Abstract PS1-08-26: A phase 1/2, multi-part, open-label study of FWD1802, a novel oral selective estrogen receptor degrader (SERD), in patients with ER+/ HER2- locally advanced or metastatic breast cancer (BC)

Abstract Background: About 2/3 of BC patients are ER+/HER2-. Endocrine therapy (ET) is the mainstay treatment, blocking the ER-driven signaling pathway to inhibit tumor growth despite rising resistance. FWD1802 is a novel oral SERD that has demonstrated potent anti-tumor effects in both wildtype and resistant ESR1-mutant xenograft tumors. Methods: Current study is an ongoing phase 1/2 single-agent trial. After a “3+3” dose escalation, and dose expansion in unselected patients in the Ph1 part, 2 doses were selected to enter the Ph2 part in ESR1 mutated (mESR1+) patients. The primary objective is to determine the recommended phase 2 dose and/or maximum tolerated dose (MTD). Secondary objectives include safety, tolerability, pharmacokinetics and anti-tumor efficacy. Key eligibilities include ≥1 prior endocrine therapy, ≤2 prior chemotherapies and ≤1 prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in the advanced setting. FWD1802 is administered orally daily in 28-day cycles. A 7-day single dosing period prior to Cycle 1 is included in Part A. Results: As of 2025/7/3, 69 patients were treated with FWD1802: 25mg (n = 1), 50mg (n = 10), 75mg (n = 23), 150mg (n = 24), 300mg (n = 7) and 450mg (n = 4). 75mg and 150mg were selected in ph2 part. The median age was 56.4 years (range, 35 - 77), ECOG PS 0 (13%) and 1 (87%). Patients were heavily pretreated, receiving median 2 (1-7) lines of prior treatment in advanced setting, including 71% with prior CDK4/6i, 46% prior fulvestrant, and 52% prior chemotherapy. Visceral disease was present in 90% of patients, 55% with liver mets. Of note, in mESR1+ patients under ph2 doses, 97% had visceral disease and 65% with liver mets. Majority of treatment-emerged adverse events (TEAEs) were Grade 1-2, with 88 % of events Grade 1. TEAEs of ≥15% occurrence in total, 75mg and 150mg patients include: sinus bradycardia (63.8%, 52.2%, 66.7%), ALT increased (33.3%, 39.1%, 37.5%), AST increased (33.3%, 34.8%, 37.5%), hypertriglyceridaemia (33.3%, 43.5%, 33.3%), electrocardiogram QT prolonged (30.4%, 17.4%, 25.0%), hypercholesterolemia (24.6%, 17.4%, 25.0%), anaemia (24.6%, 26.1%, 20.8%), hyperglycemia (21.7%, 21.7%, 20.8%), white blood cell count decreased (18.8%, 21.7%, 20.8%), γ-GGT increased (15.9%, 8.7%, 16.7%), weight increased (15.9%, 17.4%, 16.7%) and photopsia (15.9%, 13.0%, 4.2%). No DLT was observed. Grade 3 TEAEs include: electrocardiogram QT prolonged (3%), hypocalcemia (3%), γ-GGT increased (1%), anaemia (1%), hypertension (1%), pneumonia (1%), femur fracture (1%), lymphocyte count decreased (1%) and hyponatremia (1%). Half-life of FWD1802 was 46.8∼72 hours, and trend of linear PK was observed from 25mg to 450mg. Out of 60 response evaluable patients per RECIST 1.1 criteria, 10 (ORR 17%) confirmed PR were observed. In mESR1+ patients at Ph2 doses, 8 of 16 (50%) patients in 75mg reached PR (6 confirmed, 2 unconfirmed), and 3 of 11 (27%) patients in 150mg reached PR (2 confirmed, 1 unconfirmed). ctDNA analyses showed that response was associated with clearance of mESR1 ctDNA after dosing. Conclusions: FWD1802 showed great safety and tolerability with no DLT and TEAEs mostly of Grade 1-2. In late-line mESR1+ ET-resistant patients in ph2 doses, FWD1802 showed a superb 41% (11/27) ORR (unconfirmed). Considering linear PK property and comparable safety profile between 75mg and 150mg, and the overall highly promising ORR under ph2 doses, 150mg was selected for future monotherapy studies. The Ph2 expansion is still enrolling, and more monotherapy data will be updated once accumulated. (CTR20232130) Citation Format: Y. Meng, F. Xu, X. Qu, Y. Shi, H. Li, Y. Sun, X. Wang, H. Liu, S. Ding, H. Hu, H. Li, J. Li, M. Yan, Y. Yin, T. Sun, W. Xie, X. Chen, J. Wang, C. Zhu, J. Zhang. A phase 1/2, multi-part, open-label study of FWD1802, a novel oral selective estrogen receptor degrader (SERD), in patients with ER+/ HER2- locally advanced or metastatic breast cancer (BC) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-08-26.