390P Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Update of dose escalation results from a phase I/II trial

Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and had clinical activity in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer in the phase 1 dose escalation (data cutoff: Sep 30, 2021) and phase 2 expansion cohort portions of a phase 1/2 study (NCT04072952). We present updated phase 1 dose escalation data after an additional 13 months of follow-up. Eligible pts had ER+/HER2- advanced breast cancer, ≥1 prior cyclin-dependent kinase (CDK)4/6 inhibitor, and ≥2 prior endocrine therapies. Primary endpoints were safety, tolerability, and recommended phase 2 dose. As of Nov 1, 2022, 83 pts (median age: 64 y [range: 36–80]; 99% female) received vepdegestrant (30–700 mg total daily dose). Pts had a median of 4 prior regimens (range: 0–10; 100% prior CDK4/6 inhibitors, 81% prior fulvestrant, and 82% prior chemotherapy [60% in metastatic setting]). There were no dose-limiting toxicities. Treatment-related adverse events were mostly grade 1/2 (Table). Clinical benefit rate (rate of confirmed complete or partial response [PR] or stable disease ≥24 wks) for evaluable pts (n=76) was 37% (95% CI: 26–49). Of 64 pts with baseline measurable disease, 6 had a confirmed and 4 an unconfirmed PR. At data cutoff, 27 pts had treatment for ≥24 wks (7 for ≥48 wks) with 10 pts ongoing. Pharmacokinetics (PK) showed dose-dependent exposure for 30–500 mg daily doses. Substantial on-treatment reductions in mutant ESR1 circulating tumor DNA levels were observed. Vepdegestrant continued to be well tolerated across all doses and showed clinical activity in heavily pretreated pts with ER+/HER2- advanced breast cancer; PK was dose-dependent up to 500 mg daily. Data support further development of vepdegestrant; the ongoing phase 3 VERITAC-2 study (NCT05654623) is evaluating vepdegestrant 200 mg once daily vs fulvestrant.Table: 390PTRAEs reported in ≥10% of pts overall30–700 mg total daily dose (n=83)Any gradeGrade 1/2Grade 3aAny TRAE, n (%)58 (70)53 (64)5 (6)bNausea20 (24)19 (23)1 (1)Fatigue20 (24)20 (24)0Arthralgia11 (13)11 (13)0Constipation11 (13)11 (13)0Hot flush10 (12)10 (12)0aNo grade ≥4 TRAEs occurred in any pts bOther grade 3 TRAEs not listed were headache (n=1), increased aspartate aminotransferase (n=1), increased amylase (n=1), increased lipase (n=1), QT prolongation (n=1), and venous embolism (n=1); pts may have experienced more than one TRAE TRAE=treatment-related adverse event Open table in a new tab