NICE Recommends T-DXd for HER2-Low Metastatic Breast Cancer

The National Institute for Health and Care Excellence (NICE) has recommended fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) for reimbursement in England as a monotherapy for adults with unresectable or metastatic HER2-low breast cancer, according to a news release from AstraZeneca and Daiichi Sankyo.¹

The recommendation applies to patients who have received prior chemotherapy in the metastatic setting or whose disease recurred during or within 6 months of completing adjuvant chemotherapy. According to the institute, the decision has the potential to benefit more than 1000 eligible patients in England each year.¹

The decision arrives nearly 3 years after routine access to T-DXd was granted in Scotland in December 2023, and routine access for this population has also been granted in 26 other European countries.¹ AstraZeneca and Daiichi Sankyo stated that they plan to work with health bodies in Wales and Northern Ireland to support access following the NICE decision. NICE technology appraisal guidance does not automatically apply in Northern Ireland and will be reviewed by the Department of Health for local applicability, whereas in Wales, the National Health Service is required to fund treatments within 60 days of the first publication of NICE final draft guidance unless otherwise instructed by the Welsh Government.¹

T-DXd is supported by findings from the phase 3 DESTINY-Breast04 trial (NCT03734029), the same data that served as the basis for the FDA’s approval of T-DXd in HER2-low breast cancer in August 2022.^1,2 In the primary analysis, the median progression-free survival (PFS) in the overall population was 9.9 months (95% CI, 9.0-11.3) with T-DXd vs 5.1 months (95% CI, 4.2-6.8) with physician’s choice of chemotherapy (HR, 0.50; 95% CI, 0.40-0.63; P <.001); the median overall survival (OS) was 23.4 months (95% CI, 20.0-24.8) vs 16.8 months (95% CI, 14.5-20.0), respectively (HR, 0.64; 95% CI, 0.49-0.84; P = .001).³

Long-term results published in Nature Medicine showed that the survival benefit held with extended follow-up.³ After a median follow-up of 32.0 months (95% CI, 31.0-32.8), the median OS in the overall cohort was 22.9 months (95% CI, 21.2-24.5) with T-DXd and 16.8 months (95% CI, 14.1-19.5) with chemotherapy (HR, 0.69; 95% CI, 0.55-0.86). The 24-month OS rates were 47.3% vs 32.0%, and the 36-month OS rates were 26.2% vs 16.3%, respectively.

Among patients with hormone receptor (HR)–positive disease, median OS was 23.9 months (95% CI, 21.7-25.2) with T-DXd vs 17.6 months (95% CI, 15.1-20.2) with chemotherapy (HR, 0.69; 95% CI, 0.55-0.87). In an exploratory analysis of the HR-negative cohort, median OS was 17.1 months (95% CI, 13.6-23.0) vs 8.3 months (95% CI, 5.6-20.4), respectively (HR, 0.58; 95% CI, 0.31-1.08). OS also favored T-DXd in exploratory analyses of patients with estrogen receptor (ER)–low-positive tumors (22.3 vs 10.2 months; HR, 0.40; 95% CI, 0.20-0.79) and those with ER expression greater than 10% (24.0 vs 18.9 months; HR, 0.72; 95% CI, 0.56-0.93), which investigators suggested indicates that the efficacy of T-DXd is independent of ER level.³

Investigator-assessed median PFS in the overall cohort was 8.8 months (95% CI, 8.3-9.8) with T-DXd vs 4.2 months (95% CI, 3.0-4.5) with chemotherapy (HR, 0.36; 95% CI, 0.29-0.45). Median PFS2, defined as time from randomization to progression on the next line of therapy or death, was 15.4 months vs 9.7 months, respectively, which the authors noted suggests that T-DXd may not cause resistance to subsequent therapies.²

In DESTINY-Breast04, 557 patients across sites in Asia, Europe, and North America were randomly assigned 2:1 to receive T-DXd at 5.4 mg/kg intravenously every 3 weeks (n = 373) or physician’s choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (n = 184). Eligible patients had centrally confirmed HER2-low disease, defined as an immunohistochemistry score of 1+ or 2+ with a negative in situ hybridization result, and had received 1 or 2 prior lines of chemotherapy in the metastatic setting. Those with HR-positive disease were required to have received at least 1 line of endocrine therapy.²

The safety profile observed in DESTINY-Breast04 was consistent with previous clinical trials, with no new safety concerns identified. At the updated data cutoff, the median treatment duration was 8.2 months with T-DXd and 3.5 months with chemotherapy. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 54.4% vs 67.4% of patients, and 16.7% vs 8.1% discontinued treatment because of TEAEs, respectively. The most common any-grade drug-related TEAEs with T-DXd were nausea (76.0%), fatigue (55.0%), vomiting (40.7%), and alopecia (39.9%).

Adjudicated drug-related interstitial lung disease (ILD) or pneumonitis occurred in 12.1% of patients treated with T-DXd, most of which were grade 1 or 2; grade 5 events occurred in 4 patients (1.1%). The median time to onset was 129 days, and no new cases were reported after approximately 14 additional months of follow-up. Left ventricular dysfunction occurred in 5.1% of patients in the T-DXd arm and in none in the chemotherapy arm.²

The authors emphasized that proactive monitoring and management of ILD according to published guidelines is highly recommended. Because T-DXd is considered to carry a high emetic risk, prophylactic antiemetic regimens are important for patients’ quality of life. They described the analysis as the final update from DESTINY-Breast04, concluding that the results confirm T-DXd as a standard of care after chemotherapy for patients with HER2-low metastatic breast cancer.

References

1. Coffey D. AZ, Daiichi’s Enhertu wins long-awaited NICE blessing. Fierce Pharma. September 17, 2026. Accessed September 17, 2026. https://tinyurl.com/4kff7def

2. FDA approves first targeted therapy for HER2-low breast cancer. News Release. FDA. August 5, 2022. Accessed September 17, 2026. https://bit.ly/3BNUxWy

3. Modi S, Jacot W, Iwata H, et al. Trastuzumab deruxtecan in HER2-low metastatic breast cancer: long-term survival analysis of the randomized, phase 3 DESTINY-Breast04 trial. Nat Med. 2025;31(12):4205-4213. doi:10.1038/s41591-025-03981-4