Priyanka Sharma, MD
Priyanka Sharma, MD, of the University of Kansas Medical Center in Westwood, the invited discussant of the poster, noted that the DAISY study asked whether HER2-targeted antibody-drug conjugates—in this case, fam-trastuzumab deruxtecan-nxki (T-DXd)—have activity beyond the conventional HER2-positive population. For one thing, she pointed out, this class of drugs elicits bystander effects.
“Do we really need the cancer to be HER2-positive?” she questioned. “HER2 expression is continuous, from no expression to 3+ staining on immunohistochemistry. Perhaps any expression of HER2 is adequate for these newer-generation HER2-targeted agents to be effective.” She noted that almost half of metastatic breast cancers fall into the new category of HER2-low tumors.
In the HER2-low cohort of DAISY, 37.5% of patients responded. The response rate in HER2-undetectable tumors was 29.7%, which just missed the prespecified cutoff for statistical success (set at 32.5%).
“In the HER2-nondetected group, there was intriguing efficacy,” Dr. Sharma commented. “The key question here is, are we seeing activity when HER2 is totally absent, or was it simply failure to detect low-level HER2 expression?”
“The challenge with HER2 testing, especially at lower levels, is the testing technique and reproducibility,” she explained. “HER20 is defined as ‘weak or incomplete staining in less than 10% of tumor cells,’ which does not necessarily mean complete lack of expression, as these tests were not geared to detect and report low levels of expression.”
Noting there were responses among patients with triple-negative tumors and nondetectable HER2, and responses in both HER2-low and HER2-nondetected groups differed by hormone receptor status, Dr. Sharma said DAISY raises questions about the role of hormone receptor status in T-DXd’s efficacy in HER2-low or HER2-nondetected groups—that require further study.
The degree of efficacy in HER2-low expressors mirrors what has been emerging in other studies. Response rates were 37% in the recent study of T-DXd by Modi et al (with greater efficacy in hormone receptor–positive patients)1; 28% in hormone receptor–positive patients and 40% in hormone receptor–negative patients in a study of the antibody-drug conjugate trastuzumab duocarmazine2; and 40% with the investigational antibody-drug conjugate disitamab vedotin (RC-48).3 If the “encouraging” findings from DAISY are upheld in ongoing phase III trials—DESTINY-Breast04 and DESTINY-Breast06—it will result in the availability of “new treatment options for a large fraction of patients,” Dr. Shama said. For HER2-nondetected tumors, she added, the data remain “intriguing.”
DISCLOSURE: Dr. Sharma has received consulting fees or honoraria from Pfizer, Merck, Gilead, Seattle Genetics, Novartis, AstraZeneca, GSK, and Exact Sciences.
REFERENCES
1. Modi S, Park H, Murthy RK, et al: Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: Results from a phase Ib study. J Clin Oncol 38:1887-1896, 2020.
2. Banerji U, van Herpen CML, Saura C, et al: Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: A phase 1 dose-escalation and dose-expansion study. Lancet Oncol 20:1124-1135, 2019.
3. Wang J, Liu Y, Zhang Q, et al: RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: A pooled analysis of two studies. 2021 ASCO Annual Meeting. Abstract 1022.
