This study included patients suspected of having T-DXd-induced lung injury who received treatment at Tokyo Medical University Hachioji Medical Center, Japan, between April 2020 and August 2024. Clinical data for each patient were retrieved from their medical records. All patients treated with T-DXd were confirmed to have no pre-existing pneumonia, including interstitial lung disease (ILD). Consequently, the newly observed ILD on chest computed tomography (CT) was diagnosed as T-DXd-induced lung injury. High-resolution CT images were analysed by two respiratory physicians, who determined and classified the imaging patterns. The enrolled patients were divided into two groups: those diagnosed with T-DXd-induced lung injury and those without. The clinical characteristics of patients in both groups were retrospectively compared. Additionally, detailed case reports were compiled for patients diagnosed with T-DXd-induced lung injury. Patient survival was monitored until December 2024. The Ethics Committee of Tokyo Medical University approved this retrospective study protocol (Ethical Approval Number: T2024-0048) and waived the requirement for informed consent. However, we provided study participants the opportunity to refuse participation in this study using the opt-out method. All study methods were conducted in accordance with relevant guidelines and regulations.

We investigated the following patient characteristics: sex, age, estimated glomerular filtration rate (eGFR), SpO₂, T-DXd doses, the number of lines of treatment, number of courses of treatment, duration of T-DXd administration, percentage of breast cancer, and lung comorbidities, such as chronic obstructive pulmonary disease and interstitial lung disease. Patient age, eGFR value, SpO₂ percentage, and type of lung comorbidity were recorded at the start of T-DXd treatment.

All values were expressed as medians and interquartile ranges. Fisher’s exact test and the Mann-Whitney U test were used to compare baseline patient characteristics. The time of onset of T-DXd-induced lung injury was assessed using the Kaplan-Meier curve. A p-value of less than 0.05 was set as the threshold for statistical significance. Statistical analyses were performed using EZR software version 1.54 (Saitama Medical Center, Jichi Medical University, Saitama, Japan).

Between December 2020 and December 2024, a total of 16 patients underwent treatment with T-DXd. The median age of the patients was 61.5 (53 - 86) years; 81.3% were women, 87.5% had been diagnosed with breast cancer, and 12.5% with stomach cancer. Four out of 16 patients developed T-DXd-induced lung injury. No significant differences were observed in the characteristics of patients between the two groups ( Table 1 ).

The Kaplan-Meier survival curves for the patients are shown in Figure 1 . During the observation period, four patients developed T-DXd-induced lung injury, with a median onset time of 10.32 months (95% Confidence Interval: 9.26-NA).

The median values were shown. The data were shown before T-DXd was administered. Times of lines indicate the number of types of chemotherapy until T-DXd was administered, and times of courses indicate the number of times T-DXd was administered. T-DXd, trastuzumab deruxtecan; eGFR, estimated glomerular filtration rate; SpO₂, saturation of percutaneous oxygen.

Case 1

A 59-year-old woman presented to our hospital with dyspnea. Eight years ago, she had undergone surgery followed by post-operative radiotherapy for breast cancer. Later, due to a history of breast cancer recurrence, she received drug therapies, including tamoxifen, epirubicin and cyclophosphamide, paclitaxel, capecitabine, and eribulin. Dyspnea developed after two courses of T-DXd at a dose of 5.4 mg/kg had been administered to treat recurrent breast cancer, followed by a fifth-line treatment. The body temperature of the patient was 36.7˚C, respiratory rate was 20/min, and her SpO₂ was 97% with 5 L/min oxygen. Chest CT demonstrated ground-glass opacity with a diffuse alveolar damage (DAD) pattern in both lungs ( Figure 2(A)-(C) ). Blood tests showed elevated lactate dehydrogenase (LD) and c-reactive protein (CRP) levels, but no increase in Krebs von den Lungen 6 (KL-6) levels ( Table 2 ). High-dose steroids were immediately administered ( Figure 3(A) ). Although the T-DXd-induced lung injury improved, a palliative treatment approach was adopted for managing breast cancer due to the patient’s declined performance status.

WBC: white blood cell count; Neu: neutrophil; Eos: eosinophils; Bas: basophils; Lym: lymphocytes; Mo: macrophage; RBC: red blood cell count; Hb: hemoglobin; Plt: platelet; Alb: albumin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; LD: lactate dehydrogenase; BUN: blood urea nitrogen; Cre: creatinine; CRP: c-reactive protein; KL-6: Krebs von den Lungen 6.

Case 2

A 54-year-old woman received 13 courses of T-DXd at a dose of 5.4 mg/kg. This was followed by a sixth-line treatment, during which a blood test revealed an elevated KL-6 level of 1155 U/mL. Two years ago, she had undergone surgery and received drug therapies, including docetaxel, trastuzumab and pertuzumab, eribulin and trastuzumab, epirubicin and cyclophosphamide, and letrozole. There were no symptoms, but chest CT demonstrated ground-glass opacity with an organizing pneumonia (OP) pattern in both lungs ( Figure 2(D)-(F) ). Blood tests revealed elevated levels of LD and KL-6, with no corresponding increase in CRP levels ( Table 2 ). No worsening of the observed shadow was noted via imaging examination, and letrozole was administered 14 days after the diagnosis of T-DXd-induced lung injury.

Case 3

A 77-year-old woman was diagnosed with T-DXd-induced lung injury after an abnormal shadow was incidentally noted during a periodic imaging examination. This occurred while she was receiving 14 courses of T-DXd at a dose of 5.4 mg/kg, followed by a seventh-line treatment. Ten years ago, she had undergone surgery and received drug therapies, including carboplatin and paclitaxel, exemestane, fulvestrant, toremifene, tegafur gimeracil oteracil potassium, eribulin, epirubicin and cyclophosphamide, carboplatin and gemcitabine, fulvestrant and palbociclib. There were no symptoms, and chest CT demonstrated consolidation with an OP pattern that did not align with the bronchovascular bundle, which was situated just below the pleura in both lower lobes ( Figure 2(G)-(I) ). Blood tests showed no increase in LD, CRP, and KL-6 levels ( Table 2 ). Twenty milligrams of prednisolone were immediately administered. Imaging examination revealed that the shadows had a tendency to improve, so the prednisolone treatment was tapered off. She was administered capecitabine 70 days after being diagnosed with T-DXd-induced lung injury.

Case 4

A 58-year-old woman presented to our hospital with dyspnea and fever. Three years ago, she had undergone surgery and received drug therapies, including pertuzumab, trastuzumab docetaxel, eribulin, and trastuzumab. Dyspnea and fever developed after the administration of 15 courses of T-DXd at a dose of 5.4 mg/kg, followed by an eighth-line treatment. The body temperature of the patient was 36.6˚C, respiratory rate was 24/min, and her SpO₂ was 85% on room air. Chest CT demonstrated ground-glass opacity with a DAD pattern in both lungs ( Figure 2(J)-(L) ). Blood tests showed elevated LD, CRP, and KL-6 ( Table 2 ). High-dose steroids were immediately administered ( Figure 3(B) ). The patient was admitted to the intensive care unit for ventilator management; however, respiratory failure worsened, and the patient ultimately passed away.

Four cases of T-DXd-induced lung injury are summarized in Table 3 .

DAD, diffuse alveolar damage; OP, organizing pneumonia; mPSL, methylprednisolone; PSL, prednisolone.