218P Vepdegestrant, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, plus palbociclib (palbo) in ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer: Updated phase Ib cohort results
E.P. Hamilton, S.A. Hurvitz, Nicholas P. McAndrew, Melinda L. Telli, Dejan Juric, Hyo S. Han, Rita Nanda, G. Zahrah, Yaowen Zhang, Weiwei Tan, Elizabeth K. Duperret, Eric Zhi, C. Mather, R. Jeselsohn
Abstract
Preliminary phase Ib cohort results from a phase 1/2 study (NCT04072952) evaluating vepdegestrant (ARV-471) plus palbo showed promising clinical activity in heavily pretreated patients (pts) with ER+/HER2- advanced breast cancer (data cutoff: 6 Jun 2023). We present updated data after 6 additional mo of follow-up (data cutoff: 18 Dec 2023). Eligible pts had ER+/HER2- advanced breast cancer with ≥1 prior endocrine therapy and ≤2 chemotherapy regimens for advanced disease. Vepdegestrant was given orally once daily (QD) continuously (180 mg [n=2], 200 mg [n=21], 400 mg [n=3], or 500 mg [n=20]); palbo 125 mg was given orally QD for 21 days followed by 7 days off treatment in 28-day cycles. Of 46 pts in the phase Ib cohort (median 4 prior therapies [range: 1–11] in any setting; 87% with cyclin-dependent kinase 4/6 inhibitors; 80% with fulvestrant; and 78% with chemotherapy), 12 (26%) are ongoing. Grade 3/4 treatment-related adverse events (TRAEs) ≥10% to either vepdegestrant or palbo were neutropenia (91%) and decreased white blood cell count (15%); no grade 5 TRAEs or febrile neutropenia were reported. CBR, ORR, and mPFS are summarized in all pts and by ESR1 mutation status (Table). Based on 27 (59%) events, mPFS was 11.2 mo (95% CI: 8.2–16.5). Median duration of response in 13 responders was 14.6 mo (95% CI: 9.5–NR). Exploratory circulating tumor DNA (ctDNA) analyses found marked reduction in tumor fraction after 1 treatment cycle (all dose groups); substantial on-treatment decreases in mutant ESR1 ctDNA levels were sustained for multiple treatment cycles (200 mg dose).Table: 218PSummary of clinical activityTotal (N=46)Mutant ESR1a (n=29)Wild-type ESR1a (n=15)CBRb% (95% CI)63.0 (47.6–76.8)72.4 (52.8–87.3)53.3 (26.6–78.7)ORRc% (95% CI)41.9 (24.6–60.9)(n=31)47.1 (23.0–72.2)(n=17)41.7 (15.2–72.3)(n=12)PFSEvents, n (%)27 (58.7)16 (55.2)10 (66.7)mPFS, mo (95% CI)11.2 (8.2–16.5)13.7 (8.2–NR)11.1 (2.8–19.3)aBaseline ESR1 status was missing for 2 pts.bRate of confirmed complete response, partial response, or stable disease ≥24 weeks.cIn pts with measurable disease at baseline.CBR: clinical benefit rate; ESR1: estrogen receptor 1 gene; mo: months; NR: not reached; ORR: objective response rate; mPFS: median progression-free survival Open table in a new tab aBaseline ESR1 status was missing for 2 pts. bRate of confirmed complete response, partial response, or stable disease ≥24 weeks. cIn pts with measurable disease at baseline. CBR: clinical benefit rate; ESR1: estrogen receptor 1 gene; mo: months; NR: not reached; ORR: objective response rate; mPFS: median progression-free survival With longer follow-up, vepdegestrant plus palbo continued to show robust clinical activity in pts with ER+/HER2- advanced breast cancer who had received extensive prior treatment, regardless of ESR1 mutation status. Safety was consistent with that previously reported.