A phase 1 FIH study of novel oral SERD FWD1802 in patients with ER+/HER2- unresectable locally advanced or metastatic breast cancer with or without ESR1 mutations.

e13066 Background: Breast cancer (BC) is the number one cancer in women, and ER+/HER2- is the most prevalent subtype, accounting for about 2/3 of all BCs. Endocrine therapy (ET) inhibiting estrogen receptor (ER) activities has been critical in treating BC. FWD1802 is a novel oral SERD, which binds competitively to ER with higher affinity than fulvestrant. Preclinically FWD1802 exhibits significant anti-tumor activity in both wildtype and mutated ESR1 models in vitro and in vivo. Methods: This study (NCT06064812) assesses the safety, tolerability, pharmacokinetics (PK) and clinical activity of monotherapy FWD1802 in 3 parts: part A dose escalation; part B expansion; part C in patients with mutated ESR1. A “3+3” design is used for part A. The primary objectives include determining dose limiting toxicities (DLTs), maximum tolerated dose (MTD), safety, tolerability, and the RP2D of FWD1802. FWD1802 is orally administered daily in a 28-day cycle. The study is ongoing. Here we report the preliminary data. Results: As of 1/6/2025, 47 patients were enrolled, receiving doses at 25mg (1), 50mg (10), 75mg (16), 150mg (10), 300mg (6) and 450mg (4) in part A (15), part B (26) and part C (6). Patients’ median age was 56.0 years, 83% ECOG 1, and experienced a median prior line of 2 (range, 1-7) in advanced setting, median 1 line of prior ET (range, 1-3), and chemotherapies ranging from 0 to 3. Sixty-eight percent of patients received prior CDK4/6 inhibitors, and 48.9% received prior fulvestrant. Visceral metastases were present in 89.4% patients at baseline, and 42.6% had liver metastasis. Ninety-six percent of patients experienced any TEAE. The most common TEAEs include sinus bradycardia (53.2%), ALT increased (29.8%), hypertriglyceridaemia (27.7%), AST increased (23.4%), anaemia (23.4%), hypercholesterolaemia (21.3%), QT prolongation(21.3%). Over 80% TEAEs were Grade 1. Zero Grade 4/5 TEAEs and 3 Grade 3 TEAEs were reported, 1 splenic artery aneurysm unrelated to treatment, 1 GGT increased and 1 hyponatraemia related to treatment. Zero patient had DLTs. No TEAE-related dose reduction or discontinuation was reported. Therefore, the MTD of FWD1802 was not reached. PK analyses showed that C max and AUC of FWD1802 increased as dose escalated, revealing a trend of linear PK. The geometric mean terminal half-life of different dose groups ranged from 46.8 to 72.9 hours. According to RECIST 1.1, thirty-four patients were evaluable, 5/34(14.7%) had partial responses (4 PRs yet to confirm); 14 patients had ESR1 mutations, and 4/14 (28.6%) had PRs (all yet to confirm). Conclusions: FWD1802 monotherapy was well tolerated with great safety and promising efficacy in a heavily treated population. Reponses were observed in patients carrying both wildtype and mutated ESR1, and better response observed in mESR1 patients. RP2D will be determined once data are collected on more patients. Clinical trial information: NCT06064812 .