T-DXd’s Role Expands Into HER2-Low/-Ultralow Metastatic Breast Cancer, Reinforcing Need for Enhanced HER2 Testing

The expanded role for fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) beyond HER2-positive metastatic breast cancer setting and into the HER2-low and -ultralow treatment paradigms has demonstrated the importance of improving HER2 testing capabilities and diligently assessing HER2 expression by immunohistochemistry (IHC) for patients with breast cancer, according to Aditya Bardia, MD, MPH, FASCO.

On January 27, 2025, the FDA approved T-DXd for the treatment of patients with adult patients with unresectable or metastatic, hormone receptor–positive, HER2-low or -ultralow breast cancer that has progressed on at least 1 endocrine therapy in the metastatic setting.1 HER2-low classification refers to tumors with a an IHC score of 1+ or 2+ with a negative in situ hybridization result, as determined by an FDA-approved test. HER2-ultralow disease is defined as an IHC score of 0 with membrane staining.

This regulatory decision was backed by data from the phase 3 DESTINY-Breast06 trial (NCT04494425). In the study, the overall population of patients with HER2-low or -ultralow, chemotherapy-naive, metastatic disease achieved a median progression-free survival (PFS) of 13.2 months (95% CI, 12.0-15.2) with T-DXd; the median PFS was 8.1 months (95% CI, 7.0-9.0) for patients treated with chemotherapy (HR, 0.64; 95% CI, 0.54-0.76; P < .0001).2

“This is a drug that can be used in hormone receptor–positive metastatic breast cancer, and it can be used in earlier lines compared with [its previous indications],” Bardia said in an interview with OncLive®.

In the interview, Bardia discussed how this approval has affected the treatment paradigm for patients with HER2-expressing, hormone receptor–positive, metastatic breast cancer, notable toxicities associated with T-DXd, and the need for further research to improve the field’s understanding of HER2 assays and pneumonitis risk factors.

Bardia is a professor in the Department of Medicine in the Division of Hematology/Oncology, the director of Translational Research Integration, and a member of Signal Transduction and Therapeutics at the UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles, California.

OncLive: Why is the addition of T-DXd to the HER2-low/-ultralow treatment paradigm significant?

Bardia: HER2-low and -ultralow metastatic hormone receptor–positive breast cancer is an operational definition. It refers to tumors that have some expression of HER2. If that expression is less than 10% of tumor cells, that’s HER2 ultralow [disease]. If it’s more than 10% of tumor cells, that’s HER2 low [breast cancer]. [This approval] highlights that the drug works in HER2-expressing breast cancer, which is most breast cancers. The reason it works is because of its mechanism of action. T-DXd is an antibody-drug conjugate [ADC], so it binds to the HER2 cells and then delivers the payload. Even if there’s [just] some expression of HER2, that’s sufficient for this drug to work.

What does this mean in practical terms for patients? This approval addresses 2 unmet needs. The first is that T-DXd is [now a treatment] option for patients with HER2-ultralow metastatic breast cancer. Previously, T-DXd was only approved for HER2-low metastatic breast cancer. [This indication encompasses] a broader patient population now. The second [need this agent meets] is [that of an effective treatment option in] earlier lines. Previously, patients needed to have received 1 prior line of chemotherapy before the use of T-DXd, but now it can be used even in patients who have not received prior chemotherapy.

What were some of the key efficacy findings from DESTINY-Breast06?

DESTINY-Breast06 was a global, phase 3 clinical trial that evaluated T-DXd vs physician’s choice of chemotherapy, which could either be a taxane or capecitabine, in patients who had not received chemotherapy but had received endocrine-based therapy for hormone receptor–positive, HER2-negative—which is both HER2-low as well as HER2-ultralow—metastatic breast cancer. DESTINY-Breast06 showed that patients who received T-DXd had superior PFS [outcomes compared with those who received chemotherapy]. The median PFS was 13.2 months [with T-DXd] compared with 8.1 months with standard chemotherapy.1 After CDK4/6 inhibitors, with T-DXd, we’ve seen a median PFS of more than 1 year for patients with hormone receptor–positive metastatic breast cancer. The overall response rate was also much higher [with T-DXd] than with standard chemotherapy, at 62.6% [vs 34.4%, respectively].1 Interestingly, the outcomes were similar in the HER2-low and -ultralow [populations, which] speaks to the mechanism of action of this drug.

Although the toxicity profile of T-DXd is well known, what are some important safety considerations when using this agent?

In DESTINY-Breast06, there were no surprises regarding the safety profile. There are 3 adverse effects [AEs] to know that are related to T-DXd. The first is nausea. That’s the number one AE we see with T-DXd. The second is some degree of myelosuppression. The third is pneumonitis, a rare but potentially serious AE that requires early recognition and management.

Will this approval affect HER2 testing strategies in breast cancer going forward?

Absolutely. It’s now critical to look for any expression of HER2 by IHC, because even if it’s 1% to 2% of the cells, that qualifies [the patient for] the use of T-DXd. What if [a tumor has] 0% [HER2 expression]? Does T-DXd work in that scenario? Maybe it does, because even HER2 IHC 0 [does not mean there is no level of HER2 expression]. However, that was not tested in DESTINY-Breast06. The phase 3 DESTINY-Breast15 trial [NCT05950945] is asking that question. For now, we have to stick with the label. If you get a report of IHC 0 from the pathologist, it’s important to ask the pathologist: Were there some cells that had HER2 expression, which is what we call HER2 ultralow or HER2 0+?

How might future research refine the use of T-DXd for patients with breast cancer?

What’s the best assay? Moving forward, we need more sensitive assays to evaluate HER2 expression and to identify how low we can go. What’s the lowest threshold [of HER2 expression] before T-DXd would not have efficacy? Ongoing research is investigating better analytical methods to measure HER2. [Additionally], more work is needed to understand how T-DXd works and how it causes pneumonitis, so we can further improve the safety profile of this product. Research is also ongoing to better understand which patients are at risk of developing pneumonitis and how we can further improve the efficacy-safety ratio of ADCs.

References

1. Enhertu approved in the US as first HER2-directed therapy for patients with HER2-low or HER2-ultralow metastatic breast cancer following disease progression after one or more endocrine therapies. News Release. AstraZeneca. January 27, 2025. Accessed February 26, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/enhertu-approved-in-us-for-breast-cancer-post-et.html
2. Bardia A, Hu X, Dent R, et al. Trastuzumab deruxtecan after endocrine therapy in metastatic breast cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086