T-DXd Shows Activity in HER2-Low, HER2-Undetectable Breast Cancer

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The antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd) has led to practice changes in previously treated HER2-positive metastatic breast cancer. Most notably, in the DESTINY-Breast03 trial, treatment with T-DXd produced a doubling in 12-month progression-free survival vs ado-trastuzumab emtansine (T-DM1) in previously treated patients, representing a 78% reduction in risk (P = 7.8 × 10-22).1 Based on the impressive outcomes with this agent, investigators have sought to define a broader population of patients who may benefit from T-DXd.

One potential population are patients with low or even undetectable HER2 expression. Between 40% and 50% of patients with breast cancer have tumors with low HER2 expression, defined as 1+ by immunohistochemistry (IHC) or 2+ by IHC and negative by in situ hybridization (ISH). According to prevailing HER2 testing guidelines, these patients are labeled as HER2-negative and are not recommended for treatment with anti-HER2 agents.

However, in a study of 54 extensively pretreated patients, Modi et al confirmed a response rate of 37% by independent review and 44% by investigator assessment, following treatment with T-DXd.2 Median progression-free survival was 11 months, and median overall survival was 29 months. The finding led to speculation that, for reasons not yet clear, this HER2-targeted drug may have activity beyond tumors with obvious HER2 expression.

Véronique Diéras, MD

Véronique Diéras, MD

At the 2021 San Antonio Breast Cancer Symposium, investigators reported results from the phase II DAISY trial in heavily pretreated patients with metastatic breast cancer of various levels of HER2 expression.3 “T-DXd showed clinically meaningful activity in patients with HER2-overexpressed advanced breast cancer. It is noteworthy to underline that it also showed efficacy in patients with heavily pretreated HER2-low and HER2-null cancer,” the investigators commented in their poster.

Véronique Diéras, MD, of the Eugène Marquis Center in Rennes, France, presented the findings at a Poster Spotlight Session at the meeting.


The evaluable population of 179 patients with metastatic disease was primarily (71%) hormone receptor–positive; 82% had received at least three prior lines of therapy, and 38% had received six or more.

The study evaluated single-agent T-DXd in three cohorts of patients, according to HER2 tumor expression. Cohort 1 (n = 68), patients with high HER2 expression (HER2 overexpression) defined as IHC3+ or IHC2+/ISH+; cohort 2 (n = 73), patients with HER2 low-expression tumors (IHC1+ or IHC2+/ISH– tumors); and cohort 3 (n = 38), patients with HER2-null tumors (IHC0+). Cohorts 2 and 3 were resistant to anthracyclines and taxanes, and to inhibitors of cyclin D 4/6 kinase inhibitors if they were hormone receptor–positive.

Investigators reported activity for T-DXd in all three cohorts, and activity differed somewhat according to hormone receptor status.

The DAISY results in tumors exhibiting HER2 overexpression were consistent with those of the DESTINY-Breast03 trial, with responses seen in 70.6% of patients with high HER2 expression. The 38% response rate in patients with HER2-low expression tumors also was in line with previous trials of patients in this category of expression. By hormone receptor status overall, response rates were 23%; in triple-negative disease, the response rate was 42%.

The rate of interstitial lung disease in the study was 2.8%, and all cases were grade 1 or 2. A total of 13 patients discontinued treatment because of adverse events, including the 5 with interstitial lung disease. 

DISCLOSURE: Dr. Diéras has served as a consultant for Roche/Genentech, Novartis, Lilly, Pfizer, AstraZeneca, AbbVie, MSD, Daiichi Dankyo, Seattle Genetics, Gilead, Eisai, and Pierre Favre Oncologie; has participated in symposia for Roche, Novartis, Pfizer, Lilly, AstraZeneca, and Daiichi Sankyo; and has received travel expenses from Roche, Novartis, Pfizer, Lilly, AstraZeneca, and Daiichi Sankyo.


1. Cortes J, Kim SB, Chung WP, et al: Trastuzumab deruxtecan vs trastuzumab emtansine in patients with HER2+ metastatic breast cancer: Results of the randomized phase III DESTINY-Breast03 study. 2021 ESMO Congress. Abstract LBA1. Presented September 18, 2021.

2. 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.

3. Dieras V, Deluche E, Lusque A, et al: Trastuzumab deruxtecan for advanced breast cancer patients, regardless of HER2 status: A phase II study with biomarkers analysis (DAISY). 2021 San Antonio Breast Cancer Symposium. Abstract PD8-02. Presented December 9, 2021.

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