific survival, overall survival; and safety and tolerability as per CTCAE 5.0. A total of 393 pts will be enrolled. The sample size was calculated with the log-minus-log Kaplan-Meier method. The analysis will test the null hypothesis that the 3-year RFI rate is ≤94% and the alternative hypothesis that 3-year RFI rate is ≥98%. With the expectation a 20% dropout rate, a sample size of 393 pts is necessary to attain 80% power at nominal level of two-sided alpha of 0.05. The analysis for the primary efficacy and safety endpoints will be conducted with 95% confidence intervals based on Kaplan-Meier estimator. This trial was opened to accrual in May 2021.
Citation Format: José Manuel Pérez-García, Ángel Guerrero-Zotano, Jacques Medioni, Andreas Schneeweiss, Marco Colleoni, Miguel Sampayo-Cordero, Andrea Malfettone, Javier Cortés, Antonio Llombart-Cussac. A phase 2 study of chemotherapy de-escalation using a pathological response-guided strategy in patients with HER2-positive, low-risk early breast cancer: PHERGain-2 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-07.