Enhertu Displaces T-DM1 in Residual Disease but Payer and Lung Risk Loom

EU Approves Enhertu for Adjuvant HER2-Positive Early Breast Cancer

AstraZeneca and Daiichi Sankyo's Enhertu (trastuzumab deruxtecan) has received European Union approval as a monotherapy for the adjuvant treatment of adult patients with resected HER2-positive breast cancer who have residual invasive disease after neoadjuvant taxane-based and HER2-targeted treatment. This approval is based on the DESTINY-Breast05 Phase III trial, which demonstrated Enhertu significantly reduced the risk of invasive disease recurrence or death by 53% (HR 0.47) compared to trastuzumab emtansine (T-DM1). The trial showed a three-year invasive disease-free survival (IDFS) rate of 92.4% for Enhertu versus 83.7% for T-DM1, establishing a new benchmark in this curative-intent setting.

• Enhertu has secured its first EU approval in the curative-intent early breast cancer setting, specifically for adjuvant treatment of adult patients with resected HER2-positive breast cancer who have residual invasive disease after neoadjuvant taxane-based and HER2-targeted treatment. This follows a positive opinion from the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP).
• The Phase III DESTINY-Breast05 trial demonstrated Enhertu significantly reduced the risk of invasive disease recurrence or death (invasive disease-free survival [IDFS]) by 53% (based on a hazard ratio [HR] of 0.47; 95% confidence interval [CI] 0.34-0.66; p<0.0001) compared to trastuzumab emtansine (T-DM1). Enhertu achieved a three-year IDFS rate of 92.4% (95% CI 89.7-94.4), significantly outperforming T-DM1's 83.7% (95% CI 80.2-86.7).
• The safety profile of Enhertu in the DESTINY-Breast05 trial was consistent with its known profile, with no new safety concerns identified. Following this EU approval, AstraZeneca will make a $75 million milestone payment to Daiichi Sankyo for the adjuvant HER2-positive early breast cancer indication, as per their collaboration agreement.

Addressing the Unmet Need in HER2-Positive Early Breast Cancer

Patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy remain at higher recurrence risk than those achieving pathological complete response (pCR). T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy, but central nervous system relapse and cardiac safety remain limitations.

• Higher recurrence risk without pCR: After a median follow-up of 3.2 years in 526 early stage HER2-positive patients treated with an HP-based regimen, the 3-year DFS was 95% vs 91%, p = 0.03 in pCR versus non-pCR groups. In the EPHOS-B trial, after 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died, and no recurrences or deaths were observed among patients who achieved a pCR.

• Blood-brain barrier sanctuary and brain metastases: The blood-brain barrier (BBB) still shelters micrometastatic deposits, so intracranial relapse continues to pose a formidable therapeutic obstacle. This reflects limitations of large-molecule monoclonal antibodies in preventing CNS recurrence due to poor BBB permeability, illustrated by a 60-year-old woman with HER2-positive, hormone receptor-negative breast cancer who achieved pCR after neoadjuvant docetaxel combined with trastuzumab and pertuzumab, followed by 12 months of maintenance trastuzumab and pertuzumab, yet developed multifocal brain metastases two months after completing maintenance therapy, without extracranial recurrence. In the 526-patient cohort, 7 out of 286 patients with pCR had a BM while 5 out of 240 non-pCR patients had a BM, suggesting that the BM incidence could not be associated with pCR.

• Cardiotoxicity of T-DM1-containing therapy: In a pooled analysis of 1961 patients exposed to T-DM1 in seven trials, CHF/LVEF drop grade 3/4 was reported in 0.71%, cardiac ischemia in 0.1%, cardiac arrhythmia in 0.71% and grade 1/2 LVEF drop in 2.04%, with total CE rate of 3.37% (95% confidence interval (CI), 2.6%-4.3%). Multivariate analysis showed patient's age ≥65 (OR 3.0; 95% CI, 1.77-5.14; P-value <0.001) and baseline LVEF<55% (OR 2.62; 95% CI, 1.29-5.32; P-value 0.008) as risk factors, and CEs resolved in most (79%) patients after treatment discontinuation.

DESTINY-Breast05: The Pivotal Data Behind Enhertu's Approval

In patients with HER2-positive early breast cancer and residual invasive disease after neoadjuvant therapy, postneoadjuvant escalation has redefined the standard of care. The KATHERINE trial established ado-trastuzumab emtansine (T-DM1) over trastuzumab, while DESTINY-Breast05 compared trastuzumab deruxtecan (T-DXd) to T-DM1 in high-risk residual disease.

Enhertu's Broadening Impact Across HER2-Targeted Cancers

Trastuzumab deruxtecan (Enhertu, T-DXd) is being evaluated across multiple HER2-expressing, HER2-low/ultralow, HER2-mutant and HER2-amplified settings beyond high-risk residual HER2-positive early breast cancer. Trials span metastatic breast cancer, gastric/gastroesophageal cancer, non-small-cell lung cancer and tumor-agnostic solid tumors, using both monotherapy and combination intervention models.

• Hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) after one or more lines of endocrine-based therapy: phase 3, multicenter, open-label trial (DESTINY-Breast06, NCT04494425) with patients randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy.

• HER2-expressing locally advanced or metastatic disease after ≥1 systemic treatment or without alternative treatments: open-label phase II study (DESTINY-PanTumor02) of T-DXd (5.4 mg/kg once every 3 weeks) for HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) disease across seven tumor cohorts: endometrial, cervical, ovarian, bladder, biliary tract, pancreatic, and other.

• HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma after progression while receiving trastuzumab-based therapy: international, randomized, phase 3 trial (DESTINY-Gastric04, NCT04704934) comparing second-line trastuzumab deruxtecan at a dose of 6.4 mg per kilogram of body weight with ramucirumab plus paclitaxel.

• Metastatic HER2-mutant non-small-cell lung cancer refractory to standard treatment: multicenter, international, phase 2 study (DESTINY-Lung01, NCT03505710) in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered, with objective response as assessed by independent central review.

• Advanced HER2-amplified solid tumors detected by cell-free DNA testing: multicenter, single-arm, Phase II Basket Trial (HERALD/EPOC1806) administering T-DXd at 5.4 mg/kg once every 3 weeks until onset of disease progression or intolerable toxicity in 62 patients with 16 cancer types with a median baseline plasma HER2 copy number (CN) of 8.55 (range, 2.4-73.9).

• HER2-positive breast cancer with newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy: prospective, open-label, single-arm, phase 2 TUXEDO-1 trial (NCT04752059) of trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks.

• HER2-positive gastroesophageal adenocarcinoma with persistence of minimal residual disease in liquid biopsy after pre-operative chemotherapy and radical surgery: multicentre, randomized, open-label, interventional phase II study (TRINITY, NCT06253650) randomized on a 1:1 basis to adjuvant T-DXd (6.4 mg/kg IV on day 1) plus either capecitabine (1000 mg/sqm BID orally on days 1-14) or 5-fluorouracil (600 mg/sqm continuous IV infusion on days 1-5) Q3 W for 6 cycles, or to standard post-operative FLOT for 4 cycles.

• Previously treated HER2-positive metastatic breast cancer or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinomas following treatment with trastuzumab deruxtecan (T-DXd): international Phase Ib/II open-label trial (Beamion BCGC-1, NCT06324357) of zongertinib alone or in combination, with Phase Ib (dose escalation) determining the maximum tolerated dose of zongertinib plus trastuzumab emtansine (T-DM1), T-DXd, or trastuzumab ± capecitabine, in HER2-positive mBC, and plus T-DXd in HER2-positive mGEAC, and Phase II (dose optimization) assessing two doses of zongertinib in combination regimens, or as monotherapy.

Enhertu Sets New Adjuvant Standard in High-Risk HER2+ Breast Cancer

The recent European Union approval of Enhertu for adjuvant HER2-positive breast cancer with residual invasive disease represents a significant advancement for patients facing a high risk of recurrence. This decision is particularly impactful as it positions Enhertu as the new benchmark, having demonstrated superior efficacy over trastuzumab emtansine (T-DM1), the previous standard in this setting. For patients who do not achieve a pathological complete response after neoadjuvant therapy, the 53% reduction in the risk of invasive disease recurrence or death with Enhertu is a profound clinical benefit, offering a greater chance for long-term, disease-free survival.

This shift underscores the evolving landscape of HER2-positive breast cancer treatment, where advanced antibody-drug conjugates are redefining therapeutic expectations. The strategic implications are clear: Enhertu is poised to become the preferred adjuvant therapy for this specific high-risk population, solidifying its market presence and influencing future development in precision oncology. However, this progress comes with important considerations. The literature highlights that Enhertu is associated with a higher incidence of interstitial lung disease (ILD) or pneumonitis, including severe and fatal cases. This necessitates rigorous patient monitoring and proactive management strategies to ensure patient safety and maximize therapeutic benefit. Clinicians must be well-versed in identifying and managing these toxicities, as well as other common adverse events like nausea, vomiting, and neutropenia, to maintain treatment adherence over the long adjuvant course. While the invasive disease-free survival data are compelling, continued follow-up for overall survival and long-term safety, particularly for cardiac events, remains crucial. This approval not only offers a new, more effective option for patients but also reinforces the importance of tailoring adjuvant therapy based on response to neoadjuvant treatment, driving further research into optimizing outcomes for those with residual disease.