Dr Viansone on ADC Sequencing in Metastatic HER2+ Breast Cancer

“At every progression [event], it is not just the chemotherapy or the payload we have to change, but also the pressure and the selection on the HER2 [pathway].”

Alessandro A. Viansone, MD, a medical oncologist at Gustave Roussy and part of the Gustave Roussy Alumni Network, discussed how findings from the phase 2 SATEEN trial (NCT06100874), which paired sacituzumab govitecan-hziy (Trodelvy) with trastuzumab (Herceptin) after prior fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), speaks to 2 questions in HER2-positive metastatic breast cancer management: whether one antibody-drug conjugate (ADC) should follow another, and how to maintain selective pressure on HER2 signaling across successive treatment lines.

SATEEN, a single-arm, investigator-initiated trial, enrolled patients with advanced HER2-positive breast cancer who had previously received a taxane, trastuzumab, and T-DXd, and study treatment combined the anti–TROP-2 ADC sacituzumab govitecan with trastuzumab, Viansone said. The first question the study addressed was whether an ADC should be given after another ADC, he explained. A growing body of evidence suggests that an ADC-after-ADC approach is not effective, even when the monoclonal antibody or the cytotoxic payload is changed, according to Viansone. The SATEEN data appear to reinforce that view, as the combination did not demonstrate clinically meaningful activity, he emphasized. Notably, sacituzumab govitecan and T-DXd both deliver a topoisomerase I inhibitor payload, raising the concern for cross-resistance, he added.

Even though SATEEN retained HER2 blockade with trastuzumab alongside sacituzumab govitecan, that may not be enough to halt disease progression, Viansone noted, pointing to the established activity of trastuzumab combined with chemotherapies, such as eribulin or weekly paclitaxel, in advanced HER2-positive disease. The takeaway, he said, is that continued, effective pressure on the HER2 signaling pathway matters across lines of therapy.

Regarding how to maintain selective pressure on the HER2 pathway, at each progression, the chemotherapy or ADC payload should be changed, as well as the mechanism of HER2 inhibition, Viansone said.

He illustrated the concept with a sequencing strategy in which the type of HER2-directed therapy shifts from line to line rather than relying on payload changes alone. For example, he explained the potential move from the ADC T-DXd to the TKI tucatinib (Tukysa), then to a different ADC, such as trastuzumab emtansine (Kadcyla), and subsequently to another TKI, such as lapatinib (Tykerb). Trastuzumab emtansine carries a payload that is distinct from the topoisomerase I payloads of T-DXd and sacituzumab govitecan, changing both the payload class and the mode of HER2 targeting, Viansone explained.