Interstitial pneumonitis related to sacituzumab govitecan in a patient with metastatic triple-negative breast cancer: a case report.

Introduction
Human trophoblast cell-surface antigen 2 (Trop-2), a transmembrane glycoprotein, is more abundantly expressed in solid epithelial carcinoma than in normal tissue [1]. Trop-2 overexpression has been reported to induce cancer growth, proliferation, and metastasis [2]. Sacituzumab govitecan (SG) is an antibody–drug conjugate (ADC) composed of an antibody targeting Trop-2 with a cytotoxic payload, SN-38, and an acid-liable hydrolyzable linker [3]. SN-38, the active metabolite of the chemotherapeutic drug, irinotecan, is a topoisomerase-1 inhibitor. After binding to Trop-2 and internalized into to cancer cell, SG releases a payload that damages cancer DNA and induces cell death. The membrane-permeable nature of SN-38 induces antitumor actions in adjacent cells without absorbing ADC, resulting in a bystander effect.
In the phase 3 ASCENT trial, 468 patients with locally advanced or metastatic triple-negative breast cancer (mTNBC) and treatment failure from the previous chemotherapy were recruited. SG significantly improved progression-free survival and overall survival compared with single-agent chemotherapy [4]. In 2021, the US Food and Drug Administration (FDA) granted regular approval to SG for patients with unresectable locally advanced or metastatic TNBC in second-line therapy [5]. In the ASCENT clinical trial, 64% of patients receiving SG treatment experienced severe adverse events, with grade ≥ 3. The common severe adverse effects were neutropenia (51%), leukopenia (10%), and diarrhea (10%). Only one patient was reported to experience grade 3 pneumonitis. No grade 1 or 2 interstitial lung disease was reported. Previous study reported drug-induced pneumonitis was observed with irinotecan and other anti-trop-2 ADCs (for example, DS-1062) [6]. The adverse events have been infrequent with SG [7]. However, it is worth noting that pneumonitis was the predominant cause of treatment-related mortality in patients receiving ADCs [8]. Drug-induced pneumonitis can present at any time of the treatment course and is frequently delayed in diagnosis [9]. Herein, we describe a rare case of SG-induced interstitial pneumonitis with successful rechallenge.

Case presentation
A 62-year-old Taiwanese female patient presented with a past medical history of right breast cancer (ER−/PR−, HER2−), stage IIB, post-right modified radical mastectomy, neoadjuvant chemotherapy, and post-surgery radiotherapy 10 years ago, with no psychosocial–economic factors or family history of breast cancer. Her breast cancer recurred with lung metastasis 2 years ago. The progressive disease was refractory to four lines of chemotherapy, including capecitabine, eribulin mesylate, paclitaxel plus gemcitabine, and carboplatin plus gemcitabine. Therefore, she was advised to receive a new regime with SG (10 mg/kg). She did not have any discomfort after completing the first cycle of SG therapy. However, she had developed shortness of breath, dry cough, and diarrhea since the second-cycle therapy. Her dyspnea became more severe and limited her daily activities. She reported no fever, chills, chest pain, rhinorrhea, change of appetite, headache, dysuria, or flank pains, and 2 weeks later, she was admitted via the emergency room for acute respiratory distress.
On physical examination, vital signs revealed body temperature of 36.6 °C, pulse rate of 116 beats per minute, blood pressure of 120/69 mmHg, respiratory rate of 21 breaths per minute, and oxygen saturation of 82% in ambient air. Bilateral diffuse rales on chest auscultation were recorded. Cardiac, abdominal, and skin examinations were unremarkable. The laboratory analysis reported white blood cell count (WBC) of 5800/ul, hemoglobin (Hb) of 9.4 g/dl, aspartate aminotransferase of 45 U/L, alanine aminotransferase of 47 U/L, and C-reactive protein of 8.5 mg/dL. The values of serum creatinine and N-terminal pro B-type natriuretic peptide (NT-proBNP) were within normal ranges. Chest x-ray (CXR) showed multiple alveolar nodules, ill-defined consolidation in bilateral lower lungs, and increased bilateral interstitial infiltration (Fig. 1A). Chest computed tomography revealed diffuse ground grass opacity of the bilateral lungs with multiple foci of black area (reverse hall sign) and thickening of the interlobular septa (Fig. 2). Atypical pneumonia assays, including Mycoplasma pneumoniae immunoglobulin (Ig)M, Chlamydophila pneumoniae IgM, Legionella antibody, Cryptococcal serum antigen, and Aspergillus serum galactomannan were all negative. Sputum study was not performed due to her dry cough without phlegm component. Her clinical condition and pulmonary infiltration of the chest X-ray rapidly worsened 2 days later (Fig. 1B). She received higher level of oxygen therapy to correct her hypoxia, which limited the examination of bronchoscope. There was no evidence of infection or other possible cause of her pneumonitis. We strongly suspected SG-induced grade 3 interstitial pneumonitis because that was the only new drug the patient was taking before admission. Naranjo’s methodology rates the causality association with the medicine as plausible, with a score of 7.
The patient received steroid therapy with 40 mg methylprednisolone twice daily (2 mg/kg/day prednisolone). After 1-week treatment, her dyspnea and pulmonary infiltration of the chest X-ray improved significantly (Fig. 1C). Steroid tapering was performed in 1 month. Due to her limited treatment options of metastatic TNBC, she accepted SG rechallenge in half dose (5 mg/kg). No occurrence of interstitial pneumonitis was observed again. She received another four cycles of therapy. Follow-up computed tomography reported disease progression with one new pulmonary metastasis and enlargement of previous lung metastasis. The progression-free survival of SG was 5.37 months.

Discussion
Sacituzumab govitecan is an ADC, targeting Trop-2 cell-surface antigen, which is overexpressed in a variety of solid tumors, such as prostate cancers, breast cancers, and non-small cell lung cancer. SG is recommended as the second-line therapy for recurrent unresectable or metastatic TNBC by National Comprehensive Cancer Network guidelines [10]. In the ASCENT clinical trial, SG was more effective with metastatic TNBC than single-agent chemotherapy in terms of progression-free survival and median overall survival [4]. The major treatment-related adverse events of grade ≥ 3 were neutropenia (51%), leukopenia (10%), diarrhea (10%), and anemia (8%). Only one patient (0.4%) developed grade 3 drug-induced interstitial lung disease (DIILD). Here, we presented a patient with developed DIILD and acute respiratory distress after receiving second-cycle SG therapy. DIILD is a type of interstitial lung disease triggered by drug exposure, leading to inflammation and potentially pulmonary fibrosis. The definitive diagnosis depends on the temporal association between the onset of symptoms and the initiation of ADC, then excluding other possible causes [11]. Bronchoscope lavage is helpful to exclude possible infectious disease. Our patient’s acute respiratory distress and refusal of intubation limited the bronchoscope examination. Antineoplastic medicine is the leading cause of DIILD, responsible for 23–51% of cases. The common drugs of DIILD include chemotherapy (bleomycin and everolimus), target therapy (erlotinib), immune checkpoint inhibitors, and antibody–drug conjugates [12].
SG-induced pneumonitis is a rare entity and only a few cases have been reported. Table 1 lists ADC associated with DIILD in clinical trials. Trastuzumab deruxtecan (T‐DXd) is notorious with the highest DIILD incidence, 9.6~28%. In contrast, the incidence of DIILD in the SG treatment is very low. Grade 1–2 pneumonitis accounts for the majority. Grade 3–4 and 5 DIILD occurs in 1% and 0.9% of patients, respectively. High mortality rate is observed when the DIILD progresses to grade ≥ 3. Furthermore, one meta-analysis reported the overall incidence of ADC-related deaths as being low (1.3%), but pneumonitis was the most common cause (12.4%) [13]. Clinical care of patients receiving these drugs requires constant vigilance. DIILD may develop from days to months after drug administration, with most of them being reported as occurring early after starting ADC treatment [14]. The five “S” rules of screen, scan, synergy, suspend treatment, and steroids were recommended for patients with ADC therapy [9].

From a series of T‐DXd clinical trials, patients with poor oxygen saturation (blood oxygen level) < 95%, higher drug dosage, renal function impairment, preexisting lung disease, and > 4 years since initial diagnosis were at the risk for DIILD and increasing associated mortality [15]. In addition, other factors, such as advanced age, poor performance, male, Asian ethnicity, smoking, lung surgeries, prior thoracic radiotherapy, and combination of anticancer drugs, were reported to increase the incidence of DIILD [12]. Patients at risk should be monitored closely. Early steroid treatment for grade 1 pneumonitis is suggested [15].
The pathogenic processes of ADC-related interstitial lung disease are not fully known. Three types of mechanisms are often used to explain the specific toxicities [16]. Firstly, the unique toxicities are associated with normal tissues expressing the ADC-targeting antigen, often known as “on-target toxicities.” The expression of TROP-2 is low in normal human tissue and upregulated in carcinoma. However, Lara et al. found that Trop2 message was expressed higher in lung than other organs [17], a fact that might result in the occurrence of pneumonitis after SG therapy. Secondly, the different properties of the cytotoxic payload dictate their specific toxicities. Table 1 confirms the theory and presents that patients develop higher rates of DIILD from deruxtecan-contained ADCs, such as trastuzumab deruxtecan (T-DXd) and datopotamab deruxtecan. Thirdly, payload is released from unstable linker into the bloodstream and lodged in certain organs causing damage. This is called organ-specific “off-target” toxicity.
Until now, there has been no firm consensus on the management of drug-induced pneumonitis, since the application of ADCs in solid cancers are still not common internationally. Table 2 presents the protocol of DIILD management in patients receiving T-DXd therapy [18]. For grade 1 asymptomatic pneumonitis, low-dose steroids with 0.5 mg/kg/day prednisone and discontinuing ADCs are recommended. Drug rechallenge maybe applied according to the resolution time. Higher steroid dose, 1 mg/kg/day prednisone, is needed for grade 2 DIILD. Patients with grade 3 and 4 pneumonitis are recommended for hospitalized therapy with steroid pulse therapy, followed by therapy with ≥ 1 mg/kg/day prednisone and subsequent tapering. Permanent ADC discontinuation is suggested for patients with grade ≥ 2 DIILD. As has been previously reported, the risk of developing DIILD is related to the treatment dose. For limited treatment for metastatic TNBC, our patient received half-dose SG rechallenge and did not develop pneumonitis again. Progression-free survival (PFS) of SG was 5.37 months, which was close to the 5.6-month PFS in the ASCEND trial [4].

Conclusion
We presented a rare case of sacituzumab-govitecan-induced pneumonitis that was successfully treated with steroids and rechallenged by half of dose. Early assessment using chest computed tomography and the immediate discontinuation of SG, along with corticosteroid treatment, are essential to prevent further harmful effects of the drug.