Dexamethasone Premedication to Prevent Grade ≥2 Interstitial Lung Disease in Breast Cancer Patients Receiving Trastuzumab Deruxtecan

Trial ID: 2025-521798-15-00
Sponsor: Istituto Di Ricerche Farmacologiche Mario Negri

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Diseases & Conditions

Breast cancer

Objectives

The primary objective is to evaluate the efficacy of pre‑treatment with dexamethasone in reducing the incidence of grade > 1 interstitial lung disease among patients with breast cancer receiving trastuzumab deruxtecan. Secondary objectives include:

Characterization of interstitial lung disease during treatment.
Assessment of the impact of dexamethasone premedication on treatment‑related toxicities.
Evaluation of respiratory symptoms and pulmonary function parameters.
Investigation of overall safety profile and health‑related quality of life.
Analysis of prior radiotherapy as a risk factor for pulmonary toxicity.
Determination of the pharmacokinetics of deruxtecan.
Correlation of pulmonary function measures with development of interstitial lung disease.

Participants

The trial enrolled adult individuals aged ≥ 18 years, inclusive of both female and male participants, who had a diagnosis of metastatic breast cancer confirmed histologically or cytologically and were candidates for treatment with trastuzumab‑deruxtecan. Eligible subjects required an Eastern Cooperative Oncology Group performance status of 0 or 1 and demonstrated adequate bone‑marrow function (ANC ≥ 1.5 × 10⁹/L, platelets ≥ 100 × 10⁹/L, hemoglobin ≥ 9.0 g/dL) as well as hepatic function within predefined limits. No specific dietary, physical‑activity, or habit‑related criteria were stipulated. The sponsor did not provide information regarding the total number of participants enrolled in the study.

Plans and Procedures

The trial is a phase III, randomized, controlled study assessing oral dexamethasone 8 mg pre‑medication versus no pre‑medication in patients with metastatic breast cancer scheduled to receive trastuzumab deruxtecan; participants are followed for approximately 12 months after randomization. After a screening visit confirming eligibility criteria, patients undergo a baseline/randomization visit during which the study drug is assigned and the first dose of dexamethasone (or control) is administered before the initial trastuzumab deruxtecan infusion. Subsequent study visits are scheduled at months 3, 6, 9, and 12 and include high‑resolution thoracic CT imaging, laboratory assessments, adverse‑event reporting, and patient‑reported outcome questionnaires; the month‑12 visit also serves as the end‑of‑study assessment. The overall participant involvement therefore comprises the screening period plus the 12‑month treatment and follow‑up phase. Early termination may occur if a participant withdraws consent, experiences unacceptable toxicity, requires permanent discontinuation of trastuzumab deruxtecan for reasons other than interstitial lung disease > grade 1, or is lost to follow‑up, in which case the patient is withdrawn from further study procedures.

Treatment

The investigational product is dexamethasone 4 mg tablets supplied in solid oral form. Each dose consists of 8 mg (equivalent to two tablets) administered by buccal use. The medication is provided as a tablet and taken orally prior to the administration of trastuzumab deruxtecan.

All participants receive standard trastuzumab deruxtecan therapy according to the approved dosing regimen for HER2‑positive breast cancer. No placebo or alternative comparator is specified in the protocol.

Drug administration is recorded in the study case report form, and compliance with the premedication schedule is verified by pill count and patient diary entries. Dosing times are aligned with the scheduled trastuzumab deruxtecan infusion to ensure consistent exposure.

Efficacy

Efficacy will be evaluated primarily by the cumulative incidence of patients who develop interstitial lung disease greater than grade 1 (ILD > G1) as detected on high‑resolution thoracic CT scans during treatment with trastuzumab deruxtecan. Incidence will be assessed at 12 months post‑randomisation, using the local investigator’s judgement according to CTCAE version 6.0; discontinuation of trastuzumab deruxtecan for reasons other than ILD > G1 will be treated as a competing event.

Secondary efficacy assessments comprise:

Cumulative incidence of ILD > G1 at 3, 6, and 9 months post‑randomisation.
Cumulative incidence of any‑grade ILD at 3, 6, 9, and 12 months.
Proportion of patients diagnosed with ILD > G1 by central retrospective review of HR CT scans and clinical history within 12 months, based on CTCAE v6.0 and multidisciplinary team assessment.
Identification of specific radiological ILD patterns through centralized multidisciplinary discussion.
Cumulative incidence of nausea or vomiting (any grade and > G2) at 3, 6, 9, and 12 months.
Cumulative incidence of AST/ALT elevation (any grade and > G2) at 3, 6, 9, and 12 months.
Cumulative incidence of permanent trastuzumab deruxtecan discontinuation due to drug‑related adverse events at 3, 6, 9, and 12 months.
Proportion of patients requiring dose reduction due to treatment‑related adverse events.
Cumulative incidence of cough (any grade and > G2) assessed with the Cough Symptom Score at 3, 6, 9, and 12 months.
Cumulative incidence of dyspnea (any grade and > G2) assessed with the Modified Medical Research Council Dyspnea Scale at 3, 6, 9, and 12 months.
Changes from baseline in peripheral oxygen saturation (SpO₂), forced vital capacity (FVC), and diffusing capacity for carbon monoxide (DLCO) at 3, 6, 9, and 12 months.
Worst adverse‑event grade for each event type according to NCI‑CTCAE v6.0, and proportion of patients experiencing grade 3‑5 events.
Frequency, nature, and number of serious adverse events, serious adverse drug reactions, and suspected unexpected serious adverse reactions.
Change from baseline in each domain of the EORTC QLQ‑FA12 questionnaire at planned study visits.
Change from baseline in EQ‑5D‑5L health state profile, utility score, and EQ‑VAS score at planned study visits.
Cumulative incidence of ILD stratified by prior radiotherapy to the breast and/or thorax.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Provision of signed, written and dated study informed consent, data protection informed consent and any locally required
Women or men aged ≥18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature
Histologically or cytologically confirmed metastatic breast cancer for which T-DXd treatment is approved and available at the participating center.
Diagnosis of metastatic breast cancer candidate to start a treatment with T-DXd in the subsequent settings: a. HR-positive with expression of HER2 (low or ultralow) ≤ 2 lines of chemotherapy in advanced disease b. HR-negative with expression of HER2-low ≤ 2 lines of chemotherapy in advanced disease c. HER2-positive independently from HR-positivity ≤ 3 lines of treatment in advanced disease
ECOG performance status of 0 or 1.
Adequate bone marrow as defined by the following laboratory values: a. ANC ≥1.5 × 109 /L b. Platelets ≥100 × 109 /L c. Hemoglobin ≥9.0 g/dL
Adequate hepatic function: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert’s disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) < 1.5.
Adequate washout before randomization, including ≥4 weeks from major surgery or chest radiotherapy (≥2 weeks for non-chest stereotactic radiotherapy)
Patient willing and able to comply with the protocol procedures for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.

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Exclusion Criteria

Patients with uncontrolled diabetes mellitus both type 1 and type 2 (HbA1c > 8.5%).
Patients with contraindications to dexamethasone, as determined by the investigator in consultation with medical monitoring before enrolment.
Patients already undergoing chronic steroid treatment (e.g. 10 mg/day of prednisone/prednisolone or equivalent).
Patients requiring oxygen therapy at rest.
Documented pneumonitis/ILD prior to Cycle 1 Day 1.
Uncontrolled or significant cardiovascular disease, including recent myocardial infarction (within 6 months), symptomatic heart failure (NYHA II–IV), elevated troponin without symptoms requiring cardiology evaluation, uncontrolled hypertension or arrhythmias, and QTcF prolongation >470 ms in females or >450 ms in males.
Impaired renal function with creatinine clearance <30 mL/min (calculated by Cockcroft-Gault formula).
Active or newly diagnosed CNS metastases, including meningeal carcinomatosis
Patients with recent (<28 days) respiratory infections
Inability to take oral medications, refractory or chronic nausea, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impacts the absorption of the study drug.
Palliative limited-field radiotherapy: <2 weeks (non-chest) or <4 weeks (chest or >30% bone marrow).
Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 390 days after the last dose of IMP.
Active and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
Evidence of ongoing alcohol or drug abuse as assessed by the Investigator.
Any severe medical or psychiatric condition that, in the Investigator’s opinion, would preclude the patient’s participation in a clinical study
Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during study participation. Female subjects without childbearing potential are defined as women who are surgically sterile (hysterectomy or documented bilateral tubal ligation) or postmenopausal, defined as at least 12 months of spontaneous amenorrhea.
Known allergy or hypersensitivity to study drugs or any excipient.