Abstract PO1-28-04: PILHLE-001: neoadjuvant pyrotinib combined with chemotherapy in HR-positive, HER2-low (IHC 2+/FISH-negative) early breast cancer

Abstract Background: Hormone receptor (HR)-positive/HER2-low (IHC 2+/FISH negative or IHC 1+) breast cancers (BCs) represent the largest proportion of breast carcinomas. However, its response to neoadjuvant chemotherapy or endocrine therapy is the lowest, with a residual cancer burden (RCB) 0/I rate around 15%. Previous studies have demonstrated that pyrotinib (P), a pan-HER tyrosine kinase inhibitor, exhibits excellent response in HER2-positive early or advanced BC (E/ABC). In-vitro experiments have shown that pyrotinib can effectively inhibit colony formation in HER2-low (IHC 2+/FISH negative) BC cells. This PILHLE-001 study (NCT05165225) aimed to evaluate the efficacy and safety of neoadjuvant pyrotinib plus chemotherapy in HR-positive/HER2-low (IHC 2+/FISH negative) EBC patients with potential biomarkers. Methods: PILHLE-001, as a single-arm, single-center phase Ⅱ trial, enrolled patients with previously untreated HR-positive (ER or PR 1%) and HER2-low (IHC 2+/FISH negative) invasive EBC (TNM stage II-III) to receive pyrotinib 320mg QD and four Q3W of epirubicin-cyclophosphamide followed by four Q3W of docetaxel. MammaPrint/BluePrint at baseline (t0) was assessed. Breast magnetic resonance imaging (MRI) was conducted at t0, the end of cycle 2 neoadjuvant therapy (t1), and the end of all neoadjuvant therapy. Immune cell subpopulations assay and gene sequencing of tumor tissues with whole blood control samples were performed at t0 and surgery (t2). Additional core biopsy was administered to reassess Ki67 and tumor infiltrating lymphocytes (TILs) at t1. The primary outcome was RCB 0/I rate. The short-term secondary outcomes included pathological complete response (pCR, ypT0/is ypN0) rate, objective response rate (ORR), breast conservation surgery (BCS) rate, safety, and exploratory biomarkers analysis. Results: From July 2021 to March 2023, 48 patients were enrolled and treated. The median age of the patients was 48 years (range 28-66), 43 (90%) had cT1-2 tumors, 30 (63%) showed no node involvement, 37 (77%) had tumours with TNM stage II, and 47 (98%) had ER expression ≥ 50%. Twenty-eight (61%) of 46 patients had MammaPrint high risk. Out of the 48 patients, 26 (54.2%) achieved RCB 0/I, with a 95% confidence interval of 39.2% to 68.6%. The RCB 0/I rate was particularly higher in tumors with no lymph node involvement (73.3%), TNM stage II (64.9%), or abundant tumor-infiltrating lymphocytes (66.7%). Three (6.3%) patients obtained a pCR. The rate of BCS was 60.4% (29/48). The ORR was 45.8% (22/48) at t1 and 81.3% (39/48) at the end of all neoadjuvant therapy, respectively. No patients had progressive disease. All treatment-related adverse events (AEs) were mostly of grade 1 or 2 severity. Grade ≥ 3 AEs occurred in 21 (44%) patients, with the most prevalent being diarrhea 10 (21%). All AEs were reversible with symptomatic treatment and no treatment-related deaths occurred. Patients with MammaPrint risk-low BC had a lower RCB 0/I rate than those with risk-high BC (60.7% vs. 44.4%), although the difference was not statistically significant. Baseline specific immune cell subpopulations (lower PD-1, higher CD3, etc.) or the presence of non-altered PIK3CA were significantly associated with a higher likelihood of achieving RCB 0/I. Similarly, objective response, greater declines in specific MRI quantitative parameters (Ktrans and Kep), greater declines in Ki67, or more increased TILs at t1 were also significantly associated with a higher rate of RCB 0/I. Conclusions: The PILHLE-001 trial first revealed that neoadjuvant pyrotinib plus chemotherapy has encouraging efficacy and acceptable toxicity in patients with HR-positive/HER2-low (IHC 2+/FISH negative) EBC, and this regimen warrants further investigation in phase III randomized controlled trials. Citation Format: Chang Gong, Yuan Xia, Yingying Zhu, Yaping Yang, Wenqian Yang, Louis W.C. Chow, Li Ling, Yunjie Zeng, Jiajie Zhong, Ziliang Cheng, Jun Shen, Qun Lin, Yinduo Zeng, Qiang Liu, Erwei Song. PILHLE-001: neoadjuvant pyrotinib combined with chemotherapy in HR-positive, HER2-low (IHC 2+/FISH-negative) early breast cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-04.