T-DXd Side Effects in Breast Cancer Warrant Continued Attention

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) comprising a humanized anti-HER2 monoclonal antibody covalently linked to a topoisomerase I inhibitor payload via a cleavable tetrapeptide-based linker. It is approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen, and for adult patients with unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. The mechanism of action involves binding to HER2-expressing cells, internalization, and subsequent release of the topoisomerase I inhibitor, leading to DNA damage and apoptosis.¹

While T-DXd has shown superior efficacy compared to standard chemotherapy in various clinical settings, its safety profile requires specific attention. The most clinically significant adverse event associated with T-DXd is interstitial lung disease (ILD), including pneumonitis, which can be severe and, in rare cases, fatal.¹ Other common adverse events include nausea, fatigue, alopecia, vomiting, constipation, decreased appetite, and myelosuppression (neutropenia, anaemia, leukopenia).¹

Adverse Event Profile and Management

The incidence of drug-related ILD/pneumonitis with T-DXd has been reported across multiple clinical trials. In studies such as DESTINY-Breast03, the incidence of any-grade ILD was 10.9%, with grade 3 or 4 events occurring in 0.8% of patients. Fatal ILD events were reported in 0.2% of patients.² The median time to onset of ILD has varied but typically falls within the first year of treatment.²

Risk factors for T-DXd-related ILD are not fully elucidated, but pre-existing lung conditions, older age, and prior radiation therapy to the chest may increase susceptibility.¹ Early detection and management are critical for improving outcomes. Patients should be counselled on the symptoms of ILD, which include dyspnoea, cough, fever, and new or worsening respiratory symptoms.¹

Management guidelines recommend prompt interruption of T-DXd therapy upon suspicion of ILD. Grade 1 ILD typically requires dose interruption and close monitoring. For grade 2 or higher ILD, permanent discontinuation of T-DXd is generally recommended, along with corticosteroid treatment. For grade 2 ILD, corticosteroids (e.g., prednisone 0.5-1 mg/kg/day) should be initiated and tapered over at least 4 weeks. For grade 3 or 4 ILD, higher doses of corticosteroids (e.g., prednisone 1 mg/kg/day or methylprednisolone 1 mg/kg/day intravenously) are indicated, followed by a prolonged taper.¹

Regular monitoring of pulmonary function tests and chest imaging (e.g., CT scans) may be considered, particularly for patients with pre-existing respiratory conditions or those who develop new respiratory symptoms. However, routine screening with CT scans in asymptomatic patients is not currently recommended. Instead, a high index of suspicion based on clinical symptoms is paramount.¹

Other adverse events, such as nausea and vomiting, can often be managed with antiemetic prophylaxis. Myelosuppression requires regular complete blood count monitoring and dose modifications or growth factor support as appropriate. Cardiac toxicity, while less common than with other HER2-targeted therapies, should also be considered, particularly in patients with pre-existing cardiac conditions.¹

The continued clinical utility of T-DXd in breast cancer is undeniable, given its demonstrated efficacy. However, this efficacy must be balanced with a thorough understanding and proactive management of its unique safety profile, particularly concerning ILD. Adherence to established monitoring and management protocols is essential for optimising patient outcomes and ensuring the safe use of this important therapeutic agent.¹