Breast Cancer Metastatic – Oral Abstract Session

In this daily highlight on breast cancer at ASCO 2025, Prof Dr Philippe Aftimos (Institut Bordet University Hospital Brussels)  discusses some interesting presentations from the oral abstract session on metastatic breast cancer. His presentation can be summarised into two main topics: first, endocrine therapies and their combinations in ER+, HER2- metastatic breast cancer; and second, the use of ADCs in earlier treatment settings. 

The VERITAC-2 phase 3 trial investigated vepdegestrant, a novel PROTAC ER degrader, in patients with advanced breast cancer who had progressed on prior CDK4/6 inhibitors. Patients were randomised to receive either vepdegestrant or fulvestrant, with stratification based on visceral disease and ESR1 mutation status. The trial met its primary endpoint in the ESR1-mutant subgroup, demonstrating a meaningful improvement in PFS. However, there was no significant benefit in the overall population. Common adverse events with vepdegestrant included nausea, fatigue, and neutropenia.

Another trial, EMBER-3, assessed imlunestrant, another oral ER degrader, alone or in combination with the CDK4/6 inhibitor abemaciclib, compared to standard endocrine therapy. The trial showed improved PFS in patients with ESR1 mutations. Additionally, combining imlunestrant with abemaciclib was beneficial regardless of mutation status. Quality of life was maintained or improved with imlunestrant and the combination therapy, even with expected gastrointestinal side effects. Adverse events related to fulvestrant injections further support the shift towards oral therapies.

In the first-line setting, INAVO-120 examined the triplet combination of Inavolisib (a PI3Kα inhibitor), Fulvestrant, and Palbociclib versus placebo in hormone receptor-positive, HER2-negative metastatic breast cancer with PIK3CA mutations. The combination significantly improved progression-free and overall survival, though hyperglycemia was a notable side effect. Further safety data from a phase 1 study of Inavolisib in patients with obesity or pre-diabetes showed that hyperglycemia typically developed within two weeks and could generally be managed with antidiabetic medications. Discontinuation due to hyperglycemia was rare. These results suggest that with careful monitoring, patients with metabolic risk factors can benefit from PI3Kα inhibitor therapy.

The INAVO 120 phase 3 study examined first-line treatment for metastatic breast cancer with PIK3CA mutations. Patients had endocrine resistance, progressing within a year of adjuvant endocrine therapy. The study compared a triplet combination of fulvestrant, palbociclib (a CDK4/6 inhibitor), and inavolisib (a PI3KCα inhibitor) with fulvestrant plus palbociclib and placebo. The primary endpoint, improved median progression-free survival, was met, leading to regulatory approval. At ASCO 2025, results showed a median OS of 32 months for the triplet group versus 27 months for the placebo group. No new safety signals were noted, though hyperglycemia occurred in 68% of patients, including some grade 3 cases.

A phase 1 study explored inavolisib in patients with obesity or pre-diabetic risk factors, excluding those with diabetes. Hyperglycemia developed within 14 days, though permanent discontinuation was rare (<1%). Management relied on metformin and, in some cases, multiple anti-diabetic medications. These findings suggest PI3KCα inhibitors like inavolisib, can be used in patients with diabetes risk factors, provided side effects are managed carefully.

The DESTINY-Breast06 Phase 3 study investigated trastuzumab deruxtecan, an anti-HER2 ADC, versus physician-chosen chemotherapy in HER2-low or HER2-ultra-low mBC. Patients were chemo-naive in the metastatic setting and had received one or two prior endocrine-based therapies. The study has met its primary endpoint of improved PFS and has received regulatory approval in this setting. At ASCO 2025, an exploratory analysis was presented that examined genomic alterations, including mutations in ESR1, PIK3CA, BRCA1, and BRCA2. Results showed that the efficacy of trastuzumab deruxtecan was consistent regardless of mutation status. In patients with BRCA1/BRCA2 mutations, the difference in median PFS was significant, warranting further investigation.

A Phase 3 study investigating trastuzumab govitecan combined with pembrolizumab for the first-line treatment of PD-L1-positive metastatic TNBC was presented.  First-line treatment for metastatic PD-L1-positive TNBC currently involves chemotherapy plus pembrolizumab, based on the Keynote 355 study. In the second line and beyond, trastuzumab govitecan has been approved due to improved PFS and OS, as demonstrated in the ASCENT trial.

The ASCENT-04/KEYNOTE-D19 study explored a chemotherapy-free regimen in the first-line setting, combining sacituzumab govitecan with pembrolizumab. This regimen demonstrated positive results, meeting its primary endpoint of improved PFS (HR, 0.65) and an increased objective response rate. Although there was a trend toward improved overall survival (OS), data were not yet mature, and a large number of patients crossed over to other treatments. Importantly, treatment discontinuations due to adverse events were lower in the chemo-free regimen. This may lead to a potential new standard of care for first-line metastatic TNBC without chemotherapy. However, the study’s patient population had limited prior use of pembrolizumab in the neoadjuvant setting, whereas neoadjuvant pembrolizumab is now standard practice, based on the Keynote 522 study, which is commonly used in patients with tumours of a certain size and positive lymph nodes.