Dr Wander on the Evaluation of Vepdegestrant in ER+/HER2– Breast Cancer

Seth Wander, MD, PhD, instructor, medicine, Harvard Medical School, medical oncologist, the Massachusetts General Hospital, discusses the evaluation of vepdegestrant (ARV-471), a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, in patients with advanced ER-positive/HER2-negative breast cancer.

The ongoing, global, randomized, phase 3 VERITAC-2 trial (NCT05654623) is evaluating the PROTAC vs fulvestrant (Faslodex) in patients with ER-positive/HER2-negative advanced breast cancer. This PROTAC has exhibited significant promise in its clinical progression, Wander begins. Investigators hope to drive the investigation of vepdegestrant forward in several different clinical trials, Wander says, noting that this agent targets the ER for degradation within the cell. Both preclinically and in early-phase clinical trials, this agent has been well tolerated and demonstrated preliminary efficacy, even in heavily pretreated patients, Wander emphasizes.

The mechanism of action of the drug allows the ubiquitin proteasome system to target the ER, resulting in efficient degradation, Wander expands. This holds true for mutant forms of the ER, for example, in patients who develop ESR1 mutations, as well as in patients with ESR1 wild-type disease. The phase 2 expansion portion of the phase 1/2 VERITAC trial (NCT04072952) evaluated vepdegestrant a group of heavily pretreated patients with locally advanced or metastatic ER-positive/HER2-negative breast cancer, most of whom had received prior antiestrogen agents and CDK4/6 inhibitors, Wander explains. Many of these patients had also received prior cytotoxic chemotherapy, he notes. These data revealed that this agent conferred a clinical benefit rate (CBR) of 38.9% (95% CI, 23.1%-56.5%) in the cohort of patients who received the agent at 500 mg once daily. In the subgroup of patients with ESR1 mutations, a traditionally difficult subgroup to treat, the CBR was 54.5% (95% CI, 32.2%-75.6%) in the 500 mg cohort, Wander adds.

This agent is progressing in several related phase 3 trials, both alone and in combination with other agents, Wander continues. Notably, the VERITAC-2 trial is ongoing.

Regarding toxicities, vepdegestrant is associated with low-grade adverse effects (AEs), including fatigue, hot flashes, and nausea. Overall, however, this agent was well tolerated in VERITAC, he says. Investigators did not see high rates of bradycardia, cardiac abnormalities, or visual disturbances, which are some AEs associated with some of the newer agents in development over recent years, Wander concludes.