Véronique Diéras, MD

The invited discussant of the phase I/II study of patritumab deruxtecan (HER3-DXd) was Véronique Diéras, MD, of the Eugène Marquis Centre, Rennes, France. She commented that HER3-DXd showed promising activity across breast cancer subtypes with heavily pretreated metastatic breast cancer. She predicted that antibody-drug conjugates such as HER3-DXd are ushering in a “new era” of targeted breast cancer treatment.

“For decades, cytotoxic chemotherapy has been the main approach for the treatment of cancer, but we know that many cytotoxic agents present a narrow therapeutic index due to the lack of tumor specificity and the exposure to normal cells. Clearly, antibody-drug conjugates were designed to have an expanded therapeutic index and to execute efficient and specific drug delivery to antigen-expressing tumor cells,” she said.

Of relevance to the study by Krop et al,¹ Dr. Diéras said: “Targeting of HER3 is compelling, as we know that HER3 is overexpressed in metastatic breast cancer, is associated with worse survival, and plays a key role in resistance to cancer therapies.”

As a phase I trial, it is difficult to address the study by Krop et al in terms of efficacy and toxicity, as investigators evaluated different dosages of HER3-DXd (1.6–8 mg/kg) within populations with varying levels of HER3 expression. However, the pooled data for all cohorts and subgroups, with a relatively long median follow-up (31.9 months), clearly indicate “promising activity across breast cancer subtypes,” Dr. Diéras said.

“The results are meaningful not only in terms of objective response rate and duration of response, but also because there is a clear signal in progression-free and overall survival,” she commented. “The study reminds me of the DESTINY-Breast01 trial [showing a benefit for fam-trastuzumab deruxtecan-nxki in HER2-positive patients].² The safety profile was manageable; however, we must still be cautious about interstitial lung disease, which was seen in 6.6% of patients and unfortunately was grade 5 in one patient.”

Question About HER3

Regarding expression of the drug’s target, HER3, Dr. Diéras posed a question. “Does the level of target expression matter? For HER3, it’s not so clear to me. I think the determination of HER3 status is an ongoing process facing analytic issues—for example, archival vs metastatic sample—and with dynamic markers across breast cancer subtypes and cutoff for positivity…. We are probably facing a dynamic biomarker heterogeneity, and we need a better cutoff,” she suggested.

This and other questions aside, Dr. Diéras concluded: “Clearly, the data support further evaluation of patritumab deruxtecan in breast cancer…. Unraveling the mechanisms of action and resistance is crucial for the optimal use of antibody-drug conjugates in sequencing or in combinations, not only in breast cancer but in other tumor types.” 

DISCLOSURE: Dr. Diéras reported financial relationships with AbbVie/Abbott, AstraZeneca, Daiichi Sankyo, Eisai Europe, Gilead Sciences, Lilly, MSD Oncology, Novartis, Pfizer, Pierre Fabre, Roche/Genentech, and Seattle Genetics.

REFERENCES

1. Krop IE, Masuda N, Mukohara T, et al: Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate, in patients with HER3-expressing metastatic breast cancer. 2022 ASCO Annual Meeting. Abstract 1002. Presented June 4, 2022.

2. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 382:610-621, 2020.