Continued clinical activity and favorable tolerability was observed with vepdegestrant (ARV-471) across all doses examined in heavily pretreated patients with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The findings come from dose-escalation data from a phase 1/2 study (NCT04072952) presented as a poster during the 2023 ESMO Congress.1
At a median follow-up of 13.8 months, vepdegestrant resulted in a clinical benefit rate (CBR) of 36.1% (95% CI, 25.9%-47.4%) across all dose groups (n = 83) with a slightly higher CBR observed in those harboring ESR1 mutations (n = 43), at 48.8% (95% CI, 33.3%-64.5%). The objective response rate (ORR) was 11.5% (95% CI, 4.7%-22.2%), with 7 of 61 patients with measurable disease at baseline experiencing a confirmed partial response.
When the agent was administered at total daily doses ranging from 30 mg to 700 mg, it was found to be well tolerated. Across dose groups, a total of 96.4% of patients experienced treatment-emergent adverse effects (TEAEs), but the majority were grade 1 or 2. Notably, no grade 4 or higher treatment-related AEs (TRAEs) were observed, and no dose-limiting toxicities occurred.
“Data support further development of vepdegestrant, [and] 2 ongoing phase 3 studies are evaluating [the agent] in patients with ER-positive/HER2-negative advanced breast cancer,” Erika P. Hamilton, MD, director of the Breast and Gynecologic Cancer Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, and colleagues, wrote in the poster.
Vepdegestrant is an oral PROTAC ER degrader that binds an E3 ubiquitin ligase and ER to generate the ubiquitination of ER followed by proteasomal degradation. Preclinical data indicated that the agent resulted in stronger ER degradation and tumor growth inhibition than the selective ER degrader fulvestrant (Faslodex) in breast cancer xenograft models.
The phase 1/2 study enrolled patients with ER-positive/HER2-negative advanced breast cancer who had received at least 1 prior CDK4/6 inhibitor, at least 2 prior endocrine therapies, and up to 3 prior lines of chemotherapy.
The phase 1 dose-escalation portion of the multicenter, open-label trial utilized a 3+3 design with backfill and evaluated vepdegestrant at daily doses ranging from 30 mg (n = 3), to 60 mg (n = 3), to 100 mg (n = 13), to 120 mg (n = 7), to 180 mg (n = 7), to 200 mg (n = 8), to 360 mg (n = 15), to 500 mg (n = 22), to 700 mg (n = 4).1
The primary objective was to examine the safety and tolerability of vepdegestrant to estimate the maximum tolerated dose and the recommended phase 2 doses (RP2D).2,3 Investigators identified 200 mg daily and 500 mg daily as the RP2Ds.2 In the phase 2 VERITAC cohort expansion portion of the research, 200 mg daily was established as the RP2D.3
At the 2023 ESMO Congress, investigators presented updated data from the dose-escalation portion of the study, which had an additional 20 months of follow-up from the first report and looked at additional secondary and exploratory objectives such as pharmacokinetics (PK), antitumor activity, and change in baseline in ESR1 mutation–positive circulating tumor DNA (ctDNA).1
At a data cutoff date of June 6, 2023, a total of 83 patients had received the agent at total daily doses that ranged from 30 mg to 700 mg. The median patient age was 64.0 years (range, 36-80) and 98.8% were female. Regarding ECOG performance status, 50.6% had a status of 0 and 48.2% had a status of 1. More than half of patients had visceral disease (65.1%). Moreover, 60.2% had disease in the bone, 51.8% in the liver, 19.3% in the lung, and 18.1% in other. Additionally, 51.8% of patients had ESR1-mutant disease and 44.6% had wild-type disease.
The median number of lines of prior treatment received in any setting was 4, with a range of 1 to 12. In the metastatic setting, the median number of prior lines was 3 (range, 0-8). All patients had prior exposure to a CDK4/6 inhibitor and an aromatase inhibitor. Most patients (81.9%) received prior fulvestrant. Moreover, 83.1% of patients received chemotherapy in any setting and 60.2% received it in the metastatic setting.
At the time of the data cutoff, 29 patients had received vepdegestrant for at least 24 weeks and 5 patients were still receiving treatment.
PK data on day 15 revealed increases in AUC24 and Cmax from 30 mg to 500 mg total daily dose that proved to be dose dependent. Following treatment with the agent at total daily doses of 30 mg to 700 mg for 1 cycle, large on-treatment reductions in mutant ESR1 ctDNA levels were reported following cycle 1; this was sustained over several cycles.
Any-grade TEAEs were experienced by 96.4% of the total population (n = 83), with 19.3% of patients experiencing grade 3 or 4 TEAEs. One patient experienced a grade 5 TEAE in the form of cardiac arrest although this was not considered to be related to the agent. Moreover, 4.8% and 6.0% of patients, respectively, experienced TEAEs that required dose reduction or led to discontinuation.
Grade 1 or 2 TRAEs were experienced by 65.1% of patients; 7.2% experienced grade 3 TRAEs. The most common TRAEs included fatigue (grade 1/2, 26.5%; grade 3, 0%), nausea (24.1%; 1.2%), arthralgia (14.5%; 0%), constipation (13.3%; 0%), hot flush (13.3%; 0%), and headache (9.6%; 1.2%).
The phase 3 VERITAC-2 trial (NCT05654623) is comparing the safety and efficacy of vepdegestrant at a once-daily dose of 200 mg vs fulvestrant as a second- or third-line treatment in patients with advanced breast cancer.4
Additionally, the phase 3 VERITAC-3 trial (NCT05909397) is evaluating vepdegestrant in combination with palbociclib (Ibrance) vs letrozole (Femara) plus palbociclib in the first-line treatment for patients with ER-positive/HER2-negative advanced breast cancer who have not previously received systemic treatment for advanced disease.5