Trastuzumab Deruxtecan Stands Out for HER2+ and HER2-Low Breast Cancer

Aditya Bardia, MD, MPH, discusses the clinical implications of the DESTINY-Breast03 trial, the encouraging data from the DAISY trial, and sequencing questions that remain in the evolving paradigm of HER2-positive breast cancer.

The emergence of the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) has transformed the paradigm of HER2-positive breast cancer, said Aditya Bardia, MD, MPH, who added that data from the phase 2 DAISY trial (NCT04132960) reflected encouraging activity with the agent in patients with HER2-low and HER2 non-detected breast cancer.

During the 2021 San Antonio Breast Cancer Symposium, findings from the DAISY trial, as well as the phase 3 DESTINY-Breast03 trial (NCT03529110) were reported.1,2

The findings from subgroup analyses of the DESTINY-Breast03 trial demonstrated that a progression-free survival (PFS) benefit was maintained with trastuzumab deruxtecan vs ado-trastuzumab emtansine (T-DM1; Kadcyla) across prespecified subgroups, supporting the movement of trastuzumab deruxtecan as the second-line standard of care for patients with HER2-positive metastatic breast cancer.

These results were supported by those observed in the DAISY trial, which enrolled patients into 3 cohorts based on HER2 immunohistochemistry (IHC) expression: IHC3+ or IHC2+/in situ hybridization (ISH)+ (cohort 1), IHC2+/ISH- or IHC1+ (cohort 2), and IHC0+ (cohort 3). Among the enrolled population (n = 186), 72 patients fell into cohort 1, 74 patients fell into cohort 2, and 40 patients fell into cohort 3.

All patients received intravenous trastuzumab deruxtecan at 5.4 mg/kg on day 1 of 21-day cycles.

The median PFS was 11.1 months (95% CI, 8.5-14.4) in cohort 1, 6.7 months (95% CI, 4.4-8.3) in cohort 2, and 4.2 months (95% CI, 2-5.7) in cohort 3. The median duration of response was 9.7 months (95% CI, 6.8-13), 7.6 months (95% CI, 4.2-9.2), and 6.8 months (95% CI, 2.8–not reached), respectively.

No new toxicity signals were observed, and notably, lower rates of interstitial lung disease (ILD) were observed compared with earlier studies.

In cohort 1, the activity with trastuzumab deruxtecan was consistent with established data. In cohort 2, the efficacy was encouraging, and phase 3 trials are ongoing to determine whether trastuzumab deruxtecan will offer a novel treatment for this large proportion of patients with HER2-low disease, although the influence of hormone receptor–status needs to be determined.2

The data from cohort 3 were considered intriguing because it is not yet known whether only patients with hormone receptor–positive, HER2 IHC0+ disease responded. It may have also been that patients had HER2 present, but it was undetectable by IHC.2

“There is probably some expression of HER2 in those tumors but not enough to be counted as [IHC]1+. However, there is some expression that is probably sufficient for the ADC to work, particularly with its bystander effect,” said Bardia during an interview with OncLive®.

In the interview, Bardia, an attending physician of Medical Oncology at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School, discussed the clinical implications of the DESTINY-Breast03 trial, the encouraging data from the DAISY trial, and sequencing questions that remain in the evolving paradigm of HER2-positive breast cancer.

OncLive®: How are you interpreting the results of the DESTINY-Breast03 trial in HER2-positive breast cancer?

Bardia: The DESTINY-Breast03 trial showed that trastuzumab deruxtecan is superior to T-DM1 [in HER2-positive breast cancer] with a very impressive HR, clear improvement in PFS, and a trend toward improvement in overall survival as well. That is a practice-changing study. Recently, the sponsor filed for approval and [trastuzumab deruxtecan] was given priority review by the FDA. We anticipate that trastuzumab deruxtecan will be the preferred agent in the second-line setting for patients with HER2-positive metastatic breast cancer. After first-line treatment with paclitaxel, trastuzumab [Herceptin], and pertuzumab [Perjeta], in the second-line setting, trastuzumab deruxtecan would be the preferred agent.

What data were observed regarding ILD/pneumonitis with trastuzumab deruxtecan?

The other thing that was striking about that abstract was that initially there was a lot of concern about pneumonitis with trastuzumab deruxtecan, including grade 5 pneumonitis. However, the incidence of that [seen in the DESTINY-Breast03 trial] was very low, particularly regarding grade 4 and higher pneumonitis. That highlights that early recognition and intervention of this toxicity is something that needs to be considered. As long as we recognize pneumonitis early and intervene, we can prevent higher-grade toxicity.

What data were observed from the DAISY trial during the SABCS meeting?

[We also saw data with] trastuzumab deruxtecan in HER2-low breast cancer. There was an interesting abstract that looked at trastuzumab deruxtecan in HER2 IHC0+ tumors. Even in that setting, we saw some benefit with trastuzumab deruxtecan, highlighting that HER2 IHC0+ is not really 0+.

What other agents are you looking forward to hearing more about?

There are interesting HER2-directed TKIs [emerging] as well. It started with lapatinib [Tykerb] and we now have neratinib [Nerlynx]. Pyrotinib is another HER2-directed TKI. There are others in development.

How do you anticipate these updates, as well as other recent approvals in HER2-positive breast cancer, will influence treatment sequencing?

We have multiple agents now besides standard trastuzumab plus chemotherapy: trastuzumab deruxtecan, T-DM1, tucatinib [Tukysa], neratinib, and margetuximab-cmkb [Margenza]. We need more understanding of mechanisms governing resistance to these agents so we can sequence therapies for an individual to continue to prolong survival.

We will have to move a bit [away] from a cookbook ideology in terms of step 1, step 2, step 3, etc. We need a more patient-centric approach in terms of trying to identify the mechanism of resistance in an individual patient. Based on the mechanism of resistance, we would then choose therapy sequentially. [Sequencing] might look like [drug] 1, [drug] 2, and [drug 3] for one patient, but [drug] 2, [drug] 1, then [drug] 3 in another. It could be a totally different approach for someone else. We need to tailor therapy depending on not only the patient’s characteristics, but also disease evolution.


  1. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Session GS3-01.
  2. Diéras V, Deluche E, Lusque A, et al. Trastuzumab deruxtecan (T-DXd) for advanced breast cancer patients (ABC), regardless HER2 status: a phase II study with biomarkers analysis (DAISY). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021. San Antonio, TX. Abstract 617.