Abstract OT1-12-03: Phase II study of pyrotinib plus nanoparticle albumin-bound (nab)-paclitaxel as adjuvant therapy for lymph node-negative (N0) or micrometastatic (N1mi), HER2-positive early breast cancer (PHAEDRA)
Authors: Wang Changjun , Zhou Yidong , Lin Yan , Mao Feng , Guan Jinghong , Zhang Xiaohui , Shen Songjie , Wang Xuejing , Zhang Yanna , Pan Bo , Zhong Ying , Peng Li , Cao Xi , Yao Ru , Zhou Xingtong , Xu Chi , Xu Ying , Sun Qiang 
Published: March 2022

Abstract
Background: Nowadays, dual HER2-targeted therapy has become the mainstay for high-risk HER2-positive breast cancer. However, for low-risk resectable HER2-positive breast cancer, the optimal adjuvant regimen remains inconclusive. Mono anti-HER2 antibody combined with single-agent chemotherapy has become a recommended adjuvant regimen for N0, small HER2-positive tumors, but there is scarcity of evidence on tyrosine kinase inhibitors (TKIs) for low-risk HER2-positive breast cancer. The randomized phase III PHOEBE trial has proved the superiority of pyrotinib, a novel irreversible pan-ErbB receptor TKI targeting HER1, HER2, and HER4, over lapatinib when in combination with capecitabine for HER2-positive metastatic breast cancer. We believe pyrotinib can also show promising activity in early breast cancer. Regarding the chemotherapy backbone, nab-paclitaxel exhibits its therapeutic advantage over solvent-based paclitaxel and is widely used in combination with immunotherapy. This study is conducted to evaluate pyrotinib plus nab-paclitaxel in the adjuvant setting for patients with low-risk HER2-positive breast cancer. Moreover, diarrhea is the most common adverse event of pan-HER TKIs. Given the unknown incidence and severity of diarrhea with pyrotinib plus nab-paclitaxel and no consensus on therapeutic or prophylactic strategy of pyrotinib-related diarrhea, a sub-study is conducted to investigate the effect of different prophylactic strategies with loperamide for diarrhea. Trial design: This is a multicenter, open-label, single-arm phase II study. Patients will receive nab-paclitaxel 260 mg/m2 once every 3 weeks for 12 weeks and pyrotinib 240 mg once daily for one year within 90 days after surgery. In the sub-study, 120 patients will be randomly (1:1) assigned to two cohorts. Cohort A will receive loperamide during cycle 1 of adjuvant therapy with pyrotinib plus nab-paclitaxel, at a dose of 4 mg three times a day on days 1-7 and 4 mg twice a day on days 8-21. Cohort B will receive loperamide during cycles 1 and 2 of adjuvant therapy, at a dose of 4 mg three times a day on days 1-7 and 4 mg twice a day on days 8-42. Eligibility criteria: Women aged 18-75 years with histologically confirmed N0/N1mi, HER2-positive invasive breast cancer, primary tumor ≤3 cm, ECOG performance score of 0 or 1, known hormone receptor status, and adequate bone marrow, hepatic, renal, and cardiac function. Aims: The primary endpoint is invasive disease-free survival (iDFS). Secondary endpoints are safety and tolerability. In the sub-study, the primary endpoint is the incidence of grade ≥3 diarrhea, and secondary endpoints include the incidence and severity of diarrhea during the first 2 cycles of adjuvant therapy, the incidence and severity of constipation, the onset time, frequency and duration of grade ≥3 diarrhea, relationship between diarrhea and study drugs, the incidence of dose reduction, discontinuation and hospitalization due to diarrhea, and quality of life questionnaire score using the Functional Assessment of Cancer Therapy-Breast. Statistical methods: The primary efficacy analysis will be performed in the full analysis set, defined as all patients with at least one dose of study drug. iDFS will be estimated using Kaplan-Meier method. Safety will be analyzed in the safety set, defined as all patients with at least one dose of study drug and at least one safety assessment. Accrual: Target accrual is 261 patients at approximately 5 sites in China. The first patient was enrolled on January 14, 2021. Accrual is ongoing.
Citation Format: Changjun Wang, Yidong Zhou, Yan Lin, Feng Mao, Jinghong Guan, Xiaohui Zhang, Songjie Shen, Xuejing Wang, Yanna Zhang, Bo Pan, Ying Zhong, Li Peng, Xi Cao, Ru Yao, Xingtong Zhou, Chi Xu, Ying Xu, Qiang Sun. Phase II study of pyrotinib plus nanoparticle albumin-bound (nab)-paclitaxel as adjuvant therapy for lymph node-negative (N0) or micrometastatic (N1mi), HER2-positive early breast cancer (PHAEDRA) [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 OT1-12-03.