FDA Approves Veppanu, First PROTAC for ESR1-Mutant Breast Cancer

The landscape of breast cancer treatment recently underwent a as the U.S. Food and Drug Administration (FDA) granted approval to Veppanu (vepdegestrant). This approval specifically targets adult patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer whose disease has progressed following at least one line of endocrine therapy.

Veppanu represents a scientific milestone as the first-ever proteolysis-targeting chimera (PROTAC) to receive FDA approval. To understand the impact of this new therapy, CUREspoke with Dr. Komal Jhaveri, a leading oncologist at Memorial Sloan Kettering Cancer Center and an investigator in the pivotal clinical trials.

Explaining the mechanism of action

For years, patients have been treated with inhibitors or blockers like tamoxifen or aromatase inhibitors. Veppanu, however, operates through a process called proteasomal degradation.

“We are talking about another novel endocrine agent, and so I think the exciting part is that we're trying to figure out how do we optimally target the estrogen receptor,” Jhaveri explained during the interview. “What is unique about the mechanism of action of this newer novel endocrine drug which is the first-in-class PROTAC or proteolysis targeting chimera wherein not only are we binding and targeting the estrogen receptor but we're also trying to bind with the U3 ligase and that together causes proteosomal degradation of the estrogen receptor itself.”

Essentially, rather than just blocking the receptor, Veppanu marks the receptor for destruction within the cell. This is particularly critical for patients with ESR1 mutations, where tumors have learned to grow even when estrogen is suppressed by traditional therapies.

The data: A leap for ESR1 mutations

The FDA’s decision was based on the VERITAC-2 trial, a randomized, open-label study involving 624 patients. The results were notable for the subgroup of 270 patients with ESR1 mutations. In this group, Veppanu demonstrated a median progression-free survival (PFS), or the time a patient lives without their disease spreading or worsening, of five months, compared to 2.1 months for those receiving the standard treatment, Faslodex (fulvestrant).

Despite these gains in the mutant population, the benefit was less pronounced in the overall study population, where the median PFS was 3.8 months for Veppanu versus 3.6 months for Faslodex. Jhaveri noted that this speaks to the complex biology of the disease.

“I think it's not been as straightforward just because I think, one, it is a heterogeneous disease, ER-positive disease is not that straightforward, and, two, the heterogeneity becomes even more evident in the post-CDK4/6 inhibitor setting,” she said.

Managing treatment and side effects

For patients transitioning to this daily oral medication, the safety profile is a primary concern. The recommended dose is 200 mg taken daily with food. While clinical data noted common side effects such as fatigue, musculoskeletal pain and nausea, Jhaveri highlighted that these were generally manageable at home.

“The most reassuring thing I can say is that yes, we can think about some fatigue and some nausea and some musculoskeletal pain, but it was predominantly low grade,” Jhaveri said. “There were very few events of high-grade toxicity. [We’re] very reassured and very happy to see that it's predominantly low-grade toxicities that can be well managed. The discontinuation rate is a reflection of that. Very few patients had to discontinue therapy due to toxicity.”

The FDA also noted precautions regarding QTc interval prolongation and embryo-fetal toxicity. However, Jhaveri pointed out that a sub-study of 88 patients showed no “clinically worrisome increase” in QTc prolongation.

When can patients access Veppanu?

The FDA approved the drug one month ahead of its goal date, sparking hope for rapid availability. However, there is often a delay between regulatory approval and the drug appearing on pharmacy shelves.

“It takes a couple of months, or at least a minimum a few weeks, before that actually happens,” Jhaveri cautioned. “So I think the company will definitely try to make that happen as soon as it can, but it does take a little bit of a lag time, a few weeks to a couple of months, for that to actually happen.”

References

1. “Vepdegestrant, a PROTAC Estrogen Receptor Degrader, in Advanced Breast Cancer” by Dr. Mario Campone et al., The New England Journal of Medicine.
2. “FDA approves vepdegestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer,” news release.

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