Abstract PO3-05-07: SOLTI-1718 NEREA Trial: Neratinib in hormone receptor (HR)-positive/HER2-negative HER2-enriched (HER2-E) advanced breast cancer (BC)

Abstract Background Breast cancer (BC) is a clinically and biologically heterogenous disease where intrinsic subtypes play a role. Non-luminal subtypes within HR+/HER2-negative disease do not benefit to the same extent from standard of care treatments as the luminal subtypes. Thus, other strategies are needed. HER2-E subtype represents approximately 15.0% of HR+/HER2-negative tumors in metastatic setting. According to an exploratory analysis of EGF30008 trial, HER2-E advanced BC patients, despite presenting poor outcomes across treatments, showed benefit from anti-HER2 therapy with lapatinib. Here, we report the efficacy and safety of the NEREA trial, the first study designed to evaluate neratinib and endocrine therapy in HR+/HER2-negative, PAM50 HER2-E ABC. Methods SOLTI-1718 NEREA (NCT04460430) is a single-arm, multicenter phase II study evaluating neratinib in combination with endocrine therapy (ET) in patients with HR+/HER2-, PAM50 HER2-E ABC. Key inclusion criteria include progression to prior endocrine therapy, ≤ 1 line of chemotherapy for advanced breast cancer (ABC), ECOG 0-1, and HER2-E disease by PAM50 on a metastatic tumor biopsy. The availability of a metastatic tumor sample was mandatory in the pre-screening phase to assess PAM50 subtype. Included patients received neratinib 240 mg daily in combination with ET, with either exemestane, fulvestrant or tamoxifen (as per investigator´s decision). All patients received prophylactic loperamide with an established dosing scheme during the first cycle and on-demand in subsequent cycles. The primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary endpoints include other efficacy endpoints and safety. The study was based on a Simon two-stage design. Stage I of the trial would be considered successful if at least 14 of 33 patients achieved PFS > 6m. In that case, the trial would recruit up to 56 patients for a target PFS6 ≥ 50%. Results. Between July 2020 and June 2022, molecular subtyping was performed on tumors from 136 patients, and 18 HER2-E tumors were identified (7.6%). 12 evaluable patients were enrolled. Baseline characteristics were as follows: median age 60 years, 91.7% of pts were postmenopausal, 75% had visceral disease and 59% received (neo)adjuvant treatment. The median number of lines for ABC was 3 (1-5). Neratinib was combined with exemestane (41.7%), fulvestrant (33.8%) and tamoxifen (25%). At the time of data cut-off (June 2023), 9 patients (75%) had stopped their treatment because of PD and 2 (16.7%) due to toxicity. The PFS6 months occurred in one patient (8.3%, CI: 0.2% - 38.5%). Median PFS was 1.7 months (95% CI 1.6-1.9) with a patient still on treatment after 27.1 months. The incidence of treatment-related adverse events (trAEs) was 25%; diarrhea (25%), asthenia (16.7%), nausea (8.3%), vomiting (8.3%) and rash (8.3%) were most common and were predominantly grade 1/2. 25% of patients experienced grade 3 trAEs. Conclusions.Due to slow enrollment, the study was stopped early. At the time of study close, the hypothesis that neratinib has efficacy in HR+/HER2-, PAM50 HER2-E tumors was not confirmed. We thank PUMA BIOTECHNOLOGY, INC for their provision of Neratinib and financial contribution to the study. Citation Format: Eva Ciruelos, Cristina Saura, Xavier Gonzalez-Farré, Francisco Javier Salvador Bofill, Maria Vidal, Isabel Blancas, Elena López-Miranda, Maria Iglesias, Míriam Arumí, Mireia Margelí, Catarina Pulido, Serafin Morales Murillo, Fernando Henao, Pilar Sanchez, Sara Alves, Ana Godoy Ortiz, José Passos Coelho, Santiago Escrivá-de-Romaní, Alejandra Espinosa, Tomás Pascual, Aleix Prat. SOLTI-1718 NEREA Trial: Neratinib in hormone receptor (HR)-positive/HER2-negative HER2-enriched (HER2-E) advanced breast cancer (BC) [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 PO3-05-07.