Abstract P2-10-30: Classifying for HER2 Dependence to De-Escalate Neoadjuvant Chemotherapy in Patients with HER2+ Early Breast Cancer Undergoing HER2 Double-Blockade - CHERRY-PICK Trial (LACOG 0721)

Abstract Background: HER2-positive breast cancer (BC) represents 20% of BC subtypes and is marked by high proliferation and aggressive behavior due to HER2 gene amplification. Chemotherapy combined with anti-HER2 blockade is the standard of care treatment neo/adjuvant setting for HER2+ early BC. The relevance of HER2 as a therapeutic target underscores the importance of accurate HER2 testing. HER2 heterogeneity is associated with resistance to HER2-targeted neoadjuvant therapy, and thus de-escalation of standard therapeutic regimens will depend on accurate tests and HER2 enriched selected tumors. More recently, 18F-FDG-PET identified patients with HER2-positive, eBC who benefited from chemotherapy-free dual HER2 blockade with trastuzumab and pertuzumab, and in which a PET-based, pCR-adapted strategy was associated with an excellent 3-year iDFS. The CHERRY-PICK clinical trial aims to evaluate an anti-HER2 chemo-free neoadjuvant regimen using a fixed-dose combination of pertuzumab and trastuzumab (PHESGO), targeting a HER2 enriched population, selected by standard biomarkers (HR status and HER2 score) using a PET/CT response based strategy for pCR. Trial Design: CHERRY-PICK (LACOG 0721) is a nonrandomized, phase II, single-arm study assessing the efficacy of neoadjuvant pertuzumab and trastuzumab (PHESGO) and de-escalating chemotherapy in patients with HER2+ enriched tumors through a PET/CT response based pCR-adapted strategy. The study will enroll women aged 18 to 80 years who have an ECOG performance status of 0 or 1. Eligible participants must present with clinical stage T1c-T2 N0-N1 BC. Tumors must be classified by immunohistochemistry at a central pathology review before enrollment as HER2 3+ score and estrogen receptor (ER) negative, or low (≤10%), and progesterone receptor (PR) negative (<1%). At baseline for image evaluation, patients must have a PET/CT SUVMax of ≥ 2.5 at primary tumor and tumor size of at least 10mm. Initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes followed every 3 weeks by a dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes. After 3 cycles of PHESGO patients will perform PET/CT for response evaluation. Patients achieving PET/CT response (≥40% reduction in the baseline SUVMax) will continue treatment for 5 additional cycles, completing a total of 8 cycles of neoadjuvant PHESGO therapy. After surgery, patients with pCR will complete 1 year of PHESGO and those with non-pCR will receive adjuvant T-DM1 or standard of care chemotherapy plus PHESGO, as per physician choice. Patients without PET/CT response after cycle 3 will be discontinued from the study and will receive treatment according to institutional standard of care. The primary objective is to evaluate the pathological complete response (pCR) rate in patients who demonstrate a PET-CT response after 3 cycles. Approximately 63 participants will be enrolled to achieve a final sample size of 44 participants evaluable for the primary endpoint, considering a 20%-30% PET-CT non-responder rate. Secondary objectives include PET-CT response rate, objective response rate by PERCIST and RECIST 1.1, invasive disease-free survival (iDFS), event-free survival (EFS), overall survival (OS), safety, cardiotoxicity, and health-related quality of life (HRQoL). Baseline characteristics will be analyzed using descriptive statistics. The pCR rate will be reported as percentage, with a 95% confidence interval calculated using the Clopper-Pearson method. Time-to-event outcomes will be estimated using the Kaplan-Meier method. Comparisons of these outcomes will be performed using stratified log-rank tests. The trial is open for accrual, with the first site activated in June 2024 and a total of 11 centers planned to participate in Brazil. Trial Registration: NCT06068985 Citation Format: Sérgio Daniel Simon, Carlos Barrios, Jorge Canedo, Laura Testa, José Bines, Luciana Castro Garcia Landeiro, Antonio Llombart, Cristina Matushita, Karina Hiromoto Oikawa, João Nunes de Matos Neto, Katsuki Tiscoski, Marcelle Goldner Cesca, Nicole Machado Rossi Monteiro, Susana Ramalho, Pablo Barrios, Rafaela Gomes de Jesus, Gustavo Werutsky. Classifying for HER2 Dependence to De-Escalate Neoadjuvant Chemotherapy in Patients with HER2+ Early Breast Cancer Undergoing HER2 Double-Blockade - CHERRY-PICK Trial (LACOG 0721) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-10-30.