Vepdegestrant Shows Potential in ESR1-Mutant ER+/HER2– Breast Cancer

The novel PROTAC vepdegestrant (ARV-471) is emerging as a potential option for adult patients with ESR1-mutated estrogen receptor (ER)–positive/HER2-negative locally advanced or metastatic breast cancer who develop resistant disease, according to Debu Tripathy, MD. He added that continued research with this agent aims to address unmet needs by exploring its efficacy in combination regimens, potentially extending its utility into earlier lines of therapy.

Results from the phase 2 portion of the VERITAC study (ARV-471-mBC-101; NCT04072952) shared during the 2022 San Antonio Breast Cancer Symposium (SABCS) showed that in the total evaluable population (n = 71), the clinical benefit rate (CBR) achieved with vepdegestrant was 38.0% (95% CI, 26.8%-50.3%); in the subgroup of patients with ESR1-mutated disease (n = 41), the CBR was 51.2% (95% CI, 35.1%-67.1%).¹ The median progression-free survival (PFS) with the agent was 3.7 months (95% CI, 1.9-8.3) in all patients and 5.7 months (95% CI, 3.6-9.4) in the ESR1-mutated subgroup.

Updated phase 1b data presented during the 2023 SABCS showed that when vepdegestrant was paired with palbociclib (Ibrance), the objective response rate (ORR) was 42% in evaluable patients (n = 31); in those with ESR1-mutated disease (n = 17) and those with ESR1 wild-type disease (n = 12), the ORRs were 47% and 42%, respectively.² The median duration of response was 10.2 months (95% CI, 9.5-not reached [NR). The median PFS was 11.1 months (95% CI, 8.2-NR) in the overall population; in the ESR1-mutant and wild-type subsets, it was 11.0 months and 11.1 months, respectively.

Based on previously reported clinical and preclinical data, the FDA granted fast track designation to single-agent vepdegestrant for adult patients with ER-positive/HER2-negative locally advanced or metastatic breast cancer who previously received endocrine-based therapy.2Phase 3 studies on the safety and efficacy of the agent as both a monotherapy in the second line and paired with palbociclib in the first line are ongoing.

“The early studies [with vepdegestrant] look promising, and the more controlled and randomized trials that will [hopefully] tell us exactly when and where to use it are ongoing,” said Tripathy, who is a professor and chairman in the Department of Breast Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

In an interview with OncLive^®, Tripathy provided insights on unmet needs in ER-positive/HER2-negative breast cancer that could be addressed with vepdegestrant, discussed what differentiates this novel PROTAC from other oral selective estrogen receptor downregulators (SERDS) in the treatment of patients with ESR1-mutated disease, and expanded on current and ongoing research that could elucidate the agent’s potential role alone or in combination regimens.

OncLive: What is unique about the mechanism of action of vepdegestrant, and how does it compare with existing treatment options like elacestrant (Orserdu), which also targets ESR1 mutations?

Tripathy: We know that some patients do become resistant to tamoxifen and to aromatase inhibitors, and we’re starting to understand some but not all the [resistance] mechanisms. One example is the ESR1 mutations that can now be addressed by some of the newer emerging SERDS like elacestrant but there are other mechanisms, as well.

All cells have ways to degrade proteins that shouldn’t be there, and you can artificially induce the degradation of proteins in this manner. Vepdegestrant is an orally administered agent in a class of drugs known as PROTACs that can recognize specific proteins and target them for proteasomal degradation. Vepdegestrant rapidly degrades the ER and essentially removes its transcriptional activity that drives ER-positive cancer cell growth, degrading both wild-type and mutant ER.

What early-phase data have been seen thus far with vepdegestrant, particularly in the phase 1/2 VERITAC study?

[The] first-in-human phase 1 [portion of the VERITAC] study showed efficacy with a CBR rate of 40% in 47 evaluable patients, including 3 partial responders. Treatment was generally well tolerated without any dose-limiting toxicities reported from doses of 30 to 700 mg daily.Correlative studies of pre- and post-treated tumors showed nearly 90% degradation at all doses tested.

The phase 2 [portion of] VERITAC tested doses of 200 and 500 mg daily and showed a CBR rate of 37.1% in the 200-mg arm, [which consisted of] 35 patients, and 38.9% in the 500-mg arm, which consisted of 36 patients, for an overall [CBR] rate of 38.0%. Interestingly, equivalent, or slightly better CBR rates were seen at these dose levels in the subset of patients with ESR1 mutations—47.4% in the 200-mg arm, [comprising] 19 patients, and 54.5% in the 500-mg arm, [comprising] 22 patients, for an overall [CBR] rate of 51.2%. Those on the study had received a median of 3 prior regimens in the metastatic setting, with 71 patients having received CDK 4/6 inhibitor therapy, 32 having received chemotherapy, and 39 having visceral disease. [The median] PFS was 3.7 months for all patients and 5.7 months in the subset of patients with ESR1 mutations. Only 3 patients required dose reductions and 3 patients discontinued due to adverse effects.

How might continued research with vepdegestrant address unmet needs in ER-positive/HER2-negative advanced breast cancer?

[Vepdegestrant] may not address every mechanism of resistance, but we are seeing exciting results in patients who have been treated with multiple lines of therapy. In fact, after chemotherapy, and after multiple endocrine therapies, [vepdegestrant] may be one of the most successful ways to target the ER.

[Since] we have these highly effective endocrine therapies, we’re still going to be partnering them with biological drugs like CDK 4/6 inhibitors and PI3K inhibitors. The next set of trials [with PROTACs should focus on] combining them with other agents so that we get effective combinations. We may be able to push hormonal biological combinations into third, fourth, and maybe even fifth lines of therapy.

Please discuss ongoing or planned clinical trials investigating vepdegestrant in other breast cancer settings or patient populations.

Ongoing and future studies include an extension of the phase 2 VERITAC trial that is testing vepdegestrant in combination with palbociclib to select the recommended phase 2 dose for the combination. [Efforts exploring] combinations with other CDK 4/6 inhibitors are also ongoing. The [phase 3] VERITAC-2 trial [NCT05654623] that is in progress is comparing vepdegestrant with fulvestrant (Faslodex) in ER-positive/HER2-negative advanced breast cancer.

VERITAC-3 [NCT05909397] is a randomized phase 3 trial testing vepdegestrant plus palbociclib vs letrozole plus palbociclib in the same population. The TACTIVE-U trial [NCT05548127] is a phase 1b/2 umbrella study of vepdegestrant in combination with either abemaciclib [Verzenio] or ribociclib [Kisqali].

Another interesting study just recently completed, although the data have not been reported yet, is the neoadjuvant phase 2 TACTIVE-N trial [NCT05549505] of vepdegestrant or anastrozole in postmenopausal women with early-stage, ER-positive/HER2-negative breast cancer treated for 5 to 6 months, with the primary end point being Ki67 percent staining in tumors after 2 weeks of treatment, and secondary end points including safety, pathological complete response rate, rate of breast-conserving surgery, radiographic response rate, and modification preoperative endocrine prognostic index score at the time of surgical resection.

Other SERDs and selective estrogen receptor modulators such as lasofoxifene [Fablyn], all of which have activity against ESR1-mutant breast cancer, are being tested at various stages of development, and in parallel, targeted therapies that complement antiestrogen activity are being tested in combination with these drugs.

References

1. ARV-471: Phase 2 VERITAC trial results. Arvinas, Inc. December 8, 2022. Accessed April 3, 2024. https://ir.arvinas.com/static-files/e0d56eb4-13c4-43e9-935d-f24a18d2fe6e
2. Arvinas SABCS data presentation. Arvinas, Inc. December 6, 2023. Accessed April 3, 2024. https://edge.media-server.com/mmc/p/4s9bz59g/#Slides_6
3. 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. April 3, 2024. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast