Can Patients Be Retreated After Developing Serious Lung Side Effects From Enhertu?

Promising Real-World Findings From ASCO 2025

Why Does It Matter?

The antibody-drug conjugate containing trastuzumab deruxtecan (T-DXd), Enhertu, targets HER2-positive and HER2-low breast cancer and shows promising results in many solid tumors. However, this powerful treatment faces an important obstacle: interstitial lung disease (ILD). While ILD may require permanent treatment discontinuation in some patients, could treatment be interrupted and then restarted in others?

A new multicenter study addressing this critical question was presented at the ASCO 2025 Congress. The study suggests that carefully restarting T-DXd in patients who developed mild (Grade 1) ILD may be safe and effective. This article reviews the study details, data and implications for clinical practice.

T-DXd and ILD Risk: Background

• Drug Action: T-DXd stands out for its tumor-specific HER2-targeted action and cytotoxic payload.

• ILD Risk: The incidence of ILD in clinical trials ranges from 11–15%.

• Where Is the Danger?: ILD is known to cause severe respiratory failure and even death in some patients.

📚 What Is ILD Grading?

Grades 1–5 of interstitial lung disease (ILD) are defined using CTCAE v5.0 (Common Terminology Criteria for Adverse Events, Version 5.0), an international standard toxicity classification system. It is used particularly in clinical research to define and grade drug-related adverse events.

🔎 Relevant CTCAE headings:

➡️ “Pneumonitis” or “Interstitial Lung Disease”

Summary Definitions According to CTCAE:

• 🟢 Grade 1: Radiological findings present, no symptoms

• 🟡 Grade 2: Mild–moderate symptoms; no limitation of daily living

• 🟠 Grade 3: Marked symptoms; limitations in daily activities, hospitalization may be required

• 🔴 Grade 4: Life-threatening; requires intensive care and supportive treatment

• ⚫ Grade 5: An event resulting in death

What Is the Current Clinical Approach?

ASCO 2025 Presentation: Is Enhertu Retreatment Safe in Real-World Data?

Presented by Dr. Hope Rugo and her team, this study examined patients treated with T-DXd at 5 US centers between 2017–2024. The total number was 1476 , and their data were analyzed retrospectively. In this population, 9.6% (n=143) developed ILD of any grade.

Who Received Retreatment?

• Of 59 patients who developed Grade 1 ILD, 44 (75%) were retreated with T-DXd.

• After Grade 2 ILD, 19 patientswere retreated based on clinical judgment.

Findings in Numbers:

Data on Restarting the Drug After Grade 2:

• ILD recurred in 3 of 19 patients: 1 Grade 2, 1 Grade 3 and 1 Grade 4.

• No fatal ILD was observed.

What Does This Mean in Clinical Practice?

1. The Restart Strategy Should Be Individualized

• After Grade 1 ILD, the drug may be restarted if imaging shows resolution.

• Steroid support accelerates recovery: initiation at a dose of 0.5 mg/kg is particularly recommended.

2. Monitoring Protocol

• The first 12 months are a high-risk period: chest CT every 9–12 weeks is recommended.

• In high-risk patients (older adults, those with renal impairment or a history of ILD), imaging should be performed within the first 6 weeks.

3. Restarting the Drug After Grade 2?

• The standard recommendation is not to restart.

• However, if alternative diagnoses such as infection or asthma are possible, restarting may be considered after careful clinical assessment.

Conclusion: Promising Data That Require Careful Interpretation

This study indicates that, in real-world practice, T-DXd after Grade 1 ILD can be restarted and may provide long-term benefit . Steroid use substantially shortens recovery time, while the rate of ILD recurrence after restarting is acceptable. Data on restarting after Grade 2 ILD are more limited and indicate a need for caution.

Ultimately, with potent agents that prolong survival, such as T-DXd, it is possible to make individualized decisions rather than all-or-nothing decisions after toxicities such as ILD. This study suggests that advanced imaging, steroid support and multidisciplinary monitoring may keep the door open to retreatment.