FDA Grants Fast Track Designation to Vepdegestrant for ER+/HER2- Metastatic Breast Cancer
核心洞察
The FDA granted Fast Track designation to vepdegestrant for ER+/HER2- locally advanced or metastatic breast cancer (搜索) after endocrine therapy.
Vepdegestrant, an oral PROTAC protein degrader, targets and degrades the estrogen receptor (搜索) (ER), showing up to 97% ER degradation in preclinical models.
Clinical data from the VERITAC study showed a 63% clinical benefit rate with vepdegestrant plus palbociclib in heavily pretreated patients.
The FDA has granted Fast Track designation to vepdegestrant (ARV-471) as a single agent for adult patients with estrogen receptor (搜索) (ER)-positive/HER2-negative locally advanced or metastatic breast cancer (搜索) who have previously undergone endocrine-based therapy. This designation aims to expedite the development and review of this potential new treatment option for a patient population with persisting unmet needs.
Vepdegestrant is an orally bioavailable PROTAC protein degrader designed to target and degrade the ER. Preclinical data demonstrated up to 97% ER degradation in cancer cells and significant tumor reduction in ER-driven xenograft models. The combination of vepdegestrant with or without a CDK4/6 inhibitor also showed enhanced antitumor activity compared to fulvestrant.
John Houston, PhD, chairperson, chief executive officer, and president of Arvinas, Inc., stated, "We are focused on the persisting unmet needs of people with ER-positive/HER2-negative breast cancer (搜索) and doing all that we can to expedite the development of vepdegestrant as a novel, oral ER-targeted potential therapy for this patient community." He added, "We are pleased the FDA has granted fast track designation for vepdegestrant, and we continue to believe this investigational drug has the potential to harness the body’s own natural protein disposal system to selectively and efficiently degrade and remove disease-causing proteins."
VERITAC Study Results
The phase 1/2 VERITAC study (ARV-471-mBC-101; NCT04072952) evaluated the safety and efficacy of vepdegestrant combined with palbociclib in heavily pretreated patients (n = 46) with locally advanced or metastatic ER-positive/HER2-negative breast cancer (搜索). Patients were required to have received at least one prior endocrine-based regimen and up to two prior chemotherapy regimens for advanced disease. Vepdegestrant was administered at varying doses (180 mg, 200 mg, 400 mg, or 500 mg) plus palbociclib at 125 mg once daily for 21 days, followed by 7 days off treatment, in 28-day cycles. The recommended phase 3 dose (RP3D) was identified as 200 mg.
Data presented at the 2023 San Antonio Breast Cancer (搜索) Symposium (data cutoff: June 6, 2023) showed that patients had received a median of four prior therapies across all lines, including a median of three prior therapies in the metastatic setting. The majority of patients had previously received a CDK4/6 inhibitor (87%), fulvestrant (80%), and chemotherapy (76%).
The combination therapy resulted in a clinical benefit rate (CBR) of 63% (95% CI, 47.5%-76.8%) in all evaluable patients (n = 46). In patients who received vepdegestrant at the RP3D (n = 21), the CBR was 67% (95% CI, 43.0%-85.4%). Among patients with ESR1-mutated disease (n = 29), the CBR was 72% (95% CI, 52.8%-87.3%), while those with the RP3D (n = 14) experienced a CBR of 79% (95% CI, 49.2%-95.3%). In patients with ESR1 wild-type disease (n = 15), the CBR was 53% (95% CI, 26.6%-78.7%), and those given the RP3D (n = 7) had a CBR of 43% (95% CI, 9.9%-81.6%).
In the 31 evaluable patients with measurable disease at baseline, the objective response rate (ORR) was 42% (95% CI, 24.5%-60.9%). Patients who received the RP3D had a higher ORR of 53% (95% CI, 26.6%-78.7%). The ORRs in ESR1-mutated (n = 17) and ESR1 wild-type (n = 12) patients were 47% (95% CI, 23.0%-72.2%) and 42% (95% CI, 15.2%-72.3%), respectively. The median duration of response was 10.2 months (95% CI, 9.5-not reached).
The median progression-free survival (PFS) was 11.1 months (95% CI, 8.2-NE) in all 46 patients. In the ESR1-mutated and wild-type subgroups, the median PFS was 11.0 months (95% CI, 8.2-NE) and 11.1 months (95% CI, 2.8-NE), respectively. In patients with prior CDK4/6 inhibitor exposure (n = 40), the median PFS was 11.0 months, while in those without prior CDK4/6 inhibitor exposure (n = 6), the median PFS was 19.3 months.
Safety Profile
The combination of vepdegestrant and palbociclib demonstrated a manageable toxicity profile. Common treatment-related adverse effects (≥10% of patients) included neutropenia (any grade, 100%; grade 3, 48%; grade 4, 41%), fatigue (61%), decreased platelet count (50%), and anemia (35%).
Ongoing Clinical Trials
The safety and efficacy of vepdegestrant are being further evaluated in the phase 3 VERITAC-2 study (NCT05654623), comparing it to fulvestrant in the second-line treatment of advanced breast cancer (搜索). Additionally, the phase 3 VERITAC-3 study (NCT05909397) is comparing frontline vepdegestrant plus palbociclib with letrozole plus palbociclib in patients with ER-positive/HER2-negative advanced breast cancer.