The invited discussant of the study by Bar et al, Barbara Pistilli, MD, Head of the Breast Cancer Unit at Gustave Roussy Cancer Center, Villejuif, France, noted that third-generation antibody-drug conjugates, such as fam-trastuzumab deruxtecan-nxki (T-DXd), are showing activity across a wide range of target expression. She asked: “Do we still need to know the tumor target expression levels?” For HER2, the answer remains “yes,” she said.

Barbara Pistilli, MD

In vitro data indicate that T-DXd has activity in HER2-low models but not in HER2-negative ones. And clinical trials have shown that although HER2-low tumors may respond to T-DXd, patients with HER2-negative tumors are much less likely to benefit from the antibody-drug conjugate. Although new antibody-drug conjugates have mechanisms beyond target expression (such as the bystander effect), she said, they are less likely to work when the target is low or absent.

Additionally, surface protein expression is not sufficient for assuring efficacy. The activity of the antibody-drug conjugate also depends on “how targets move,” which can be over time (evolution of target expression), within and across tumor sites (spatial distribution), and across tumor cell membrane and internal compartments (internalization). The question, therefore, is when and how to assess target expression to maximize the drug’s efficacy.

The study by Bar et al demonstrated that HER2 expression can certainly change over time. The probability of a HER2-low result increases with the total number of biopsies, and new HER2-low results continue to be detected with repeat biopsies, the investigators reported. This is in line with other studies showing fairly high discordance between primary and recurrent tumors and instability of HER2 expression in both hormone receptor–positive and hormone receptor–negative disease. For instance, in the DAISY trial of T-DXd, 65% of patients had a decrease in HER2 expression upon disease progression. These observations raise questions, she said. For example, are these changes related to variance in analytic methods and guidelines, or do they reflect a true evolution of HER2 status?

“In the expanding antibody-drug conjugate landscape, target assessment could support the choice of the most suitable agents for each patient and avoid those that have little chance of working,” Dr. Pistilli pointed out. To this end, there is a need to pursue multiple “moving targets,” including intermetastasis heterogeneity, over time, she added. “We need to better quantify target expression and define the minimal threshold of expression, which may be different for each target and each antibody-drug conjugate.” 

DISCLOSURE: Dr. Pistilli has served as a consultant for AstraZeneca, Seagen, Gilead, Novartis, Lilly, MSD, Pierre Fabre, and Daiichi-Sankyo; has received research funding from AstraZeneca, Daiichi-Sankyo, Gilead, Seagen, and MSD; and has received travel support from AstraZeneca, Pierre Fabre, MSD, Daiichi-Sankyo, and Pfizer.