FDA Grants Fast Track Status to Vepdegestrant for ER+/HER2– Metastatic Breast Cancer

The FDA has granted fast track designation to vepdegestrant (ARV-471) for use as a single agent in adult patients with estrogen receptor (ER)–positive/HER2-negative locally advanced or metastatic breast cancer who previously received endocrine-based therapy.¹

The orally bioavailable PROTAC protein degrader was developed to target and degrade the ER for use in this population. Preclinical data have indicated that the monotherapy led to ER degradation of up to 97% in cancer cells and elicited robust tumor reductions in several ER-driven xenograft models. Moreover, the use of vepdegestrant with or without a CDK4/6 inhibitor was also found to boost antitumor activity vs standard fulvestrant (Faslodex).

“We are focused on the persisting unmet needs of people with ER-positive/HER2-negative breast cancer and doing all that we can to expedite the development of vepdegestrant as a novel, oral ER-targeted potential therapy for this patient community,” John Houston, PhD, chairperson, chief executive officer, and president of Arvinas, Inc., stated in a press release. “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.”

In the phase 1/2 VERITAC study(ARV-471-mBC-101; NCT04072952), the safety and efficacy of vepdegestrant paired with palbociclib (Ibrance) was evaluated in heavily pretreated patients with locally advanced or metastatic ER-positive/HER2-negative breast cancer (n = 46).^2,3

Patients were required to have received at least 1 prior endocrine-based regimen and up to 2 previous chemotherapy regimens for advanced disease. Vepdegestrant was administered at 180 mg (n = 2), 200 mg (n = 21), 400 mg (n = 3), or 500 mg (n = 20) plus palbociclib at 125 mg once daily for 21 days, followed by 7 days off treatment, in 28-day cycles. Investigators identified 200 mg as the recommended phase 3 dose (RP3D).

Data from the study were shared during the 2023 San Antonio Breast Cancer Symposium and had a data cutoff date of June 6, 2023. Patients had received a median of 4 prior therapies across all lines, with a median of 3 prior therapies in the metastatic setting alone. Most patients previously received a CDK/4 inhibitor (87%), fulvestrant (80%), and chemotherapy (76%).

The doublet led to a clinical benefit rate (CBR) of 63% (95% CI, 47.5%-76.8%) in all evaluable patients (n = 46). In those who received vepdegestrant at the RP3D (n = 21), the CBR was slightly higher, at 67% (95% CI, 43.0%-85.4%). In a subset of patients with ESR1-mutated disease (n = 29), the CBR was 72% (95% CI, 52.8%-87.3%); those in this group given the RP3D (n = 14), experienced a CBR of 79% (95% CI, 49.2%-95.3%). In the subset of patients with ESR1 wild-type disease (n = 15), the CBR was 53% (95% CI, 26.6%-78.7%); those given the RP3D (n = 7) had a CBR of 43% (95% CI, 9.9%-81.6%).

In the 31 evaluable patients who had measurable disease at baseline, the objective response rate (ORR) achieved with the doublet was 42% (95% CI, 24.5%-60.9%). Within this group, those who received the RP3D had a higher ORR of 53% (95% CI, 26.6%-78.7%). In the ESR1-mutated (n = 17) and ESR1 wild-type (n = 12) patients, the ORRs were 47% (95% CI, 23.0%-72.2%) and 42% (95% CI, 15.2%-72.3%), respectively; within these mutated (n = 10) and wild-type (n = 5) groups, those given the RP3D experienced ORRs of 60% (95% CI, 26.2%-87.8%) and 40% (95% CI, 26.6%-78.7%), respectively. The median duration of response was 10.2 months (95% CI, 9.5-not reached).

Moreover, the median progression-free survival (PFS) was 11.1 months (95% CI, 8.2-not evaluable [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 a subset of patients who had prior exposure to CDK4/6 inhibitors (n = 40), the median PFS was 11.0 months with the doublet. In those who had not previously received CDK4/6 inhibitors (n = 6), the median PFS was 19.3 months.

The combination was found to have a manageable toxicity profile. The most common treatment-related adverse effects attributable to either agent that occurred in at least 10% of the 46 total patients included neutropenia (any grade, 100%; grade 3, 48%; grade 4, 41%), fatigue (61%; 4%; 0%), decreased platelet count (50%; 9%; 2%), anemia (35%; 7%; 0%), decreased white blood cell count (26%; 11%; 4%), constipation (24%; 0%; 0%), QT prolongation (22%; 2%; 0%), diarrhea (17%; 0%; 0%), nausea (17%; 0%; 0%), hot flush (15%; 0%; 0%), alopecia (13%; N/A; N/A), arthralgia (13%; 0%; 0%), reduced appetite (11%; 2%; 0%), and vomiting (11%; 0%; 0%).

The safety and efficacy of vepdegestrant is also being compared with fulvestrant in the second-line treatment of patients with advanced breast cancer as part of the ongoing phase 3 VERITAC-2 study (NCT05654623).⁴ In the phase 3 VERITAC-3 study (NCT05909397), frontline vepdegestrant plus palbociclib is being compared with letrozole plus palbociclib in patients with ER-positive/HER2-negative advanced breast cancer.⁵

References

1. Arvinas and Pfizer’s vepdegestrant (ARV-471) receives FDA fast track designation for the treatment of patients with ER+/HER2- metastatic breast cancer. News release. Arvinas, Inc. February 6, 2024. Accessed February 6, 2024. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast
2. Arvinas and Pfizer announce interim data from phase 1b trial of vepdegestrant in combination with palbociclib (Ibrance) and plans to expand vepdegestrant development program. News release. Arvinas, Inc. and Pfizer Inc. December 5, 2023. Accessed February 6, 2024. https://www.pfizer.com/news/press-release/press-release-detail/arvinas-and-pfizer-announce-interim-data-phase-1b-trial
3. Arvinas SABCS data presentation. Arvinas, Inc. December 6, 2023. Accessed February 6, 2024. https://edge.media-server.com/mmc/p/4s9bz59g/#Slides_6
4. A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer. (VERITAC-2). ClinicalTrials.gov. Updated September 21, 2023. Accessed February 6, 2024. https://clinicaltrials.gov/study/NCT05654623
5. A study of ARV-471 (PF-07850327) plus palbociclib versus letrozole plus palbociclib in participants with estrogen receptor positive, Human Epidermal Growth factor negative advanced breast cancer (VERITAC-3). ClinicalTrials.gov. Updated February 2, 2024. Accessed February 6, 2024. https://clinicaltrials.gov/study/NCT05909397