Vepdegestrant, a PROTAC estrogen receptor (ER) degrader, vs fulvestrant in ER-positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer: Results of the global, randomized, phase 3 VERITAC-2 study.
Erika Hamilton, Michelino De Laurentiis, Komal Jhaveri, Xichun Hu, Sylvain Ladoire, Anne Patsouris, Claudio Zamagni, Jiuwei Cui, Marina Elena Cazzaniga, Timuçin Çil, Katarzyna J. Jerzak, Christian Sebastian Fuentes, Tetsuhiro Yoshinami, A. Rodríguez-Lescure, Olga Valota, Dongrui R. Lu, Marcella Martignoni, Janaki Parameswaran, Xin Zhi, Mario Campone
Abstract
LBA1000 Background: Vepdegestrant, an oral PROTAC (PROteolysis TArgeting Chimera) ER degrader, showed encouraging clinical activity and was well tolerated in a phase 1/2 study in pretreated patients (pts) with aBC, and is the first PROTAC to be evaluated in a phase 3 trial (VERITAC-2). Methods: Eligible pts (aged ≥18 y) had ER+/HER2- aBC, 1 prior line of a cyclin-dependent kinase (CDK)4/6 inhibitor plus endocrine therapy (ET) and ≤1 additional line of ET (most recent ET given for ≥6 mo before disease progression); pts with prior chemotherapy in the advanced setting or prior fulvestrant were excluded. Pts were randomized 1:1 to vepdegestrant 200 mg orally once daily continuously or fulvestrant 500 mg intramuscularly (days 1 and 15 of cycle 1; day 1 of subsequent cycles); pts were stratified by ESR1 mutation status and presence of visceral disease. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) in pts with ESR1 mutations ( ESR1m ) and all pts. Overall survival (OS) was a key secondary endpoint. PFS was tested by stratified 1-sided log-rank. Median PFS (mPFS) was estimated by Kaplan-Meier method and hazard ratio (HR) by a stratified Cox proportional hazard model; study was designed to detect HR<0.60 with 88% power in pts with ESR1m and HR<0.67 with 92.5% power in all pts (1-sided α=0.01875). Results: 624 pts (median age: 60.0 y [range 26–89]) were randomized (n=313 vepdegestrant; 311 fulvestrant); 43.3% had ESR1m tumors (n=136 vepdegestrant; 134 fulvestrant). PFS by BICR was significantly longer with vepdegestrant vs fulvestrant among pts with ESR1m (174 events, HR=0.57 [95% CI 0.42–0.77]; P =0.0001); mPFS (95% CI) was 5.0 mo (3.7–7.4) vs 2.1 (1.9–3.5). PFS by BICR in all pts was not significantly different (384 events, HR=0.83 [95% CI 0.68–1.02]; P =0.0358); mPFS (95% CI) was 3.7 mo (3.6–5.3) vs 3.6 (2.2–3.8). OS data are immature (20% of targeted events in all pts). In 619 treated pts, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. Grade ≥3 TEAEs occurred in 23.4% of pts in the vepdegestrant arm (vs 17.6% fulvestrant). The most common TEAEs in the vepdegestrant arm were fatigue (26.6% vs 15.6% fulvestrant), increased ALT (14.4% vs 9.8%), increased AST (14.4% vs 10.4%) and nausea (13.5% vs 8.8%). TEAEs led to discontinuation of vepdegestrant in 2.9% of pts (vs 0.7% fulvestrant). Conclusions: Vepdegestrant demonstrated statistically significant and clinically meaningful improvement in PFS vs fulvestrant in the ESR1m population. No statistically significant improvement in PFS was observed in the all-pt population. Vepdegestrant was generally well tolerated with low discontinuation rates due to TEAEs. Results support vepdegestrant as a potential oral treatment option for previously treated pts with ESR1m ER+/HER2- aBC. Clinical trial information: NCT05654623 .