Debu Tripathy, MD

Hope S. Rugo, MD, FASCO

The ASCO Post asked Debu Tripathy, MD, Professor and Chair of Medical Breast Oncology at The University of Texas MD Anderson Cancer Center, Houston, and Hope S. Rugo, MD, FASCO, Professor of Medicine, Director of Breast Oncology and Clinical Trials Education at the University of California San Francisco, for their thoughts on the emerging antibody-drug conjugate datopotamab deruxtecan. In the TROPION-Pan-Tumor01 study,¹ the drug yielded response rates of 34% in patients with triple-negative breast cancer and 52% for those patients without prior treatment with another topoisomerase 1 inhibitor antibody-drug conjugate.

Dr. Tripathy said the initial data for datopotamab deruxtecan are encouraging and suggest that yet another antibody-drug conjugate could soon become available in breast cancer. “But I think that datopotamab deruxtecan is different from the anti–Trop-2–SN-38 antibody-drug conjugate sacituzumab govitecan-hziy in terms of its toxicity profile and perhaps its activity profile as well,” he said. Sacituzumab govitecan appears to be associated with more myelosuppression and gastrointestinal toxicity, he noted.

Safety Profile

So far, interstitial lung disease has not been seen with the newer drug, in contrast to the first-generation antibody-drug conjugate trastuzumab deruxtecan-nxki, which is also a topoisomerase inhibitor (approved in HER2-positive disease). No cases of interstitial lung disease were reported in the pivotal study of sacituzumab govitecan. Although this may be related to the differences in the drugs, it is also likely that with experience, investigators are more selective with patients and are recognizing and intervening early enough to prevent problems, he suggested.

Dr. Rugo also zeroed in on this aspect of the datopotamab deruxtecan’s safety profile. “One interesting aspect of this drug is that in these 44 patients, we did not see a case of interstitial lung disease,” she said. “This doesn’t mean it will not happen, but it’s good to see this. We think it’s probably due to the toxin, but antibody delivery [which was different with trastuzumab deruxtecan] probably plays a role.”

The drug is not, however, without some safety concerns, Dr. Rugo added, primarily stomatitis, which occurred (any grade) in almost half the patients and was grade ≥ 3 in about 10%. Stomatitis, which does not occur with trastuzumab deruxtecan, may occur throughout treatment, which indicates that “longer term maintenance might be tough,” she said. “We are working on ways to mitigate this toxicity, but it’s an interesting question…. With different toxicities for these drugs, we will have to figure out where they all fit.”

Dr. Tripathy agreed: “It will be interesting to see how the studies play out and how we position these drugs.”

Predictions for the Future

Dr. Tripathy, in fact, predicted that as antigen targeting becomes more refined, the whole class of antibody-drug conjugates will expand in breast cancer. “We actually have a program at MD Anderson using a NanoString technology to identify a whole different set of antigens. Using that, we will be able to customize the antibody-drug conjugate for an individual patient’s tumor, based on both the antigens expressed and the drugs the patient has received in the past,” he said.

Dr. Tripathy also suggested that the amount of trophoblast cell surface antigen (Trop-2) expressed by an individual patient could make a difference in response. “We are going to need more exploration of that,” he said.

Meanwhile, Dr. Rugo observed that “datopotamab deruxtecan clearly shows efficacy in patients with triple-negative breast cancer.” She looks forward to further findings in triple-negative disease and new data for hormone receptor–positive disease. 

DISCLOSURE: Dr. Tripathy has received institutional research funding from Novartis and Pfizer; and has served as a consultant for AstraZeneca, Gilead, GlaxoSmithKline, OncoPep, and Exact Sciences. Dr. Rugo has served as a consultant or advisor to Puma Biotechnology, Napo, and Samsung; has received institutional research funding from AstraZeneca, Ayala, Boehringer Ingelheim, Daiichi Sankyo, Genentech, Gilead, Lilly, Merck, Novartis, OBI Pharma, Pfizer, Polyphor, Sermonix, and Seattle Genetics.

REFERENCE

1. Krop I, Juric D, Shimizu T, et al: Datopotamab deruxtecan in advanced/metastatic HER2 negative breast cancer: Triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-05. Presented December 7, 2021.