Dr Viansone on the Future of HER2+ Metastatic Breast Cancer Management

“After the CLEOPATRA trial 11 years ago, we have not had another trial in development about monoclonal antibodies [for HER2-positive breast cancer].”

Alessandro A. Viansone, MD, a medical oncologist at Gustave Roussy and part of the Gustave Roussy Alumni Network, discussed how the HER2-positive metastatic breast cancer treatment landscape is poised to shift as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) moves into earlier settings, and why he views renewed anti-HER2 monoclonal antibodies as central to the future of the field.

The metastatic HER2-positive treatment paradigm will change rapidly as T-DXd advances into the neoadjuvant and adjuvant settings, Viansone said. He also anticipates that genomic testing will begin to provide answers in HER2-positive disease across both the early and metastatic settings. For early-stage disease that does not respond to chemotherapy, adjuvant antibody-drug conjugates (ADCs) are a reasonable treatment option, he noted.

Despite progress, the field needs new agents and new ADCs, according to Viansone. A key lesson from the phase 2 SATEEN trial (NCT06100874), he said, is that ADCs used in this setting must still target HER2, and that an ADC that is not actionable against the HER2 pathway is not a sound strategy. In the trial, sacituzumab govitecan-hziy (Trodelvy) was paired with trastuzumab (Herceptin) in patients with HER2-positive metastatic breast cancer who had received prior T-DXd; this approach did not demonstrate clinically meaningful activity.

At present, relatively few new ADCs are expected to emerge over the coming year, with much of the pipeline weighted toward TKIs, Viansone noted. Several new TKIs are anticipated in the near future, he said.

Monoclonal antibodies, by contrast, have had little innovation in HER2-positive breast cancer, Viansone observed. After trastuzumab and then pertuzumab (Perjeta), established as first-line dual HER2 blockade by the CLEOPATRA trial 11 years ago, no successful new anti-HER2 antibody has followed. The most recent, margetuximab-cmkb (Margenza), an anti-HER2 antibody, was evaluated in the phase 3 SOPHIA trial (NCT02492711), but its final overall survival analysis showed no significant advantage over trastuzumab, Viansone said.

The future, in his view, lies in pairing the strategies now available, including new TKIs and new ADCs, with a renewed monoclonal antibody directed at the HER2 receptor, Viansone concluded.