Effectiveness of trastuzumab deruxtecan rechallenge in a patient with HER2-positive metastatic breast cancer: a case report

Abstract

Trastuzumab deruxtecan (T-DXd), a high-payload antibody drug conjugate, has been reported to exert potent antitumor effects and has recently shown promising efficacy against human epidermal growth factor receptor 2 (HER2)-positive adenocarcinoma. Despite its high efficacy, interstitial lung disease (ILD) is a severe adverse event (AE) associated with T-DXd. This report describes a patient who was successfully treated with a dose-reduced T-DXd challenge after recovery from ILD. Little disease progression was observed during the treatment interruption period; thus, the effect of T-DXd was considered to have been maintained. T-DXd may induce ILD, and re-administration under careful observation is considered an important option for treating patients with HER2-positive breast cancer.

Introduction

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) that is registered for the treatment of HER2-positive advanced breast cancer and several other solid malignancies. It is composed of an antibody, a terapeptide-based cleavable linker, and a topoisomerase I inhibitor payload, which is selectively cleaved by cathepsins upregulated in cancer cells to release the payload. Recently, it has been shown to have a promising effect on other cancers, including low-HER2 breast cancer. T-DXd can effectively target tumor cells expressing low levels of HER2 and deliver its cytotoxic payload through a bystander effect on neighboring tumor cells [1, 2]. Despite its potential for high efficacy, there are concerns regarding life-threatening adverse events (AEs), particularly interstitial lung disease (ILD). Although the precise pathophysiology is unknown, it has been suggested that T-DXd-induced ILD may be dose-dependent [2–4]. This report describes a case of successful treatment by rechallenge with dose-reduced T-DXd after recovery from ILD, and provides a review of the relevant literature.

Case report

A 70-year-old woman was diagnosed with de novo Stage IV breast cancer and lung metastasis in 2019. The patient also had axillary, subclavian, bilateral mediastinal, and pulmonary hilar lymph node metastasis. The tumor was immunohistopathologically diagnosed as estrogen receptor (ER)- and progesterone receptor (PgR)-negative with a HER2 score of 3 (Fig. 1). Two months after administering systemic combination chemotherapy, including taxanes, trastuzumab and pertuzumab, the patient complained of a fever of > 39 ℃, dyspnea, and heavy cough, with low blood oxygen saturation level (SpO2 93% in room air). A laboratory analysis revealed an inflammatory reaction (white blood cells [WBC]; 13,600/L, neutrophil; 82.3%, C-reactive protein [CRP]; 9.93 mg/dl) without elevation of procalcitonin, endotoxin or β-D-Gulcan. Computed tomography (CT) revealed ground-grass opacities. The patient developed ILD (Common Terminology Criteria for Adverse Events [CTCAE] grade 3), and required hospitalization and steroid therapy. Intravenous prednisolone was administered once at a dosage of 20 mg/day and thereafter was maintained at a dosage of 0.5 mg/kg/day (20 mg/body/day) which was orally administered and the dosage was gradually decreased until its administration was finally terminated after 4 months. Subsequently, since the cause of ILD was thought to be taxane, combination therapy with trastuzumab and pertuzumab was continued for approximately one and a half years without taxane. A mastectomy for local control was performed during this process. However, the lung metastases gradually enlarged and were resistant to treatment. Trastuzumab emtansine (T-DM1) was administered as the next-line treatment; however, the disease progressed and was diagnosed as progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors (RECIST). At this point, the tumor was growing, but there were no findings suggestive of ILD in the lung fields (Fig. 2). The patient was thoroughly informed regarding AEs, especially ILD, due to T-DXd, and the drug was administered at a dosage of 5.4 mg/kg with a careful follow-up. Therefore, T-DXd was administered, and the patient’s condition improved remarkably with a decrease in tumor marker levels. Two months later, after the administration of the third dose, a slight elevation in CRP level (Fig. 3), which had never been observed before, occurred without any complaints, including fatigue or cough. Due to the pre-existing ILD condition and the patient’s concern, chest CT was performed, which revealed other findings in the bilateral lung besides metastases. ILD (CTCAE grade1) was confirmed, without physical abnormalities. The patient’s SpO2 value was 98%. Treatment with T-DXd was discontinued, and oral steroids, were subsequently administered as a precautionary measure for ILD, based on the high possibility of an exacerbation of ILD due to the patient’s past history of ILD in the past. Prednisolone was started at a dosage of 0.8 mg/kg/day (35 mg/body) for 1 week, and thereafter the dosage was gradually decreased until its administration was finally terminated after 7 months.

Fig. 1.

A-F Microscopic appearance of the breast tumor. A-B, Hematoxylin–eosin staining, A low-power fields (× 40), B high-power field (× 200). C-F Immunohistochemical findings (× 200), showing the tumor cells were. C MIB-1 index 30%, D negative for ER, E negative for PgR, F positive for HER2, score 3 by IHC

Fig. 2.

Time series of chest CT finding of ILD. A. At the start of T-DXd treatment, there were no obvious findings of pneumonia in the lung fields. B At the time of the onset of ILD. Some degree of reticulation was observed in both lungs. C At the start of the T-DXd rechallenge, the reticulated findings clearly decreased

Fig. 3.

Time series of the laboratory examination findings. A ILD, KL-6, and SP-D levels improved after the discontinuation of the drug and initiation of oral steroid treatment. B The CEA level was decreased at the time of the administration of T-DXd and remained low during the interruption of treatment with T-DXd

The patient’s symptoms did not worsen, and her lung CT and laboratory examination findings (ILD, KL-6, and SP-D), improved. At 6 months after treatment, the tumor marker levels began to increase (Fig. 3). Subsequently, we sought the next treatment option. Although the patient still had some possible treatments, she had already undergone several combination chemotherapies and was willing to undergo cancer profiling testing. We conducted this test and simultaneously reinitiated T-DXd at a lower registered dose of 3.2 mg/kg every 3 weeks. To evaluate whether ILD recurred, we performed physical evaluations and assessed the respiratory function by measuring the SpO₂ before each cycle. KL-6, SP-D, and CRP levels were also measured. Moreover, ILD recurrence and response to treatment were evaluated every month using plain CT. The patient underwent five retreatment cycles, and the treatment response and the patient’s condition were maintained. The cancer genome profiling test with circulating tumor DNA (ctDNA) results showed no genetic variants linked to treatment, including a copy-number increase of ERBB2. Therefore, the treatment was not changed and the administration of T-DXd was continued. Despite the long duration without treatment after temporarily stopping the administration of T-DXd, the effect of T-DXd was maintained for approximately 6 months (Figs. 4, 5).

Fig. 4.

Time series of the chest CT findings showing the therapeutic effect against lung metastasis (during initial treatment with T-DXd). A At the time of administration of T-DXd. B Two months later, showing shrinkage of the tumor. C Six months after the interruption of T-DXd. Shrinkage of the tumor was maintained

Fig. 5.

Time series of chest CT findings showing the therapeutic effect against lung metastasis (after rechallenge with T-DXd). A Eight months after the interruption of T-DXd, showing just slight regrowth of the tumor. T-DXd was restarted at a lower dose. B Two months after rechallenge of T-DXd. Shrinkage of the tumor was observed

Discussion

The over-expression of HER2, which has previously been suggested to lead to a poor prognosis, is found in approximately 15–20% of breast cancers. The advent of anti-HER2 agents has significantly improved the prognosis of such patients. The recent development of new anti-HER2 agents is remarkable, and the approval of these agents has played a vital role in the development of new therapeutic opportunities for individuals with HER2-positive breast cancer. Although HER2-positive metastatic breast cancer remains incurable, multiple compounds, including new antibodies, tyrosine kinase inhibitor such as tucatinib, and conjugated antibody drugs, have significantly improved the treatment course and prognosis. Furthermore, following the approval of other anti-HER2 agents, T-DXd has become an indispensable drug in the treatment of HER2-positive advanced or metastatic breast cancer in Japan [5, 6].

In T-DXd trials, drug-related ILD severity was graded based on the CTCAE pneumonitis criteria, and asymptomatic ILD was graded as 1, as in the present case [7]. The pattern and incidence of drug-related ILD varies depending on the type of anticancer agent used. The trigger is unknown, although various mechanisms may underlie the induction of drug-related ILD. These mechanisms include direct cytotoxic pulmonary injury and immune-mediated lung injury. Although lung epithelial cells express HER2, it is not clear whether it is associated with ILD induced by HER2-targeting agents because ILD has also been observed in other DXd-containing ADCs that target different proteins [3, 8]. In the key trials of T-DXd, ILD/pneumonitis occurred in 15.8% (among them 2.7% were grade 5) in DESTINY-Breast01 [9], 10.5% with no grade 4 or fatal events in DESTINY-Breast03 (the incidence was lower in comparison to prior DESTINY trials) [10], 12.1% (among them 0.8% were grade 5) in DESTINY-Breast04 [1], 10% in DESTINY-Gastric01 [11], 10% (among them 3.0% were grade5) at DESTINY-Gastirc02 [12], 26.4% at DESTINY-Lung01 (among them 2.2% were grade5) [13] and 12.9% (among them 1.0% were grade5) at DESTINY-Lung02 [14]; in addition, the incidence rate of ILD/pneumonitis was 10.5% in DESTINY-PanTumor02 (fatal events were observed in 1.1% [3 patients; 1 each in the biliary tract, endometrial, and other tumors cohorts]) [15]⁾. Another report reviewed previous data that among all patients with different types of malignancies who received T-DXd, the T-DXd-induced ILD/pneumonitis was judged to have occurred in 11.4% of cases [15]. Hackshaw et al. reported that the rate of ILD induced by HER2-tageting therapy for HER2-positive breast cancer was 2.4%, with the highest incidence of ILD (21.4%) reported among patients receiving trastuzumab combined with everolimus and paclitaxel and 17.4% in T-DXd [16].

Although anti-HER2 ADCs have been associated with ILD/pneumonitis, some previous reports have suggested that they may have dose-limiting toxicity with respect to T-DXd [4, 7]. However, it has been suggested that the relationship between ILD/pneumonitis and dose may vary among agents, and there have been no reports on the dose-dependent effect of ILD with other ADC [7, 8]. The incidence of T-DXd-induced ILD has been reported to be higher than that of other anti-HER2 ADCs. This suggests that the different molecular and structural characteristics, particularly its cytotoxic topoisomerase inhibitor “deruxtecan,” may cause that AE. In a cynomolgus monkey study, T-DXd was found to cause lung toxicity, characterized by diffuse lymphocytic infiltrates and slight fibrosis [4, 7]. These findings are likely to be observed in non-specific interstitial pneumonia in humans, based on histopathological features. According to another report, T-DXd is primarily localized in alveolar macrophages and not in pulmonary epithelial cells. Target-independent uptake of T-DXd by alveolar macrophages and payload release have been suggested as mechanisms underlying off-target toxicity [3]. Although the mechanism of ILD induced by T-DXd may still be unclear, one of the causes is bystander killing by free payload released from cells following the catabolism of ADC. T-DXd injury may occur because of the cytotoxic effect of the payload as the final step in the pathway [3, 4]. Considering these factors, a lower dose is likely to reduce this risk.

General guidelines to establish the diagnosis and management of T-DXd-induced ILD/pneumonitis recommend that all patients receiving T-DXd should be monitored for signs and symptoms of ILD/pneumonitis, such as cough, dyspnea, fever, or any deterioration of respiratory condition. Radiographic imaging, including CT scans, should be carried out as regular monitoring during treatment with T-DXd [8, 17, 18]. Consultation with a pulmonary specialist for monitoring and treatment is required if T-DXd-induced ILD or pneumonitis occurs. The appropriate treatment approach for suppressing inflammation and preventing fibrosis depends on the severity of ILD [7].

T-DXd could be a viable solution for asymptomatic ILD/pneumonitis with incomplete recovery, given its high effectiveness. It is recommended that T-DXd be permanently discontinued for patients with grade ≥ 2 ILD, whereas rechallenge may be permitted for patients with grade 1 ILD, if they completely recover from ILD/ pneumonitis [19]. Rechallenge is recommended only for cases that recover to Grade 0. If ILD takes longer than 28 days (from the onset) to resolve, reduction of the T-DXd dosage is recommended based on the DESTINY-Breast03 and DESTINY-Breast04 protocols (e.g., example reducing the starting dose of 5.4 mg/kg q3w to 4.4 mg/kg q3w, the second-level reduction is 3.2 mg/kg q3w-). If further reduction is needed or if ILD remains beyond day 22 and has not resolved within 49 days of the last infusion, discontinuation is recommended [1, 7, 8, 10, 16, 19]. For patients with grade 1 disease, which is defined as asymptomatic with radiographic findings only, it is recommended to temporarily discontinue T-DXd and monitor the patient until radiological findings recover [7, 8]. Although the ILD persisted for 6 months, a dose-reduced T-DXd rechallenge was administered with careful observation in the present case. The guidelines recommend administering steroids for patients with grade ≥ 2 ILD and for patients with grade 1 ILD who are at an increased risk for progression of ILD. This is expected to help prevent progression to higher-grade ILD [8, 17, 18]. Steroid treatment for grade 1 ILD/pneumonitis may be warranted for patients with extensive lung involvement or those who are at increased risk for progression of ILD/pneumonitis, such as the present case [20].

We found 3 previous reports of T-DXd rechallenge (Table 1). Ogata et al. reported a case of HER2-positive gastric cancer that was highly affected by the dose gain rechallenge of T-DXd [21]⁾. Weger et al. described a case of HER2-positve breast cancer with brain metastasis that was successfully treated with a dose-down rechallenge with T-DXd [2]⁾. Moss et al. reported the case of a patient with breast cancer with multiple supratentorial metastases. The patient was successfully treated with T-DXd rechallenge after recovering from ILD [22]. Providers and patient education regarding ILD are important for immediately identifying these symptoms. It is recommended that clinicians educate patients about the signs or symptoms of ILD/pneumonitis such as cough or changes in exercise tolerance during treatment with T-DXd [7, 20].

Table 1.

Summary of reported cases that were successfully treated with T-DXd rechallenge

	Authors	Primary lesion	Age	Sex	Metastatic lesion	Cause of interruption	Period of interruption	Dose at rechallenge	Overall best response after rechallenge	Publication
1	Ogata T, et al	Gastric cancer	67	Male	Bone	Sacral fracture due to osteoporosis	15.2 months	Gain	SD	2022
2	De Weger VA, et al	Breast cancer	39	Female	Brain	ILD, grade2	3 months	Reduce	SD	2023
3	Moss NS, et al	Breast cancer	37	Female	GI tract, multiple supratentorial metastases	ILD, grade 1	6 months	Not mentioned	PR	2022

Further assessment is needed to ensure the safety of these patients, and simultaneous development of safe rechallenge protocols is needed. However, T-DXd is an excellent treatment option. Moreover, rechallenge with T-DXd should be considered as a strategy for HER2-positive solid tumors.

Conclusion

We report a case of a successful rechallenge with T-DXd after recovery from ILD. In the present case, although there was no genomic information available regarding ERBB2 in the tumor, T-DXd, an anti-HER2 agent, was extremely effective. To avoid progression to severe conditions, close monitoring and adequate patient education are required during T-DXd treatment.

This valuable case requires careful ongoing observation.

Abbreviations

T-DXd

Trastuzumab deruxtecan

HER2

Human epidermal growth factor receptor 2

ADC

Antibody-drug conjugate

AE

Adverse event

ILD

Interstitial lung disease

ER

Estrogen receptor

PgR

Progesterone receptor

WBC

White blood cells

CRP

C-reactive protein

CT

Computed tomography

CTCAE

Common Terminology Criteria for Adverse Events

T-DM1

Trastuzumab emtansine

PD

Progressive disease

RECIST

Response Evaluation Criteria in Solid Tumors

ctDNA

Circulating tumor DNA

Author contributions

Y.T. managed the patients, searched the literature, and drafted the manuscript. N.I. and S.N. managed the patients. K.I. evaluated the histopathological features and contributed to the histological analysis. All authors have read and approved the final manuscript.

Data availability

The histological images supporting Fig. 1, clinical data supporting Fig. 3 and CT images supporting Figs. 2, 4 and 5 are not publicly available to protect patient privacy.

Declarations

Conflict of interest

The author fully declares any financial or other potential conflict of interest.

Informed consent

Written patient’s informed consent was obtained for publication of this report.