2025+SGO临床实践声明：靶向治疗中的间质性肺疾病

ABSTRACT

Interstitial lung disease(ILD) is a potentially serious and sometimes fatal complication of targeted therapies, in-cluding antibody-drug conjugates and immunotherapies, in gynecologic oncology. Risk factors include pre-existing lung disease, advanced age and prior thoracic radiation. Early detection, patient and clinician education,and prompt multidisciplinary collaboration are critical to mitigate ILD morbidity and mortality. This Society of Gynecologic Oncology clinical practice statement provides evidence-based recommendations for the diagnosis,grading and management of ILD associated with gynecologic cancer therapies,emphasizing the importance of baseline risk assessment, ongoing monitoring and standardized intervention protocols to optimize patient outcomes.

©2025 Elsevier Inc.All rights are reserved, including those for text and data mining, Al training, and similar tech-nologies.

1.Introduction

Drug-related interstitial lung disease(ILD) is a recognized potential complication of anti-neoplastic therapy[1].ILD comprises a group of disorders characterized by acute, sub-acute or chronic inflammation of the thin layer of tissue in the lungs that separates the gas exchange alveoli units, which is typically occupied by fluid, cells, blood vessels,

and connective tissue components[2-4]. Although, the terms pneumo-nitis and ILD are often used interchangeably, pneumonitis refers to in-flammatory conditions that affect the lung parenchyma, such as drug toxicity or radiation pneumonitis, whereas ILD encompasses multiple disorders that can be due to a broad range of etiologies that include auto-immune disorders, occupational exposures, idiopathic fibrosis,and drug toxicity[2].

Dyspnea and cough are the most frequent symptoms of ILD. Other symptoms can include low-grade fever, hypoxia, malaise, and chest pain. Chronic complications include pulmonary fibrosis, pulmonary hypertension, congestive heart failure,and respiratory failure.Radiologic findings often precede the onset of symptoms and may present as unilat-eral or bilateral pulmonary infiltrates on chest imaging(See Fig.1).

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  Fig.1.Computed Tomography of the chest showing interstitial lung disease.

Top image: Bilateral peripheral multi-focal areas of consolidation in the lower lobe and ground glass opacity in the right middle lobe, representing cryptogenic organizing pneu-monia(COP) pattern. Bottom image: Right upper lobe peripheral opacity with surround-ing ground glass halo and posterior consolidation opacities, representing COP pattern.

Cytotoxins, targeted therapies(including antibody-drug conjugates(ADCs)), and immunotherapy used to treat gynecologic cancers can all be associated with ILD(Table 1)[5]. Although ILD is not a common ad-verse event related to advanced cancer therapeutics, it is a leading cause of treatment-related death events. The diagnosis of drug-induced ILD requires a temporal association with the suspected agent and is a diag-nosis of exclusion, emphasizing the need to promptly rule out other causes of ILD, such as infection, heart failure, pulmonary vascular dis-ease, other concomitant medications(Table 2), and cancer progression including lymphangitic carcinomatosis.

A new class of anti-cancer agents called antibody-drug conjugates(ADCs) allows for biomarker-targeted therapy in gynecologic cancers.ADCs are made up of three components: 1) a monoclonal antibody se-lectively targeting tumor-associated antigens, 2) a cytotoxic molecule,often referred to as the“payload”, and 3) a linker that connects the two. Several ADCs have been approved in recent years, and some have shown broad applicability across tumor types, three in gynecologic can-cers[6-8]. Fam-trastuzumab deruxtecan(T-DXd) recently received a tumor-agnostic FDA-accelerated approval for adult patients with unre-sectable or metastatic human epidermal growth factor 2(HER2) posi-tive(3+ by immunohistochemistry) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options. T-DXd is composed of an anti-HER2 humanized monoclonal antibody, a tetrapeptide-based cleavable linker, and a topoisomerase I inhibitor payload. Mirvetuximab soravtansine, an ADC targeting folate receptor a(FRα), is conjugated via a disulfide-containing cleavable linker to a microtubule-inhibiting payload. Tisotumab vedotin, is an ADC conjugated via a protease cleavable linker to a tubulin inhibitor and directed against tissue factor, an antigen that is highly expressed in 90-95% of cervical cancer tumors.

T-DXd and mirvetuximab, unlike tisotumab vedotin, are associated with a relatively high-rate of ILD. Differences in antibody targets,payloads, and linkers underpin the differences in adverse events seen

Table 1

Recently approved therapies used in gynecologic malignancies associated with drug-induced interstitial lung disease.

|Drug|Indication|Description|Incidence|Mortality|Management| |---|---|---|---|---|---| |Mirvetuximab soravansitine|Ovarian|● FRα-positive, platinum-resistant epithelian ovarian cancer treated with 1-3 prior systemic treatment regimens|$$10\%^{*}$$|$$0.1\%^{*}$$|Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 1: Hold* Grade 2/3/4: Permanently discontinue* Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 3/4: Permanently discontinue*| |Mifrutuximab soravansitine|Solid Tumor|● Unresectable/mastetic HER2-positive(HIC3+) tumors that have received prior systemic therapy|$$10.5\%^{*}$$|$$1.1\%^{*}$$|Grade 3/4: Permanently discontinue* Grade 1: Hold* Grade 2/3/4: Permanently discontinue* Grade 2: Hold* Grade 3/4: Permanently discontinue*| |Derutaxemab serodutem|Endometrial|● Treatment of MSI-H/dMMR advanced endometrial cancer with disease progression following prior systemic therapy|$$3.4\%^{*}$$|$$0.1\%^{*}$$|Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 1: Hold* Grade 2/3/4: Permanently discontinue* Grade 2: Hold* Grade 3/4: Permanently discontinue*| |Pembrolizumab|Endometrial|● Treatment of MSI-H/dMMR advanced endometrial cancer with disease progression following prior systemic therapy|$$3.4\%^{*}$$|$$0.1\%^{*}$$|Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 3/4: Permanently discontinue*| ||||||| ||Cervical|● Combination with chemoradiotherapy for treatment of FIGO 2014 stage III-IVA ● Combination with chemotherapy, with or without bevacizumab, for treatment of persistent, recurrent, or metastatic cervical cancer expressing expressing PD-L1(CPS≥ 1) ● Treatment of recurrent or metastatic cervical cancer expressing PD-L1(CPS≥ 1)|||| |Dostarlimab|Endometrial|● Combination with carboplatin and paclitaxel, followed by dostarlimab as a single agent for treatment of primary advanced or recurrent endometrial cancer|$$2.3\%^{*}$$|$$0.0\%^{*}$$|Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 3/4: Permanently discontinue*| |Durvalumab|Endometrial|● As a single agent for treatment of dMMR recurrent or advanced endometrial cancer ● Combination with carboplatin and paclitaxel, followed by durvalu- mab as a single agent in primary advanced or recurrent endometrial cancer that is dMMR|$$2.4\%^{*}$$|$$0.1\%^{*}$$|Grade 2: Hold* Grade 3/4: Permanently discontinue* Grade 3/4: Permanently discontinue*|

Information from[6-8].

CPS, combined positive score.dMM, mismatch repair deficient. FIGO, International Federation of Gynecology and Obstetrics. MSI-H, microsatellite instability high. pMMR, mismatch repair proficient.

* Based on prescribing information[20,23,26,33,36,38].

${}^{\dagger}$ Based on results from DESTINY-PanTumor0[15].

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Table 2

Medications known to potentially cause interstitial lung disease.

|Class|Agents| |---|---| |Antineoplastic agents|Chemotherapy Bleomycin Gemcitabine Methotrexate Pemetrexed Irinotecan Taxanes Antibody drug Conjugates T-DM1 Fam-trastuzumab Deruxtecan Mirvetuximab soravtansine Molecular targeting agents Trastuzumab Pertuzumab Lenvatinib Lapatinib Gefinitib Everolimus Temsirolimus CDK4/6 inhibitors: palbociclib,riociclib,abemaciclib Erlotinib Panitumum Cetuximab PARP inhibitors Immunotherapy Anti-PD-1/PD-L1 Anti-CTLA-4 Methotrexate Lefunomide Anti-TNF therapy Etanercept Infliximab, Adalimumab Certolizumab Tociizumab| |Anti-receptor|| |Rheumatologic therapy|Methotrexate Ruetzumab Pertuzumab Lenvatinib Lapatinib Gefinitib Everolimus Temsirolimus CDK4/6 inhibitors: palbociclib,riociclib,abemaciclib Erlotinib Panitumum Cetuximab PARP inhibitors Immunotherapy Anti-PD-1/PD-L1 Anti-CTLA-4 Methotrexate Lefunomide Anti-TNF therapy Etanercept Infliximab, Adalimumab Certolizumab Tociizumab Tictizumab| |Anti-infection agents|Nitrofurantoin Daptomycin Interferon Sulfa drugs Sulfa drugs Amiodarone| |Anti-Transplant rejection therapy Nonsteroidal anti-inflammatory drugs|Sirolimus Ibuprofen Ibuprofen Naproxen Phenytoin|

Information from Skeoch et al.[4] and Fiona et al.[58]

CDK, cyclin-dependent kinase; PD-1, programmed cell death protein 1; PD-L1,pro-grammed death-ligand 1; CTAI-4, cytotoxic T lymphocyte protein 4; TNF, tumor necrosis factor,PARP, Poly(ADP-ribose) polymerase.

between drugs such as pulmonary toxicity[9,10]. Critically, ILD is the most common cause of treatment-related death in clinical trials of ADCs(up to 12.4%)[10]. Early detection, prompt intervention, and in-volvement of a multi-disciplinary team are critical in preventing pro-gression of drug-associated ILD pneumonitis to a fatal event. This document serves as a guideline for practitioners for diagnosis and man-agement of ILD/pneumonitis as new technologies and treatments emerge in the landscape of gynecologic oncology.

1.1. Risk factors for drug-related ILD

Clinical factors associated with an increased risk of ILD, such as inter-stitial lung abnormalities, are also contributory risks for ILD associated with anti-cancer therapies(Table 3)[11]. Advanced age over 65 years,smoking history, and the presence of baseline interstitial lung abnor-malities(asymptomatic interstitial opacities) can be associated with an increased risk of progression of interstitial lung abnormalities to

Table 3

Characterization of interstitial lung disease.

|Term|Description| |---|---| |Potential Risk Factors|Age≥ 65 years Smoking history Baseline interstitial lung abnormalities Lung comorbidities such as asthma, COPD,prior ILD,pulmonary fibrosis,and radiation pneumonitis Impaired renal function Higher drug dose Baseline oximetry readings<95%| |Pneumonitis Grading per CTCAE v5 [60]|| |Grade 1|Asymptomatic with clinical or diagnostic observations only| |Grade 2|Symptomatic; requires medical intervention; limiting instrumental activities of daily living(ADLs)| |Grade 3|Severe symptoms limiting self-care ADLs; oxygen supplementation indicated| |Grade 4|Life-threatening respiratory compromise requiring urgent intervention(such as intubation or tracheotomy or support with high-flow nasal cannula therapy Death| |Grade 5|| |Patterns of ILD on CT|| |Nonspecific interstitial pneumonitis|Characterized by bilateral ground glass opacities and diffuse alveolar damage pattern characterized by dense bilateral| |Anti-CTLA-4|consolidations typically associated with volume loss and pleural effusions. The diffuse alveolar damage pattern is| |Anti-TNF therapy|associated with severe impairment of gas exchange and high risk of respiratory failure and death.| |Usual interstitial pneumonitis(UIP)|Typically associated with lower lobe peripheral predominant opacities that are associated with honeycombing,| |Hypersensitivity pneumonitis(HP)|Typically characterized by upper lobe-predominant centrilobular granulomas and ground glass opacities Most common presentation: typically manifests as multiple peripheral nodular opacities that are comprised of a solid and| |Cryptogenic organizing pneumoniaia (COP or OP)|Most common presentation: typically manifests as multiple peripheral nodular opacities that are comprised of a solid and a ground glass component(see Fig.1).| |Mixed pattern(hypersensitivity pneumonitis|Newly recognized pattern associated with the antibody-drug conjugate fam-trastuzumab deruxecan| |Pulmonary Function Test Findings in ILD|| |Early stage Late stage|Decreased diffusion capacity Restrictive ventilatory defect with decreased forced vital capacity and total lung capacity.|

COPD,chronic obstructive pulmonary disease; CTCAev5,Common Terminology Criteria for Adverse Events version 5; ALDs, activities of daily living; CT, computed tomography;UIP; Usual interstitial pneumonitis; HP, Hypersensitivity pneumonitis; COP,Cryptogenic organizing pneumonia;OP, organizing pneumonia; ILD, interstitial lung disease.

interstitial pulmonary fibrosis, drug-related pneumonitis(Table 3),and mortality attributable to respiratory and/or cardiac causes[12]. To identify the risks associated with the development of ILD related to the ADC T-DXd, Powell et al. used a multivariate model in subjects en-rolled in 9 single arm studies[11]. Potential risk factors identified were age greater than 65 years; residency in Japan versus other areas of the world; presence of lung comorbidities such as asthma, chronic obstructive pulmonary disease(COPD), prior ILD, pulmonary fibrosis,and radiation pneumonitis; impaired renal function; higher dose of T-DXd(6.4 versus 5.4 mg/kg) and baseline oximetry readings less than 95%.These findings from single-arm clinical trials should be considered hypothesis generating and should not be used summarily as inclusion or

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exclusion criteria for ADC treatment, but they could be used to identify patients who may require more intensive monitoring of symptoms and imaging to detect early-onset ILD. Pre-existing lung disease is associated with an increased risk for development of drug associated ILD; equally important, it can be associated with an increased risk of respiratory fail-ure in those who develop drug-related ILD.

1.2. Education and early detection of ILD is essential

Before initiation of an ADC or other anti-cancer therapy associated with ILD, patients should have baseline chest imaging, including high-resolution computed tomography(CT). This enables evaluation of the extent of inactive as well as the presence of active disease. Vaccination against the influenza virus, respiratory syncytial virus, COVID-19, and pneumonia should be considered, as clinically indicated. It is recom-mended that patients who have ongoing active ILD should not be treated with ADCs or other medications with a high risk for drug-related ILD. For those with a past history of ILD that is inactive, or those with asymptomatic interstitial lung abnormalities, it is important to closely monitor for ILD during therapy to facilitate early detection of new symptoms.

General strategies for all patients(but especially those with a history of ILD and those with identified risk factors associated with ILD inci-dence) include implementation of baseline in-office exercise walking test to examine for exercised induce hypoxemia and“as needed” repeat of this test. Additionally, routine in-office oximetry should be consid-ered for implementation in treatment protocols and remote monitor-ing/home oximetry can be considered to enhance the early detection and management of incident ILD should it occur. Specifically, pulse ox-metry in the office is an important“vital sign” for patients on therapies with a higher risk of ILD or a past history of ILD as even mild changes in a patient who has otherwise been stable should be considered as poten-tially clinically significant. Similarly, educating the patient to be aware of even mild symptoms(e.g. mild dyspnea with exertion, new cough,or changes in fatigue levels) is also critical.

1.3. Guidelines for diagnosis/grading and management

1.3.1. General

Clinically,ILD can present acutely or subcutly with non-specific symptoms. Typical symptoms include dry cough and dyspnea on exer-tion. The non-specific symptoms associated with ILD can frequently be attributed to other conditions such as asthma, heart failure, respiratory infection, or disease progression. It is important to emphasize that the first symptoms and signs associated with early ILD are dyspnea on exer-tion and hypoxemia with exercise. On physical examination in the late stages of ILD, abnormal chest sounds such as rosa or rhonchi can be heard at the base of the lungs.

Several recognized CT patterns of drug-induced ILD are outlined in Table 3. These same patterns are also used to describe ILD associated with other conditions[13]. The pattern of infiltrates on CT imaging can vary and include acute manifestations such as diffuse aralovam darage, subacute presentations such as organizing pneumonia, hypersensi-tivity pneumonitis, and sarcoidosis, and chronic presentations such as usual interstitial pneumonitis[2]. A newly recognized pattern has been observed in ILD associated with the ADCT-DXd; it displays a mix-ture of hypersensitivity pneumonitis and organizing pneumonia pat-terns. Impairment of gas transfer as detected by a significant decrease(>10%) in diffusion capacity compared to baseline, is the first pulmo-nary function testing abnormality that occurs in the setting of ILD. In ad-vanced ILD, pulmonary function testing will reveal hypoxemia, an increased A-a gradient, and a restrictive ventilatory defect, as noted by a decrease in forced vital capacity and total lung capacity.

Drug-related ILD is a diagnosis of exclusion as there are many other causes of ILD. A diagnosis of ILD requires a temporal association with the initiation of the suspected drug and new onset of lung

parenchymal opacities detectable on chest CT scan[14]. The next required step is to exclude other possible causes, such as lung infec-tions. Lung infections are more common in immunosuppressed pa-tients; these can include pneumocystis jirovecii pneumoniae,cytomegalovirus, influenzaa, respiratory syncytial virus, COVID-19 pneumonia, and community acquired pneumonia. Other causes can include pulmonary edema, which can be cardiogenic or non-cardiogenic in origin or can be caused by aspiration, pulmonary vascular disease, other concomitant medications(Table 2), and can-cer progression including lymphangitic carcinomatosis. Another common cause of ILD in patients with cancer is radiation pneumoni-tis, which typically is localized to the radiation field and the immedi-ately surrounding lung.

Given the non-specific imaging findings and the diagnostic chal-lenge of drug associated ILD, a multidisciplinary approach is essential for accurate diagnosis. This multidisciplinary team may include tho-racic radiologists and pulmonary, infectious disease and cardiology consultants. Guidance for the diagnosis and management of drug re-lated ILD has been developed for patients treated with T-DXd because the early experience with T-DXd showed a high incidence of fatal grade(5) ILD events that were associated with delay in diagnosis and treatment[11]. These observations motivated an education cam-paign to enhance early recognition and an updated management guideline to facilitate a standardized approach to ILD treatment and monitoring. These guidelines were associated with a decreased inci-dence of fatal events in T-DXd-treated patients and have been applied to the management of lung events caused by several advanced cancer therapeutics[15].

1.3.2. Management of ILD and grading

In cases of suspected ILD, the first step is immediate interruption of the drug

Please refer to Table 1 for specific drug recommendations. It is im-portant to note for certain Grade 1 findings not all drugs will need to be held; however, if uncertain as to grade or cause then interrupting the drug is recommended. ILD should be suspected if a patient develops new radiographic imaging findings or new or worsening symptoms such as dyspnea, cough or fever[14]. This proactive approach allows time for diagnosis or exclusion of drug-associated ILD, avoids repetitive lung injury in cases of drug-associated ILD, and permits the prompt re-sumption of the study drug after appropriate evaluation, as guided by the management plan.

The second step is to confirm the diagnosis of drug-related ILD.Typical components of the diagnostic evaluation will include clinical re-assessment of ILD risk factors, review of prior treatment with radiation or other drugs associated with ILD, drug infusion timing and signs or symptoms of concurrent illness. Imaging review with high-resolution chest CT should focus on temporal change as assessed by comparing new imaging findings to those present at baseline(before introduction of the drug), those subsequent to initiation, and those from before presentation of the new findings;to exclude other causes, the infectious disease evaluation can include complete blood cell counts, cultures of the blood and sputum, viral diagnostics to evaluate for influenza, COVID-19,or other endemic respiratory viral infections and serum testing forβ-D-glucan and galactomanann. Other testing to consider includes pulmonary function testing, exercise oximetry analysis, arterial blood gas analysis, transhoracic echocardiography,electrocardio-gram,and bronchoscopy when clinically indicated and feasible.In some centers, blood biomarkers such as Krebs von den Lungen-6(KL6) and surfactant protein D(SPD) are examined, but the low specificity of these tests diminishes the impact of biomarker testing at this time.

The third step is ILD management. Management is guided by severity as graded in the NCI CTCAE v5 Pneumonitis Severity Assess-ment system(Table 3). The majority of cases are grade 1 or 2, but

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Table 4

Management of drug related ILD.

|Severity|Management| |---|---| |Grade 1|In cases of suspected ILD, the first step is immediate interruption of the drug.The second step is to confirm the diagnosis of drug-related ILD| |Grade 2|Patients should be monitored and followed closely for the development of clinical symptoms. Clinical follow-up can include imaging in 2-4 weeks or as clinically indicated for detection of resolution or progression. In cases that occur in patients with significant pre-existing lung disease or in cases that show extensive lung involvement, we suggest considering steroid treatment at a dose of at least 0.5 mg per kilogram(mg/kg) per day until improvement followed by a gradual taper over at least 4 weeks.| |Grade 2|Systemic steroids should be started promptly at a dose of at least 1 mg/kg per day of prednisone or its equivalent for at least 2-3 weeks followed by a gradual taper over at least 4 weeks. If there is no clinical improvement in 5-7 days, then consider increasing the dose of steroids to at least 2 mg/kg per day of prednisone or switch to treatment with intravenous(IV) steroids such as methylprednisolone| |Grade 3-Grade 4|Prompt initiation of high dose methylprednisolone IV treatment at doses of 500-1000 mg per day for 3 days followed by at least 1 mg/kg per day of prednisone or its equivalent for at least 2 weeks followed by a gradual taper over at least 4 weeks and reimaging as clinically indicated. If there is no improvement within 3-7 days an additional diagnostic evaluation should be conducted for alternative etiologies and treatment with other immunosuppressants such as infliximab or mycophenolate fertil should be considered.| |Grade 2|Prophylaxis for PJP should be considered for patients requiring prednisone greater than 20 mg/day or other intensive immunosuppression treatment.|

rapid progression of symptoms and changes can occur, especially if exposure to the causative drug continues(Table 4).

Grade 1ILD is asymptomatic. Patients should be monitored and followed closely for the development of clinical symptoms. Pulse oxim-etry can detect exercise related hypoxemia. Clinical follow-up can in-clude imaging in 2-4 weeks or as clinically indicated for detection of resolution or progression. In cases that occur in patients with significant pre-existing lung disease or in cases that show extensive lung involve-ment, we suggest considering steroid treatment at a dose of at least 0.5 mg per kilogram(mg/kg) per day until improvement followed by a gradual taper over at least 4 weeks.

Grade 2ILD is associated with the presence of symptoms and re-quirement for treatment of the condition, typically with steroids. For grade 2 events systemic steroids should be started promptly at a dose of at least 1 mg/kg per day of prednisone or its equivalent for at least 2-3 weeks or until complete resolution of symptoms and resolution of acute chest CT findings followed by a gradual taper over at least 4 weeks. If there is no clinical improvement in 5-7 days, then consider increasing the dose of steroids to at least 2 mg/kg per day of prednisone or switch to treatment with intravenous(IV) steroids such as methyl-prednisolone. It is important at this time to reconsider the diagnosis by performing additional evaluations for alternative etiologies and to promptly escalate care as clinically indicated.

Grade 3 ILD is associated with requirement for hospitalization or supplemental oxygen, and grade 4 ILD is associated with require-ment for mechanical ventilation or respiratory support with high-flow nasal cannula oxygen. Treatment of grade 3 and 4 events includes the prompt initiation of high dose methylprednisolone IV treatment at doses of 500-1000 mg per day for 3 days followed by at least 1 mg/kg per day of prednisone or its equivalent for at least 2 weeks followed by a gradual taper over at least 4 weeks and reimaging as clinically

indicated. If there is no improvement within 3-7 days an additional di-agnostic evaluation should be conducted for alternative etiologies and treatment with other immunosuppressants such as infliximab or myco-phenolate moftilell should be considered. A prolonged course of steroids requires appropriate supportive medication including pneumocystis jirovecii pneumonia prophylaxis and consideration of a proton pump inhibitor to protect the Gl tract during prolonged steroid use.

2. Gynecologic Cancer Therapies Associated with Drug-Induced ILD

Tables 1 and 2 highlight conventional and novel therapeutics associated with ILD, their indications in gynecologic malignancies, and the incidence of pulmonary toxicities.

2.1.Antibody-drug conjugates

The pathogenesis of ADC-associated ILD is not well defined but is likely primarily related to the cytotoxic payload and immune-mediated lung injury[3,14]. Clinical risk factors include pre-existing lung disease and a prior history of ILD. Other contributing factors may include: expression of the target antigen in normal lung tissue, instabil-ity of the linker resulting in off-target effects, drug-drug interactions,and genetic variability[16,17]. It is important to maintain a high degree of vigilance in the event of new pulmonary symptoms or pulmonary findings on imaging. In recognition of the increased propensity for ILD development, early clinical trials of ADCs instituted ILD adjudication committees, consisting of pulmonologists, oncologists, and radiologists.These committees review clinical information and imaging for all suspected ILD cases identified through site reporting of pulmonary events that were coded with prespecified MedDRA terms. Swain and colleagues reported that the centralized expert reviewers identified signs of ILD earlier than study investigators,thus,highlighting an oppor-tunity for more timely detection of ILD[14]. Subsequent to updates of ILD management protocols, lower rates of severe ILD/pneumonitis were identified in phase III studies, which may be due in part to the im-proved monitoring and management protocols instituted within studies of these agents[16]. The frequency and severity of ILD is evolving as new compounds with these drugs being used in new indications in combination regimens. Extra caution and continued vigilance are war-ranted when combining ADCs with immunotherapy, as studies have shown an increased, although not statistically significant, rate of ILD[16].

2.1.1.Fam-trastuzumab deruxtecan

In DESTINY- PanTumor02(NCT04482309) a phase II trial evaluating T-DXd in HER2-positive, locally advanced or metastatic solid tumors,the confirmed objective response rate(ORR) was 51.4%(95% CI:41.7-61.0) and duration of response(DOR) was 19.4 months(range 1.3-27.9+)[18]. Studies in seven different tumor types including endometrial, cervical, and ovarian were evaluated. Among the entire co-hort the ORR was 37.1%, median DOR was 11.3 months, median progression-free survival(PFS) was 6.9 months, and median overall sur-vival(OS) was 13.4 months. Interestingly, the disease sites with the highest rates of response included endometrial, cervical, and ovarian tu-mors. However,ILD/pneumonitis rates in T-DXd studies have been high(~15%)[11]. In a pooled analysis of 9 T-DXd monotherapy studies the median onset was~5 months after initiation of therapy. The risk of de-veloping ILD appeared to plateau after 12 months[11]. However,ILD can present at any point during treatment. Importantly, 10.0% of patients had ILD with the majority being low grade. Three patients(1.1%) died from pneumonitis, with one being from the endometrial cohort[19,20].

2.1.2. Mirvetuximab sorvansine

Mirvetuximab soravansine is the first ADC to obtain FDA-accelerated approval in ovarian cancer based on the SORAYA trial

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(NCT04296890)[21]. This single-arm, phase II study evaluated women with platinum-resistant epithelial ovarian cancer who had received 1-3 prior lines of therapy and had high FRα expression.Rimetuxab soratansiv demonstrated a 32.4% ORR and DOR of 6.9 months as assessed by investigator. MIRASOL(NCT04209855)was the phase III confirmatory trial comparing mirvetuxabimor soratansiv to investigator's choice chemotherapy in those with platinum-resistant ovarian cancer with high FRα expression[22].Moore et al. also demonstrated an improvement in median PFS with mirvetuxabop soratansivine(5.62 months versus 3.98 months with chemotherapy;P<0.001). Additionally, mirvetuxabimor soratansiv was shown to have a median OS of 16.46 months versus 12.75 months with chemotherapy(P=0.005). Mirvetuxabimor soratansivine is cur-rently approved for patients with FRα-positive, platinum-resistant epithelial ovarian cancer who have received 1-3 prior systemic treat-ment regimens[23]. Pneumonitis has been seen in 10% of patients treated with mirvetuxabop soratansivine with one patient(0.1%)who died from respiratory failure secondary to pneumonitis and lung metastases[23].

2.1.3. Tisotumab vedotin

Tisotumab vedotin obtained approval for the treatment of recurrent or metastatic cervical cancer that progressed on or after chemotherapy in April 2024. InnovaTV 204/GOG-3023/ENGOT-cx6(NCT03438396)was a single-arm phase II study that evaluated the use of tisotumab vedotin in patients with metastatic cervical cancer who had received two or fewer previous systemic regimens for recurrent or metastatic disease. Patients that received tisotumab vedotin had an ORR of 24%[24]. InnovaTV301/ENGOT-cx12/GOG-3057(NCT04697628) was the confirmatory phase III trial comparing sitotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer versus investigator's choice chemotherapy. The primary outcome was OS in which median OS was longer with sitotumab vedotin versus chemotherapy(11.5 months versus 9.5 months, respec-tively; hazard ratio,0.70;95% CI,0.54-0.89;two-sided P=0.004)[25].Across clinical trials, four patients(0.9%) experienced pneumonitis with one patient having a fatal outcome[26].

2.2. Immunotherapy

2.2.1. Pembrolizumab

Pembrolizumab is an immune anti-programmed cell death protein 1(PD-1) checkpoint inhibitor that has numerous indications in gyneco-logic malignancies. For endometrial cancer, pembrolizumab is approved both for first-line treatment and for recurrence. The phase II KEYNOTE-158 study(NCT02628067) examined the use of pembrolizumab in recurrent endometrial cancer with microsatellite instability-high(MSI-H) or mismatch repair-deficient(dMMR) tumors, with a median PFS of 13.1 months and median OS not reached[27]. Pembrolizumab was also examined in women with mismatch repair-proficient(pMMR) and dMMR recurrent endometrial cancer in the phase III study 309-KEYNOTE-775(NCT06517449), which examined the combi-nation of pembrolizumab and levansin vs physician choice che-motherapy with the former agents being associated with improved PFS and OS compared to chemotherapy[28]. Given these encouraging data, pembrolizumab was also evaluated in frontline management in the phase III NRG-GY018 study(NCT03914612), which evaluated women with advanced or recurrent endometrial cancer[29]. Women were randomized to either pembrolizumab or placebo with platinum-taxane chemotherapy followed by pembrolizumab or placebo mainte-nance. The addition of pembrolizumab to platinum chemotherapy followed by maintenance pembrolizumab demonstrated a 70% risk re-duction for disease progression in the dMMR cohort and 46% risk reduc-tion for progression in the pMMR cohort[29].

Within cervical cancer, pembrolizumab is an option for primary and recurrent/metastatic treatment. ENGOT-Cx11/GOG-3047/KEYNOTE-A18(NCT04221945) evaluated whether the effects of chemoradiother-apy could be improved with the addition of immunotherapy in women with locally advanced cervical cancer. Women were randomized to pembrolizumab versus placebo every 3 weeks with concurrent chemo-radiation followed by maintenance pembrolizumab or placebo[30].The addition of pembrolizumab with chemoradiotherapy reduced the risk of progression by 30% compared to placebo. Pembrolizumab is also ap-proved for patients with recurrent/metastatic cervical cancer.KEYNOTE-158(NCT02628067) demonstrated a 14.6% ORR for pembrolizumab in women with recurrent cervical cancer who had pro-grammed death-ligand 1(PD-L1) positive tumors(combined positive score≥1)[31]. Additionally, pembrolizumab is also approved for use with platinum-based chemotherapy, with or without bevacizumab, in women with persistent, recurrent, or metastatic cervical cancer based on the phase III KEYNOTE-826 trial(NCT03635567), which demon-strated an improved PFS and OS benefit with the addition of pembroli-zumab[32].

Importantly, pembrolizumab has been shown to cause immune-mediated pneumonitis with higher rates in those with prior thoracic radiation. Pneumonitis has occurred in 3.4% of patients treated on all clinical trials across multiple indications with 0.1% of patients dying from this adverse event[33]. Notably, there has been no reported immune-mediated pneumonitis events among women included in the previously discussed cervical and endometrial cancer trials[33].

2.2.2. Dostarlimab

Dostarlimab is an anti-PD-1 immune checkpoint inhibitor that has approval in endometrial cancer. The GARNET trial(NCT02715284) is a phase I clinical trial that evaluated the utility of dostarlimab in patients with dMMR recurrent endometrial cancer following previous platinum-based chemotherapy. The ORR for the 71 patients with measurable disease was 42.3%, which led to the approval for dostarlimab as a single-agent treatment in dMMR recurrent or advanced endometrial cancer[34]. More recently, the use of immune checkpoint inhibitors has been brought to the frontline. The phase III RUBY/ENGOT-EN6/GOG-3031/NSGO trial(NCT03981796) evaluated the use of carboplatin and paclitaxel plus dostarlimab in the first-line setting.The combination of dostarlimab with carboplatin and paclitaxel demonstrated a signifi-cant improvement in PFS, with the largest benefit seen in the dMMR population; this led to its approval in combination with carboplatin and paclitaxel for primary advanced or recurrent endometrial cancer[35]. Dostarlimab may cause immune-related pneumonitis,which can be fatal and has been reported in approximately 2.3% of patients, again with a higher risk in those treated with prior thoracic radiation[36].

2.2.3. Durvalumab

Durvalumab is an anti-PD-L1 immune checkpoint inhibitor that has been approved for use with carboplatin and paclitaxel followed by single-agent durvalumab in patients with primary advanced or re-current dMMR endometrial cancer. This approval came from the DUO-E/GOG-3041/ENGOT-EN10(NCT04269200) phase III trial evalu-ating first-line carboplatin and paclitaxel in combination with durva-lumab, followed by maintenance durvalumab by itself or with opolarabir[37]. Among the entire cohort there was a significant im-provement in PFS for durvalumab with chemotherapy versus chemo-therapy alone. However, the improvement in the entire cohort was largely attributed to the improvement in the dMMR population. The incidence of immune-related pneumitis with durvalumab is 2.4%,with<0.1% being fatal. Similar to other immune checkpoint inhibi-tors, the risk for pneumonitis and higher with prior use of thoracic radi-ation[38].

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2.3. Cytotoxic chemotherapy

There are numerous cytotoxic chemotherapy that have also been associated with ILD. Bleomycin is currently used in gynecologic ma-lignancies for treatment of malignant germ cell tumors and high-risk gestational trophoblastic neoplasia(GTN)[6,39]. Bleomycin can lead to lung injury by both direct toxic and immune-mediated effects[4].Importantly, bleomycin lung toxicity is potentiated by exposure to high concentration of supplemental oxygen. Bleomycin has been associated with lung toxicity in 6.8-21% of patients, with associated mortality of up to 48%[4]. Importantly, the presentation of lung tox-icity with bleomycin can be variable, with some patients being asymptomatic as upward of 39% of cases are detected by imaging alone[40].

Gemcitabine is another cytotoxic agent associated with ILD.Gemcitabine can be used for high-risk GTN resistant to multiagent che-motherapy[39], as a radiosensitizer for cervical/vulvar cancer[7,41], in uterine sarcomas[8], and recurrent epithelial ovarian cancer[6]. The in-cidence of ILD for gemcitabine ranges from 1 to 4%, with severe cases associated with mortality of 20%.The risk for ILD is highest when gem-citabine is used in combination with other agents also known to have lung toxicity[4].

Rinotecan is a topoisomerase 1 inhibitor agent for recurrent cervical and platinum-resistant ovarian cancer[6,7]. The dose-limiting toxicity for irinotecan is pneumonitis with a rate of 0-20% in patients treated on clinical trials[42]. Symptoms include fever, shortness of breath, and cough. Topotecan, another topoisomerase 1 inhibitor, has not been associated with pulmonary toxicity. Notably, duerextrucet, the payload of the ADC T-DXd, is a topoisomerase inhibitor that is associ-ated with lung toxicity.

Cyclophosphamide is used for high-risk GTN, malignant germ cell and sex cord-stromal tumors, and recurrent epithelial ovarian cancer[6,39]. Pulmonary toxicity from cyclophosphamide is rare, with a fre-quency<1%[43]. Patients generally present with cough and difficulty breathing, although fever may also be present[44].

Methotrexate is another agent used for both low- and high-risk GTN[39]. The incidence of ILD for methotrexate has been reported as 0.3-2.1%[4].Taxanes are used ubiquitously in gynecologic malignan-cies with platinum across all disease sites. The incidence of pneumonitis with taxanes is 1-5[5].Symptoms of taxane-induced pneumonitis can be nonspecific. Patients may present with dyspnea at rest, low-grade fever, malaise, dry cough, hypoxia, and tachypnea[1].

2.4. Tyrosine kinase inhibitors

Lenvatinib is a tyrosine kinase inhibitor used in combination with pembrolizumab for treatment of patients with pMMR advanced endo-metrial cancer who have progressed following primary systemic ther-apy. Although trials in endometrial cancer did not show risk for pneumonitis, levinatib 20 mg orally per day in combination with pem-brolizumab 200 mg IV every 3 weeks has been associated with a 3% risk for ILD in first line treatment of renal cell cancer[45] Erlotinib is another tyrosine kinase inhibitor that is used for recurrent/metastatic vulvar cancer[41].The incidence of ILD for erlotinib is 1.2-6.6% with a mortal-ity rate from early studies reported as high as 22.8%[4].

2.5. Mechanistic target of rapamycin protein(mTOR) inhibitors

Sirolimus, everolimus, and tensirolimus are mTOR inhibitors used in the management of gynecologic cancer. Temsirolimus can be used for second-line therapy in recurrent endometrial cancer; everolimus in combination with letrozole for recurrent or metastatic endometrial cancer; and sirolimus, everolimus, and tensirolimus for management of perivascular epithelioid cell neoplasms[8]. The incidence for ILD among patients treated with mTOR inhibitors is approximately 10.4%[4].

2.6. Poly(ADP-ribose) polymerase(PARP) inhibitors

The introduction of PARP inhibitors over the past decade has drasti-cally changed the treatment landscape for ovarian cancer. Of the current approved PARP inhibitors in gynecologic cancer, olaparib is associated with ILD, with pneumonitis occurring in 0.8% of patients exposed and some cases being fatal[46].

2.7. Experimental therapies

Although it is beyond the scope of this guideline to address all new technologies that are being studied, the two main current classes of drug development, new ADC/peptide drug conjugates(ADCs/PDCs)and immune system engages need to be addressed, at least in broad terms.

For ADCs,research has continued to identify specific target antigens,cytotoxic payloads, and linker technology.The furthest advancement has come in the realm of linkers, as these influence stability, release and payload coupling which may increase or decrease immunogenicity[47-49]. More recently, the macroscopic view of utilizing antigens has also shifted to the realm of PDCs with multiple clinical trials utilizing single peptide linkers either as direct targeting agents for immune mod-ulation or linked to various cytotoxic payloads[50,51].

For direct immune engagement, there are now multiple avenues through which the cancer can be targeted. The first is bi-specific anti-bodies which bind both tumor specific antigens and then include a secondary antibody to engage the immune system. This can occur via binding immune cells directly, also known bispecific T-cell engagers(or BiTEs) that target CD-3+ cells, CD-16 natural killer cells or CD64 phagocytic cells, or immune blockade targeting multiple checkpoint proteins such as PD-1 and CTLA-4[52]. Additionally, adoptive cell immunotherapy via autologous tumor Infiltrating lymphocytes(TILs),chimeric antigen receptor(CAR) and T-cell receptor(TCR) engineered T cells for solid tumors has advanced significantly over the past decade.In brief, TIL therapy involves harvesting and ex vivo expansion of ex-tracted lymphocytes from the tumor itself. CAR and TCR modifications are both genetically engineered lymphocytes. CAR-T lymphocytes are modified to incorporate a specific extracellular tumor antigen and can incorporate genes for modulation of the local immune microenviron-ment which ultimately leads to cell killing in the presence of the initial stimulatory receptor. TCRs recognize a wider variety of tumor antigens,both extra- AND intracellular, and have high antigen sensitivity compared to CAR-T, but they are limited often by haplotype(i.e., HLA specific)[53].

With the adversarial of these new technologies, the potential for therapy-induced toxicity has increased. Direct drug-induced lung injury can arise from multiple aspects, including off-target effects from conjugated cytotoxic therapy;“on target” toxicity but off target secondary to antigen heterogeneity and expression in non-cancerous tissue; immune-mediated pneumonitis; and cytokine release syn-drome(CRS) induced injury. All the mechanisms except CRS have already been discussed; CRS results from activated immune cells(depending on the method of therapy) and the vascular endothelium microenvironment leading to significant efflux of pro-inflammatory cy-tokines such as IL-6, IL-11, TNFα MCP-1 and interferon gamma(INF-y). CRS can range in severity and include fever, rigors, hypoten-sion, hypoxia/respiratory failure, capillary leak, kidney injury and neurologic signs and symptoms among others[52-57]. Lung toxicity in the acute phase of severe CRS can result in non-cardiogenic pulmo-nary edema, interstitial pneumonia, and acute respiratory distress syndrome(ARDS).

The treatment strategies for these experimental therapies are deter-mined based on the presumptive mechanism of injury. However, in the specific case of immune mediated pneumonitis and CRS the typical therapy would be similar to what has been described previously: judi-cious and early use of corticosteroids, with first-line use of the IL-6

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Gynecologic Oncology 202(2025) 137-145

cytokine receptor inhibitor tocilizumab for adoptive T-cell therapy-induced acute lung toxicity becoming more common in combination with corticosteroids(methylprednisolone for severe). Anakinira(IL-1 receptor antagonist) is being studied and increasingly used in hemato-logic CAR/TCR toxicity[55-57]. The treatment of CRS toxicity and of hemophagocytic lymphohistiocytosis(HLH), which often is a fatal com-plication that occurs after resolution of CRS with pulmonary manifesta-tions, is reviewed extensively in Chang et al.[59].

3.Conclusion

Conventional cytotoxic agents, targeted therapies, and immunother-apy can cause ILD[5].Given the significant clinical benefit of newer anti-cancer agents and their potential for broad use across multiple disease types, with an extended duration of use, there is renewed emphasis for clinician education to maintain a high index of suspicion for the de-velopment of ILD/pneumonitis. Early detection and prompt interven-tion is required to mitigate pulmonary toxicity and prevent potentially catastrophic clinical events.

Authors contribution

Dr.O'Cearbhaill,Dr. Powell and Dr. Weiner contributed to the outline and oversaw development. All authors reviewed and edited the final draft.

Funding

Dr. O'Cearbhaill is supported in part through the NIH/NCI Cancer Center Support Grant P30CA008748. Dr. Powell is supported in part through a NIH/NCI Cancer Center Support Grant P30CA196521.

Disclaimer

SGO Statements are intended to be educational devices that provide information that may assist in caring for patients. This Statement is not a rule and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring or discouraging any particular treatment. SGO Statements are not intended to supplement the judgment of the health care provider with respect to particular patients or special clinical situations. Clinical decisions in any particular case involve a complex analysis of a patient's condition and available courses of action with the ultimate determination to be made by the health care provider in light of each individual patient's circumstances. Therefore, clinical considerations may lead a healthcare provider to appropriately take a course of action that varies from this document.

Declaration of competing interest

Dr. Powell reports payments to his institution from the National Institutes of Health; consulting fees from Daiichi-Sankyo, Astra Zeneca, Duality Biologics, BioTech, Rizer, BMS, Seagen, and Merus:horonia from Roche; and a position on Fleischner Society Executive Committee.

Dr.Gaillard reports payments to her institution from Compugen,Genentech/Roche, Clovis/Pharma8,ivova, Prestem, Tesaro/GSK,Blueprint, Immunogen, Volraa, Beigene, GOG-Foundation, and AstraZeneca; consulting fees from Immunogen, Novartis, Verastem,and Compugen; United States Patent Nos 10.258,604& 10.905,659,Lasofoxifene treatment of breast cancer, licensed by Duke; a non-compensated role on SignPath Pharma Advisory Board; and role as Phase I Subcommittee trait in CardN Oncology.

Dr. Winer reports institutional payments from Chimer-IT and clinical trial design/review consulting fees from Theratechnologies.

Dr.O'earbraill reports personal fees from Loxo,OnCusp,Cardinal Health, Tesaro/GSK,Regeneron, Seattle Genetics, Genentech.

Gynecologic Oncology Foundation, Bayer, Mylteni, 2seventybio and Immunogen/Abbvie, travel support for the Gathering Around Cancer,Ireland, all outside the submitted work. She is a non-compensated steering committee member for the PRIMA, Moonstone(Tesaro/GSK)and DUO-O(AstraZeneca) studies and non-compensated advisor for Carina Biotech. Her institute receives funding for clinical research from Alkermes, Bayer/Celgene/Juno, Tesaro/GSK, Merck, Ludwig Cancer Institute, Lyell Therapeutics, Context Therapeutics, lovance, Fate Thera-peutics, Abbvie/StemCentrx, Regeneron, TCR2 Therapeutics, Atara Biotherapeutics, MarkerTherapeutics, Syndax Pharmaceuticals,Genmab/Seagen Therapeutics, Sells Therapeutics, Genentech, Kite Pharma,and Gynecologic Oncology Foundation.

Dr.Tarney does not have any potential conflicts to disclose.

The views expressed herein are those of the authors and do not re-flect the official policy of the Uniformed Services University of the Health Sciences, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Army/Navy/Air Force,Department of Defense, or U.S. Government. Mention of trade names,commercial products, or organizations does not imply endorsement by the U.S. Government.

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