Breaking Down the Utility of Vepdegestrant in First-Line ER+/HER2– Breast Cancer

Based on early demonstrations of efficacy with the novel proteolysis targeting chimera (PROTAC) vepdegestrant (ARV-471) investigators have initiated the phase 3 VERITAC-3 trial (NCT05909397) to further explore the agent’s frontline potential in combination with palbociclib (Ibrance) in patients with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer.¹

“Vepdegestrant is a drug with a new mechanism of action that is in itself novel,” Carlos L. Arteaga, MD, said. “It may be a way of getting rid of the ER; wild-type and mutant ERs may be better than having a selective ER degrader that works for a different mechanism.”

The agent received fast track designation from the FDA for use as a single agent in adult patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who previously received endocrine-based therapy.²

In an interview with OncLive, Arteaga highlighted unmet needs in ER-positive, HER2-negative advanced breast cancer, expanded on how research with the novel PROTAC vepdegestrant addresses these needs, and discussed the importance of considering vepdegestrant’s distinct mechanism of action and its potential effects in the first line.

Arteaga is the Annette Simmons Distinguished University Chair in Breast Cancer Research and the Lisa K. Simmons Distinguished Chair in Comprehensive Oncology, as well as a professor of internal medicine and the director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center in Dallas, Texas.

OncLive: What unmet needs currently exist in ER-positive, HER2-negative advanced breast cancer? How could vepdegestrant address these needs?

Arteaga: Vepdegestrant is a SERD that works differently than other SERDs in development or that are currently approved, [such as] elacestrant [Orserdu]. These are drugs that would work after aromatase inhibitors, after fulvestrant [Faslodex], or in lieu of fulvestrant because they may hit mutations [in] the ER, which occur in many patients with late ER-positive disease. The novel PROTAC could address this by bringing a new mechanism of action that may be good for these patients with ER-positive, HER2-negative disease.

What early data have been seen with vepdegestrant in combination with palbociclib?

That [combination] is very interesting. The [phase 1/2 VERITAC trial (NCT04072952)] was done in a heavily pretreated population, all of whom had progressed on a CDK4/6 inhibitor. Most patients were post-primary endocrine therapy and many patients had ER mutations.

[Vepdegestrant in combination with palbociclib] was well tolerated. [The investigators] did not sacrifice the dose of palbociclib––the agent was used at its full dose. [The regimen] showed a remarkable progression-free survival of 11.1 months. Therefore, it is worth following through with randomized studies using vepdegestrant post-fulvestrant or just before fulvestrant in an ER-mutant population. There was also equally potent activity in patients with ER wild-type [disease].

[This] may be [because of] the class of a drug like vepdegestrant [which] has a unique mechanism of action compared with other competitors. It [may then] become a better alternative to fulvestrant, which is a drug that doesn’t have great pharmacology. The company is following [up] with phase 3 trials in the post–first-line setting in combination with CDK4/6 inhibitors, and those studies should be done.

Could this combination compete with inavolisib plus palbociclib and fulvestrant in the PIK3CA-mutant population?

[It is unknown] whether vepdegestrant is active against tumors with PI3K mutations. I don’t [believe] those data [were collected]. I suspect that something like vepdegestrant may not have any intrinsic activity against tumors that have a PI3K mutation that are also ER-positive. Therefore, if [the combination] was limited to that population, [inavolisib plus palbociclib and fulvestrant] would probably win. It’s hard to make the comparison without knowing whether vepdegestrant has activity against PI3K-mutant tumors.

Vepdegestrant was compared with fulvestrant in patients who progressed on endocrine-based therapy in the phase 3 VERITAC-2 study (NCT05654623). What are your thoughts on the design of the trial?

I have spoken with [colleagues] about this, and the design we spoke about is vepdegestrant after progression on first-line aromatase inhibitors and a CDK4/6 inhibitor. The design I liked was vepdegestrant plus a CDK4/6 inhibitor vs fulvestrant plus another CDK4/6 inhibitor. However, the question then is which CDK4/6 inhibitor [would work best]?

For trials with chemotherapy, we also do physician’s choice; therefore, why don’t we do the same for this? [CDK4/6 inhibitors fall within] the same class of drugs. [We can then] just pair vepdegestrant vs fulvestrant with the CDK4/6 inhibitor of the physician’s preference. [This is] thought [to be a] crazy idea, but not too crazy to discard. That would be a [simple] head-to-head comparison.

Regarding the CDK4/6 inhibitor, let the physicians decide, and power [the study] to have enough patients with mutations in the ER where vepdegestrant can outcompete fulvestrant.

To randomize a patient post-CDK4/6 inhibitor to fulvestrant is not unethical, but it is known that the PFS is [not significant with that approach], so I am not too excited about that. Additionally, physicians like to keep the CDK4/6 inhibitor. This goes back to a time when we were struggling with whether patients should stay on trastuzumab [Herceptin] or not after progression on trastuzumab. Physicians knew that the drug was doing something, and they were not willing to randomize patients to discontinuation of trastuzumab. Sometimes we must listen to our colleagues.

[In terms of other research] I would love to, for example, compare head-to-head in the laboratory this PROTAC with other SERDs. It may be that because of the mechanism of action the mechanisms that bypass them are different; that would be an interesting [area to understand]. However, it will not be of clinical use immediately. I like the fact that [vepdegestrant] is a SERD that has a different mechanism of action than the other ones [because it] may provide useful treatment for patients.

References

1. 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 March 22, 2024. Accessed March 22, 2024. https://clinicaltrials.gov/study/NCT05909397
2. 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 April 1, 2024. https://ir.arvinas.com/news-releases/news-release-details/arvinas-and-pfizers-vepdegestrant-arv-471-receives-fda-fast