Successful Trastuzumab-Deruxtecan Rechallenge After Interstitial Lung Disease: A Case Report

Abstract

Trastuzumab deruxtecan (T-DXd) is used to treat human epidermal growth factor receptor 2-positive advanced breast cancer. Interstitial lung disease (ILD) is a severe adverse event associated with T-DXd. Current guidelines recommend permanent discontinuation of T-DXd after Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 2 ILD. Here, we describe a case of successful rechallenge with T-DXd after CTCAE grade 2 treatment-induced ILD. After discontinuation of T-DXd, ILD was treated with steroids until complete resolution. Given the initial beneficial antitumor response, retreatment was discussed during disease progression. In a shared decision with the patient, T-DXd was restarted at the lowest registered dose, along with low-dose steroids. ILD did not reoccur. Importantly, both clinical and radiological responses to the treatment were observed, with an improvement in the patient’s quality of life. This case demonstrates that retreatment with T-DXd after a grade 2 ILD event is feasible and yields clinical benefit.

INTRODUCTION

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) registered for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (also known as ERBB2) advanced breast cancer [1,2]. Recent trials have proven its efficacy in several cancers [2,3], including HER2-low breast cancer [4]. Unlike other approved HER2-targeted therapies, T-DXd effectively targets tumor cells expressing low levels of HER2 and delivers its cytotoxic payload (deruxtecan) through the bystander effect on neighboring tumor cells [4]. Although effective, adverse drug reactions to T-DXd, especially lung toxicity, can be serious and life-threatening. The precise pathophysiology of T-DXd-induced Interstitial lung disease (ILD) is unknown; however, preclinical animal models suggest a dose-dependency [2,5]. Furthermore, toxicity appears to be related to the target-independent (and thus HER2-independent) uptake of deruxtecan by immune cells in the lungs, causing alveolar damage [2].

A recent pooled analysis of trial data from T-DXd showed that the incidence of ILD, including pneumonitis, was 15.4% [6]. The majority of ILD events were of Common Terminology Criteria for Adverse Events (CTCAE) grade < 3, with 4.2% of grade 1 (asymptomatic), 7.7% of grade 2 (symptomatic, with medical intervention indicated), 1.2% of grade 3 (medically significant, oxygen therapy indicated, not immediately life-threatening), 1% of grade 4 (life-threatening), and 25 patients (2.2%) with a grade 5 event (death related to the adverse event).

The present toxicity management guidelines and the summary of product characteristics recommend that once T-DXd-induced ILD is suspected, treatment should be interrupted until further evaluation and high-dose corticosteroids are advised. In case of computed tomography (CT) abnormalities only (CTCAE grade 1: asymptomatic), T-DXd may be restarted only if the event is fully resolved [1,7]. The same dose can be administered when resolution occurs within 28 days; however, if resolution takes longer, dose reduction is recommended. In the case the event is CTCAE grade ≥ 2 with symptoms and limiting instrumental activities of daily living (ADL) or a medical intervention is indicated, permanent discontinuation is recommended [1,7].

However, deviations from the guidelines can sometimes be considered. Here, we describe a case of T-DXd rechallenge after the resolution of ILD/pneumonitis (CTCAE grade 2).

CASE REPORT

A 39-year-old woman with HER2-positive breast cancer and multiple brain metastases who had been treated previously with trastuzumab/pertuzumab/chemotherapy, trastuzumab-emtansine (TDM-1), tucatinib/trastuzumab/capecitabine and whole-brain radiotherapy, was initiated on T-DXd treatment at the dose of 5.4 mg/kg every three weeks in an expanded access program. After three cycles a partial response was observed (Figure 1). She was subjected to evaluation four days after the start of the third cycle of T-DXd with mild dyspnea and a mild decrease in blood oxygen saturation (SpO₂, 97% in ambient air). Her medical history was unremarkable, with no pulmonary or chronic kidney disease history. She had never smoked. Laboratory tests showed clinically non-relevant anemia and an increase in liver chemistry CTCAE grade 1, whereas all other diagnostics, including high-resolution CT (HR-CT) chest, were unremarkable (Figure 1). Eleven days later, she presented with significantly worsened symptoms, including shortness of breath upon exertion and a non-productive cough on deep inhalation. Relevant findings on physical examination showed a SpO₂ of 94% (ambient air), tachycardia of 111 beats/min, and wheezing upon exhalation. The laboratory results were comparable, except for new leukocytopenia (CTCAE grade 1). A repeat chest CT examination showed no signs of pulmonary emboli; however, bilateral ground-glass opacities had developed (Figure 1). Diagnosed ILD was considered to be related to T-DXd and graded as CTCAE grade 2. Treatment with T-DXd was discontinued, and prednisolone 60 mg/day was initiated. The dyspnea abated quickly, with normal SpO₂ (97%) while breathing ambient air, six days later. After discontinuing T-DXd, treatment, trastuzumab monotherapy (6 mg/kg) was continued until radiologic progression of the brain metastases was observed three months later. Thereafter, rechallenge with T-DXd was considered because of the lack of other effective palliative treatment options. The apparent risk of ILD recurrence with the risk of death and guideline recommendations to refrain from restarting T-DXd, together with the imminent risk of progressive brain metastases, were discussed with the patient. Through shared decision-making, T-DXd was reinitiated at the lowest registered dose of 3.2 mg/kg every three weeks under a shield of prednisone 10 mg once daily. Furthermore, the patient was advised to measure her SpO₂ with a home monitoring device. She was instructed to contact the hospital in case of a recurrence of respiratory symptoms (e.g., dyspnea and nonproductive cough) or a decrease in SpO₂ to < 94%. Before each cycle, an evaluation was performed at the outpatient clinic, including SpO₂ measurement, physical examination, and laboratory evaluation. The response to treatment was evaluated using magnetic resonance imaging given the absence of other Response Evaluation Criteria In Solid Tumours (RECIST)-evaluable lesions on conventional CT. Moreover, ILD recurrence was evaluated using chest CT every 3–4 months. Prednisone-related side effects were monitored at the outpatient clinic. She was advised to take vitamin D 800 IE/day and maintain a sufficient dietary calcium intake. She was previously prescribed bisphosphonates for more than two years to prevent bone metastasis-related events. Pneumocystis jirovecii pneumonia prophylaxis was not indicated given the dose and duration of steroid therapy. The patient underwent 12 retreatment cycles (Figure 1). During retreatment, her oxygen saturation remained at a SpO₂ of 98%–99% while breathing ambient air without any respiratory symptoms. The glucose levels did not indicate steroid-induced diabetes mellitus. There was a partial radiologic response of both cerebral and non-cerebral metastases after three cycles of T-DXd rechallenge, and this response was maintained. No signs of ILD recurrence were observed on the chest CT. The patient’s quality of life has improved since the reintroduction of T-DXd.

Figure 1. Timeline overview of treatment, computed tomography chest images, and response evaluations using brain magnetic resonance imaging.

(A) Day 46, HR-CT chest with no significant abnormalities. (B) Day 57, HR-CT chest with bilateral ground glass opacities. (C) Day 128, dCT chest (with contrast), showing minimal residual ground glass opacities. (D) Day 231, dCT chest (with contrast), showing minimal to no residual ground glass opacities. (E) Day 330, HR-CT chest, showing no residual ground glass opacities. (F) Day 450, dCT chest (with contrast), showing no significant residual changes. (G) Timeline (on the scale) of initial T-DXd cycles (C1–C3) and retreatment/rechallenge T-DXd cycles (rC1–rC12). Days are counted from the start of C1d1 of the initial dosing of T-DXd. Between C3 and rC1 the patient was treated with trastuzumab 6 mg/kg every 3 weeks. The spaces between rC6 and rC8 are planned vacations. Radiological responses to treatment according to Response Evaluation Criteria In Solid Tumours (RECIST) 1.1 are indicated above the timeline, with a PR and PD.

HR-CT = high-resolution computed tomography; dCT = diagnostic computed tomography; T-DXd = trastuzumab deruxtecan; PR = partial response; PD = progressive disease; ED = emergency department; ECG = electrocardiogram; GGT = gamma-glutamyl transferase; ALT = alanine aminotransferase; MRI = magnetic resonance imaging.

^*Diagnostic workup included a normal ECG, low NT-proBNP, low inflammation markers, hemoglobin 6.3 mmol/L, leukocytes 7.1 × 10⁹/L, GGT 266 U/L, ALT 116 U/L, normal X-chest, negative viral swab (influenza A/B, respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2) and a HR-CT chest, see (A).

^†ECG: tachycardia 104 beats/min, intermediate axis, normal conduction times, negative T wave in III, aVF, V2–V3, otherwise normal, laboratory results: hemoglobin 5.8 mmol/L, leucocytes 3.7 × 10⁹/L, d-dimer 1.29 mg/L, C-reactive protein 43 mg/L, LDH 790 U/L, alkaline phosphatase 64 U/L, GGT 236 U/L, aspartate transaminase 56 U/L, ALT 90 U/L, creatinine 68 umol/L and a HR-CT chest, see (B).

Ethics

The patient described in this case report consented to the publication of a report detailing the case, including images and photographs (reviewed and approved).

DISCUSSION

T-DXd is an ADC with activity against tumors expressing HER2. A significant T-DXd associated side-effect is ILD [2]. When patients develop ILD it generally occurs within the first 12 months of treatment, as observed in this case [6]. Close monitoring and adequate patient education are vital for the early detection of ILD [8]. Moreover, even before symptoms occur, early detection halts further deterioration and has the advantage that T-DXd may be restarted if the event is fully resolved [1,2,7,8].

Other HER2-targeting antibodies, such as TDM-1 and trastuzumab-duocarmazine, can also cause ILD, although the reported incidences are much lower than those for T-DXd [2]. Moreover, drug-related ILD has been observed in other deruxtecan-containing ADCs with different targets, such as datopotamab-deruxtecan (targeting TROP2 instead of HER2) [2]. In the other ADCs, ILD management is different. For instance, for TDM-1, it is recommended to permanently discontinue only in case of grade ≥ 3 or grade 2 if the patient is not responding to the standard treatment [9].

Currently, we cannot predict those at risk of developing ILD. Furthermore, an early, accessible, and sensitive diagnostic tool is lacking [2,8]. Suspicion is based solely on the development of respiratory symptoms such as dyspnea or cough. Investigations are ongoing to determine whether changes in oxygen saturation, which could be monitored at home, may potentially be useful in the early diagnosis of ILD [8]. In the present case, HR-CT did not show abnormalities at the onset of symptoms, suggesting that HR-CT is not an optimal early screening tool for T-DXd-induced ILD. HR-CT may detect ILD changes only multiple days after the onset of symptoms. Further investigations into the pathophysiology of T-DXd-induced ILD and screening methods to allow for the early diagnosis of ILD are needed, and research on these topics is ongoing.

Although successful rechallenge has been described after CTCAE grade 1 ILD, this is the first case-report of a rechallenge after CTCAE grade 2 ILD. In this patient, rechallenge provided significant improvement in the quality of life and an ongoing clinical and radiologic response.

The current T-DXd management guidelines for ILD might need adaptation when more evidence-is available for the possibility of re-initiating treatment after the resolution of high-grade ILD (grade ≥ 2). Further research is required to identify the precautions and safety measures necessary for such a rechallenge.

ILD is a serious side effect of the novel ADC T-DXd. Given the impact of ILD, strict limitations have been described for a rechallenge. This case describes a well-considered rechallenge following a diagnosis of T-DXd-induced pneumonitis of CTCAE grade 2 when the ILD resolved completely while continuing low-dose steroids. Further studies are warranted to develop safe rechallenge protocols, with the prospect of continued access to an effective treatment for patients with limited therapeutic options.