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ADC相关间质性肺病：风险、识别、预防与管理的研究缺口
抗体药物偶联物（ADC）相关间质性肺病（ILD）是一个日益受到关注的严重不良事件，可能危及生命，尽管大多数病例为低级别且可有效治疗。然而，在理解、识别、预防和管理ADC-ILD方面，仍存在显著的研究空白。以下将详细阐述这些研究缺口：
1. 风险因素与机制的理解不足
- 特定风险因素的识别不清晰： 尽管已知ADC与ILD风险增加相关，且曲妥珠单抗-德鲁替康（T-DXd）被报道为最常见的诱导ILD的ADC，但在识别高风险患者方面仍面临挑战 。目前推荐对具有ILD发展风险因素的患者进行预测性生物标志物评估，但这些生物标志物的具体内容和有效性尚未完全阐明 。肺癌患者的诊断尤其具有挑战性，因为其症状和放射学表现与肺炎、感染或疾病进展等其他常见疾病相似，且许多肺癌患者本身就存在潜在的肺部疾病，可能使其更容易出现严重或致命的肺炎结局 。对于乳腺癌患者，T-DXd的使用日益增加，尽管已知其会增加ILD的风险，特别是在这一患者群体中 。此外，不同类型的ADC和不同肿瘤类型中ILD的发生率和严重程度也存在差异，这表明可能存在特异性风险因素，但尚未完全解析 。
- 发病机制未完全阐明： 尽管有研究提出DILD可能源于多种重叠过程，包括免疫介导的炎症激活、直接上皮细胞毒性、脱靶激酶抑制和有效载荷依赖的旁观者损伤，但这些机制的具体细节和相互作用仍需进一步研究 。深入了解ADC诱导ILD的潜在病理生理学机制对于预防其发生和开发有效的管理策略至关重要 。
2. 早期识别与诊断的挑战
- 症状非特异性和诊断延迟： ADC相关ILD的症状通常是非特异性的，包括咳嗽、呼吸困难、胸痛和全身症状如疲劳、发热等 。这使得早期识别症状变得困难，导致诊断常常延迟 。在没有特异性临床或放射学指征的情况下，药物诱导的ILD通常是一种排除性诊断 。
- 缺乏统一的诊断标准和生物标志物： 当前的诊断标准包括新发现的肺部混浊、症状发作与药物治疗开始时间的关系以及排除其他ILD原因 。然而，这些标准仍需细化，并且缺乏特异性的预测性或诊断性生物标志物来辅助早期诊断 。有专家建议，对于疑似ILD的病例，应由肺科医生和放射科医生评估CT扫描，强调多学科专家网络在主动早期管理中的重要性 。
3. 预防与管理策略的优化空间
- 预防措施的有效性： 患者教育是预防高级别ILD的关键，通过确保患者密切关注并及时报告肺部症状来改善患者结局 。然而，除了患者教育之外，针对高风险患者的更具体的预防策略（如剂量调整或预处理）的有效性仍需研究。
- 管理策略的标准化与个性化： 目前的ILD管理策略包括剂量减少、治疗中断、停药、皮质类固醇治疗和支持性护理 。然而，对于无症状的1级ILD，皮质类固醇的疗效尚未明确建立 。对于更高级别的ILD，应考虑长期皮质类固醇治疗的益处/风险平衡，包括剂量和治疗持续时间 。入院和氧气补充对于3-4级严重病例是必需的 。尽管这些指南提供了结构化的分级管理方法，但如何根据患者的具体情况和ADC类型进行个性化治疗，以最大限度地提高益处并最小化毒性，仍需进一步研究 。
- 多学科协作和随访： 建立一个多学科专家网络对于ADC诱导ILD的主动早期管理至关重要，包括肿瘤学家、放射科医生、肺科医生、感染病专家和护士 。肺科医生的专业知识对于患者随访、重复胸部CT扫描、肺功能检查（如肺活量测定和DLCO）是必要的 。然而，如何优化这些多学科团队的协作效率以及如何在不同医疗系统和资源水平下实施这些建议，仍是挑战。
- ADC再引入的考量： 对于症状性ILD，通常建议停用ADC。仅在无症状病例且症状完全消退后才可考虑重新引入ADC，但这方面的具体指导和风险评估仍需更多证据 。
- 新型抗癌药物（如Dato-DXd）的特殊关注点： 针对新兴的ADC，例如Datopotamab deruxtecan (Dato-DXd)，已经确定了一些需要特别关注的不良事件（AESI），包括ILD/肺炎、输注相关反应、口腔黏膜炎/口腔炎和眼表事件 。对于这些新型ADC，需要更好地理解其不良事件，并制定最佳的预防、监测和管理策略，以确保安全有效地给药 。
4. 持续监测与数据收集
- 真实世界数据的整合与分析： FDA不良事件报告系统（FAERS）等真实世界药理警戒研究已经揭示了ADC诱导ILD的高安全信号，并指出T-DXd是报告最频繁的药物 。然而，现有证据基础仍然受限于回顾性研究、病例报告和不完整的机制验证的普遍性 。未来需要更系统地收集和分析真实世界数据，以全面了解ADC与肺部疾病之间的关系，并优化治疗方案和提高安全性 。
- 人工智能辅助工具的应用： 新兴的人工智能辅助工具在ILD的早期检测和风险分层方面具有潜力，这为未来的研究提供了方向 。
- 特定人群的关注： 胃癌或胃食管交界腺癌患者使用T-DXd时，ILD/肺炎的发生率为13.9%，且主要为低级别 。对于不同肿瘤类型（如胃癌、非小细胞肺癌、乳腺癌、妇科癌症、结直肠癌等）中ILD的发生率、严重程度和管理策略的差异，需要进行更深入的研究和具体的指导 。
总结
ADC在妇科癌症、乳腺癌、胃癌和非小细胞肺癌等多种肿瘤治疗中展现出显著疗效，但其独特的安全性风险，特别是ILD，需要密切关注 。为了最大限度地提高ADC的益处并最小化毒性，未来的研究必须致力于填补在风险因素、发病机制、早期识别生物标志物、个性化预防和管理策略以及多学科协作优化方面的知识空白 。这包括利用多组学方法和人工智能辅助工具，并进行前瞻性、设计良好的临床试验，以推动ADC治疗在保证患者安全的前提下，更广泛和有效地应用 。
References
1Antibody-drug conjugates as targeted therapy for treating gynecologic cancers: update 2025.PubMed
Jordyn Silverstein, Beth Karlan, Nasim Herrington, et al.
PURPOSE OF REVIEW: Provide the most up-to-date information on the dynamic landscape of antibody-drug conjugates (ADCs) in gynecologic cancers. We discuss the latest research that supports the approved ADCs and outline the ongoing trials and preliminary results that may lead to ADC approvals in the future. Current gaps in knowledge and areas for future research are discussed. RECENT FINDINGS: ADCs are rapidly changing the landscape of gynecologic cancer care. Three ADCs are currently FDA approved and used routinely in clinical practice, with many more currently in clinical development. The most common ADC target is folate receptor alpha of which there are 8 different folate receptor targeting ADCs in development. Other targets under investigation include trophoblast cell surface antigen-2 (Trop-2), claudin-6 (CLDN6), cadherin-6 (CDH6), nectin-4, HER-2 and B7-H4. ADCs can cause new and unique adverse effects, including ocular toxicities and interstitial lung disease. SUMMARY: ADCs offer the opportunity for a more effective and personalized treatment approach for gynecologic cancer patients. Side effects must be closely monitored, and preventive measures must be followed to maximize benefit and minimize toxicity. A better understanding of the role of target proteins as biomarkers to predict response to ADCs will be critical for successful clinical implementation of ADCs and further research in this area is necessary.
2Interstitial lung disease with antibody-drug conjugates: a real-world pharmacovigilance study based on the FAERS database during the period 2014-2023.PubMed
Jing Shi, Xinya Liu, Li Wu, et al.
BACKGROUND: Antibody-drug conjugates (ADCs) combine the targeted nature of monoclonal antibodies with the potent efficacy of small-molecule cytotoxic drugs. However, they also carry unique safety risks, including lung toxicity. OBJECTIVE: To conduct a systematic review and analysis of ADC-related interstitial lung disease (ILD) incidence, characteristics, and risk factors to optimize safe and effective clinical use. DESIGN: ADC-related ILD reports from the FDA Adverse Event Reporting System (FAERS) database between January 2014 and March 2023 were analyzed. METHODS: ADC-related ILD reports were retrieved from the FAERS database. Statistical analyses were conducted using reporting odds ratio (ROR) and information components (ICs). The lower limit of the 95% confidence interval (CI) was set for ROR (ROR025) >1 or IC (IC025) >0, and statistical significance was determined based on a minimum of three reports. RESULTS: The study analyzed the statistical data on ADC-induced ILDs (1277 cases). Trastuzumab deruxtecan was reported to be the most frequent (38.4%). Among the 33 preferred terms (PTs) in standardized MedDRA queries (SMQ) = "Interstitial lung disease," the three most common were as follows: ILD (40.6%), pneumonitis (27.9%), and acute respiratory distress syndrome (ARDS) (7.6%). Trastuzumab deruxtecan showed the strongest association with ILD (PT) and pneumonitis, whereas ARDS was associated with four different drugs. The median time to onset of ADC-related ILDs was 51 days (interquartile range (IQR), 16-196), with ARDS having the earliest median time to onset at 15 days (IQR, 6-52). The onsets of pneumonitis, ILD, lung infiltration, and pulmonary toxicity were similar. More than 26% of ADC-related ILD cases result in death, with ARDS having the highest mortality rate of 65.0%. CONCLUSION: ADCs are associated with an increased risk of pulmonary adverse events, such as ILDs, with significant differences between drugs and varying mortality rates for different adverse events, necessitating distinct monitoring and appropriate management.
3Multidisciplinary clinical guidelines in proactive monitoring, early diagnosis, and effective management of trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) in breast cancer patients.PubMed
D Wekking, M Porcu, B Pellegrino, et al.
Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), has altered the treatment landscape in breast cancer (BC), irrespective of the HR-receptor status. The use of the agent is increasing, despite the finding that exposure to T-DXd increases the risk of interstitial lung disease (ILD), particularly in BC patients. Although T-DXd-related ILD can be potentially severe and life-threatening, most low-grade cases can be treated safely using a multidisciplinary approach comprising early and accurate diagnosis, effective management, close monitoring, and the prompt administration of steroids. Additionally, increasing patients' education on ILD symptoms ensures close attention and enables prompt reporting, enhancing patient outcomes. It is recommended that predictive biomarkers are assessed in patients with risk factors for developing ILD. Currently, diagnostic criteria comprise newly identified pulmonary opacities, the relation of symptom onset to medication initiation, and the exclusion of other causes of ILD. The general condition of patients is weakened during the management of ILD (BC progression and corticosteroid treatment). Consequently, BC chemotherapy might be attenuated. This highlights the importance of preventing (high-grade) ILD, especially since its use is expanded. Identifying high-risk patients, diagnosing, and customizing treatment is, however, challenging and additional information on patient selection is often not fully clarified. In this paper, we provide updated multidisciplinary clinical guidance for patient selection, proactive monitoring, early diagnosis, and effectively management of T-DXd-induced ILD in HER2-positive BC patients. We describe the risk factors for developing ILD, patients' characteristics of ILD, and the histopathological and radiographic characteristics of ILD, including real-world clinical practice reports. These recommendations provide a structured step-by-step approach for managing each suspected BC-related ILD grade.
4Balancing Innovation and Safety: Prediction, Prevention, and Management of Pneumonitis in Lung Cancer Patients Receiving Novel Anti-Cancer Agents.PubMed
Sarah Liu, Daniel Wang, Andrew Robinson, et al.
Pneumonitis is characterized as inflammation of the lung parenchyma, and a potential adverse effect of several anti-cancer therapies. Diagnosing pneumonitis can be particularly challenging in lung cancer patients due to inherent similarities in symptoms and radiological presentation associated with pneumonitis, as well as other common conditions such as infection or disease progression. Furthermore, many lung cancer patients have underlying pulmonary conditions that might render them more susceptible to severe or fatal outcomes from pneumonitis. Novel anti-cancer agents, such as antibody-drug conjugates (ADCs) and bispecific antibodies (BsAbs), are being incorporated into the treatment of lung cancer; therefore, understanding the risk and mechanisms underlying the potential development of pneumonitis with these new therapies is important to ensure continuous improvements in patient care. This narrative review provides an overview of the incidence of pneumonitis observed with novel anti-cancer agents, characterizes potential pathophysiological mechanisms underlying pneumonitis risk and emerging predictive biomarkers, highlights management strategies, and explores future directions for minimizing the risk of pneumonitis for lung cancer patients.
5Safety and Efficacy of Trastuzumab Deruxtecan for Metastatic HER2+ and HER2-low Breast Cancer: An Updated Systematic Review and Meta-Analysis of Clinical Trials.PubMed
Zaheer Qureshi, Faryal Altaf, Abdur Jamil, et al.
OBJECTIVES: Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate (ADC) promising in treating metastatic HER2+ and HER2-low breast cancer. This updated systematic review and meta-analysis, integrating data from the latest clinical trials, aimed to evaluate the safety and efficacy of T-DXd in this patient population. METHODS: We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A comprehensive search was conducted across PubMed, Scopus, and Web of Science up to January 2024, focusing on clinical trials that assessed T-DXd's efficacy and safety. Eligibility criteria were based on the PICOS framework, and selected studies underwent rigorous quality assessment and data extraction. The primary outcomes were progression-free survival (PFS), overall survival (OS), and the incidence of adverse events. A random-effects meta-analysis was performed to synthesize the data. RESULTS: Seven studies involving 2,201 patients met the inclusion criteria. The pooled analysis revealed that T-DXd significantly improved PFS (OR=0.37, 95% CI: 0.27-0.52), indicating a robust efficacy in slowing disease progression. However, treatment was associated with an increased risk of anemia (OR=2.10, 95% CI: 1.36-3.25), fatigue (OR=1.56, 95% CI: 1.21-2.02), nausea (OR=6.42, 95% CI: 4.37-9.42), vomiting (OR=6.21, 95% CI: 3.14-12.25), constipation (OR=2.26, 95% CI: 1.53-3.34), and notably, drug-related interstitial lung disease (OR=10.89, 95% CI: 3.81-31.12). The efficacy outcomes demonstrated significant heterogeneity, which was addressed through sensitivity analysis. CONCLUSIONS: T-DXd shows significant efficacy in treating metastatic HER2+ and HER2-low breast cancer, offering a valuable therapeutic option for patients with advanced disease. However, the treatment is associated with notable adverse events, including a heightened risk of ILD. These findings underscore the need for careful patient selection, monitoring, and management strategies to mitigate risks. Future research should focus on optimizing treatment protocols and exploring methods to enhance safety profiles.
6A Systematic Review of Mechanisms, Incidence, and Management of Trastuzumab Deruxtecan Induced ILD/Pneumonitis in Solid Tumors.PubMed
Dehua Liao, Jiwen Zhang, Ting Yan, et al.
Trastuzumab deruxtecan (T-DXd) has been approved to treat various tumors. While most adverse events (AEs) associated with T-DXd are manageable, interstitial lung disease (ILD)/pneumonitis is a notable AE of special concern. This review describes the incidence, severity, and management of T-DXd-induced ILD/pneumonitis across different tumors. We conducted a systematic search of PubMed, Embase, Cochrane Library, and Web of Science for literature published up to 13 September 2024, regarding the use of T-DXd in the treatment of HER2-positive tumors. Studies included were clinical trials involving HER2-positive tumors with reported ILD/pneumonitis cases.The main data extracted from the full-text articles included the incidence and severity of T-DXd-induced ILD. 18 studies involving 3380 patients with various advanced solid malignancies were included in our review. The overall incidence of adjudicated drug-related ILD/pneumonitis was 12.40%. Although most ILD/pneumonitis cases were low-grade, the risk of ILD/pneumonitis-related death should not be overlooked. Given the prolonged exposure to the drug, careful monitoring and management of T-DXd-induced ILD/pneumonitis are critical. Management strategies include dose reduction, treatment interruption, discontinuation, corticosteroids, and supportive care. Further research is needed to clarify the risk factors and mechanisms underlying T-DXd-induced ILD/pneumonitis. This review highlights critical gaps in understanding the risk factors and mechanisms of T-DXd-induced ILD, underscoring the need for further research.
7Trastuzumab Deruxtecan-Induced Interstitial Lung Disease/Pneumonitis in ERBB2-Positive Advanced Solid Malignancies: A Systematic Review.PubMed
Ziad Abuhelwa, Abdurahman Alloghbi, Ali Alqahtani, et al.
BACKGROUND AND OBJECTIVE: Trastuzumab deruxtecan (T-DXd) is a novel anti-ERBB2 antibody drug conjugate that appears to be associated with an increased risk of lung toxicity. We performed a systematic review to describe the incidence, severity, and management of T-DXd-induced interstitial lung disease (ILD) or pneumonitis. METHODS: We searched PubMed/MEDLINE, Embase, Cochrane, and Web of Sciences through to 1 January, 2022, for human clinical trials that assessed T-DXd in adults with ERBB2-positive advanced solid tumors and described the rate of ILD/pneumonitis. Study screening was performed by two researchers. Data were extracted from the full-text articles. RESULTS: Fourteen studies with a total of 1193 patients with different types of advanced solid malignancies were included in our systematic review. The overall incidence of all-grade ILD/pneumonitis cases that were adjudicated by an independent committee was 11.40% (ILD/pneumonitis cases, n = 136 out of total n = 1193). Grading of the adjudicated T-DXd-induced ILD/pneumonitis was reported in 122 patients with the majority of the cases (78.69%, n = 96) occurring as grade 1 or 2. Death was reported in 13 out of 122 (10.66%) patients. The highest incidence of ILD/pneumonitis was seen in patients with uterine carcinomatosis (26.47%) and non-small cell lung cancer (24.77%). Interstitial lung disease/pneumonitis events were treated with a dose interruption or reduction, treatment discontinuation, corticosteroids, and supportive care. CONCLUSIONS: Interstitial lung disease/pneumonitis is a well-described, serious, and potentially life-threatening adverse event that is associated with T-DXd. Further studies are needed to identify the risk factors and the underlying pathophysiology of T-DXd-induced ILD/pneumonitis to prevent occurrence and to develop effective management strategies.
8[Diagnosis and management of interstitial lung disease induced by antibody-drug conjugates in breast cancer: A French expert opinion paper].PubMed
Luis Teixeira, Véronique Diéras, Bruno Crestani, et al.
Interstitial lung disease (ILD) has been reported with many cancer drugs including some recent antibody-drug conjugates (ADCs). The mechanisms of ILD induced by many chemotherapy drugs, other drug classes and ADCs used in cancer, including breast cancer, are not clearly elucidated. In the absence of specific clinical or radiological signs, the diagnosis of drug-induced ILD is often a diagnosis of exclusion. When present, the most frequent symptoms are respiratory signs (cough, dyspnea, chest pain) and general signs (fatigue, fever). Any suspicion of ILD should be evaluated by imaging and, if in doubt, the CT scan should be evaluated by a pulmonologist and a radiologist. A network of multidisciplinary experts for proactive early management of ILD is important, including oncologist, radiologist, pulmonologist, infectious disease specialist and nurses. Patient education is essential to report new or exacerbated lung symptoms and prevent high-grade ILD. Study drug is discontinued temporarily or permanently according to ILD severity and type of ADC. For asymptomatic cases (Grade 1), the efficacy of corticosteroids is not clearly established; for higher grades, the benefit/risk balance of long-term corticosteroid therapy should be considered for the dose and treatment duration. Hospitalization and oxygen supplementation are required for severe cases (Grades 3-4). For patient follow-up, the expertise of a pulmonologist is necessary with repeated chest scans, spirometry and DLCO. Preventing ADC-induced ILDs and evolution to high grade rests on a network of multidisciplinary experts for assessment of individual risk factors, early management, close follow-up and patient education.
9Targeted Therapy-Induced Interstitial Lung Disease in NSCLC: Mechanisms, Clinical Signatures, and a Precision Medicine Roadmap.PubMed
Jia-Feng Wang, Lei-Lei Jiang, Meng-Chuan Wang, et al.
Molecularly targeted therapies have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), establishing precision oncology as the foundation of modern disease management. However, these advances are increasingly complicated by drug-induced interstitial lung disease (DILD), a potentially life-threatening adverse event that can disrupt treatment continuity and compromise clinical benefit. In this review, we provide a comprehensive evaluation of interstitial lung disease associated with targeted agents in NSCLC, including oncogene-directed tyrosine kinase inhibitors, antibody-drug conjugates (ADCs), and angiogenesis inhibitors. We summarize reported differences in ILD incidence, onset timing, clinical manifestations, and radiographic characteristics across targeted agents, with particular emphasis on high-risk populations and the elevated ILD incidence observed with deruxtecan-based ADCs. We further summarize current mechanistic evidence suggesting that DILD may arise from multiple overlapping processes, including immune-mediated inflammatory activation, direct epithelial cytotoxicity, off-target kinase inhibition, and payload-dependent bystander injury. Finally, we discuss current challenges and future directions for improving pulmonary safety, including real-world datasets, multi-omics approaches, and emerging AI-assisted tools for earlier detection and risk stratification. Importantly, the current evidence base remains limited by the predominance of retrospective studies, case reports, and incomplete mechanistic validation. These insights may help guide safer and more sustained implementation of targeted therapies in NSCLC.
10Trastuzumab Deruxtecan or Ramucirumab plus Paclitaxel in Gastric Cancer.PubMed
Kohei Shitara, Eric Van Cutsem, Mahmut Gümüş, et al.
BACKGROUND: On the basis of phase 2 studies, trastuzumab deruxtecan was approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma who had previously received trastuzumab-based therapy. Ramucirumab plus paclitaxel is also a standard second-line treatment option regardless of HER2 status. METHODS: We conducted an international, randomized, phase 3 trial comparing second-line trastuzumab deruxtecan at a dose of 6.4 mg per kilogram of body weight with ramucirumab plus paclitaxel in patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma confirmed on tumor biopsy conducted after the patient had progression while receiving trastuzumab-based therapy. The primary end point was overall survival. Secondary end points included progression-free survival, confirmed objective response (complete or partial response lasting ≥4 weeks), disease control, duration of response, and safety. RESULTS: Among 494 patients who had undergone randomization, overall survival was significantly longer with trastuzumab deruxtecan than with ramucirumab plus paclitaxel (median, 14.7 vs. 11.4 months; hazard ratio for death, 0.70; 95% confidence interval, 0.55 to 0.90; P = 0.004). Significant results were also seen with regard to progression-free survival (hazard ratio for disease progression or death, 0.74; 95% CI, 0.59 to 0.92) and confirmed objective response (in 44.3% of the patients in the trastuzumab deruxtecan group vs. 29.1% of those in the ramucirumab-paclitaxel group). The incidence of drug-related adverse events of any grade was 93.0% with trastuzumab deruxtecan and 91.4% with ramucirumab plus paclitaxel; the incidence of drug-related adverse events of grade 3 or higher was 50.0% and 54.1%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 13.9% of the patients who received trastuzumab deruxtecan (grade 1 or 2 in 33 patients and grade 3 in 1) and in 1.3% of those who received ramucirumab plus paclitaxel (grade 3 in 2 patients and grade 5 in 1). CONCLUSIONS: Trastuzumab deruxtecan led to significantly longer overall survival than ramucirumab plus paclitaxel among patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Adverse events were common in both groups. Events of interstitial lung disease or pneumonitis with trastuzumab deruxtecan, a known risk, were mainly low-grade. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Gastric04 ClinicalTrials.gov number, NCT04704934.).
11Assessing safety concerns of interstitial lung disease associated with antibody-drug conjugates: a real-world pharmacovigilance evaluation of the FDA adverse event reporting system.PubMed
Wanlong Lin, Jiabing Xu, Yufang Liao, et al.
BACKGROUND: Antibody-drug conjugates have revolutionized cancer therapy due to their selectivity and efficacy. However, concerns have been raised regarding the potential effects of trastuzumab deruxtecan in interstitial lung diseases. AIM: This study aimed to investigate the safety signals and time to onset of antibody-drug conjugates induced interstitial lung disease. METHOD: We utilized the FDA Adverse Event Reporting System database (2004-2022) to identify interstitial lung disease safety signals in 13 FDA-approved antibody-drug conjugates. Disproportionality analysis was conducted to estimate the reporting odds ratios for interstitial lung disease. RESULTS: Seven antibody-drug conjugates exhibited safety signals of interstitial lung disease: trastuzumab deruxtecan [reporting odds ratio, ROR (95% confidence intervals, CI) = 64.15 (57.07-72.10)], enfortumab vedotin [ROR (95% CI) = 5.24 (3.25-8.43)], trastuzumab emtansine [ROR (95% CI) = 3.62 (2.90-4.53)], brentuximab vedotin [ROR (95% CI) = 3.22 (2.49-4.17)], polatuzumab vedotin [ROR (95% CI) = 2.56 (1.59-4.12)], gemtuzumab ozogamicin [ROR (95% CI) = 2.53 (1.70-3.78)], and inotuzumab ozogamicin [ROR (95% CI) = 2.33 (1.21-4.49)]. Five antibody-drug conjugates with limited reports were excluded from further analysis: belantamab mafodotin, loncastuximab tesirine, mirvetuximab sorafenib, tisotumab vedotin, and moxetumomab pasudotox. Japan and the United States were the primary reporting countries. CONCLUSION: This real-world study highlights high safety signals of interstitial lung disease associated with antibody-drug conjugates. Clinicians should be aware of these safety concerns and risk factors and implement early identification measures for their patients. Future research should prioritize comprehensively exploring the relationship between antibody-drug conjugates and lung diseases.
12Interstitial Lung Disease Induced by Anti-ERBB2 Antibody-Drug Conjugates: A Review.PubMed
Paolo Tarantino, Shanu Modi, Sara M Tolaney, et al.
IMPORTANCE: In the past decade, ERBB2 (formerly HER2)-directed antibody-drug conjugates (ADCs) have substantially changed treatment of both advanced and early-stage ERBB2-positive breast cancer. Novel conjugates are now showing activity in trials of other ERBB2-associated tumors, leading to the recent US Food and Drug Administration approval of trastuzumab deruxtecan for ERBB2-positive gastric cancer, as well as beneficial results in colorectal, lung, and bladder cancer. It is thus possible that anti-ERBB2 ADCs may become a treatment option for multiple types of tumors because many have at least some expression of ERBB2. Despite an improved overall therapeutic index, clinical observations have recently raised a concern regarding potential lung toxicity of anti-ERBB2 ADCs. Deaths related to interstitial lung disease (ILD) have been reported with variable incidence in trials testing anti-ERBB2 conjugates, warranting appropriate training of clinicians for the identification and management of this toxic effect. OBSERVATIONS: Although no specific guidelines are available for the diagnosis and management of ADC-related ILD, some recommendations can be derived based on general principles adopted for drug-induced and immunotherapy-related ILD. Overall, in symptomatic ILD, the ADC should be discontinued. Reintroduction of the conjugate can be considered only in asymptomatic cases after complete resolution. Corticosteroids represent the cornerstone of ILD treatment, and dosing should be adapted according to the severity of the event. Additional treatments can be considered based on the clinical scenario. CONCLUSIONS AND RELEVANCE: This review summarizes the current knowledge on the pathogenesis and epidemiologic characteristics of anti-ERBB2 ADC-related lung toxicity, proposing strategies for its diagnosis and treatment. Earlier diagnosis and more adequate treatment of ADC-induced ILD may improve the therapeutic index of this important class of anticancer agents, allowing for a safe expansion of anti-ERBB2 ADCs across tumor types.
13Trastuzumab deruxtecan in non-breast solid tumors: Expanding indications, efficacy, and future directions.PubMed
A Ghidini, R Bukovec, L Roncari, et al.
BACKGROUND: HER2 alterations occur across multiple malignancies beyond breast cancer, including gastric, non-small-cell lung, colorectal, gynecologic, salivary gland, biliary tract, and urothelial cancers. Trastuzumab deruxtecan (T-DXd), a next-generation antibody-drug conjugate, has transformed outcomes through its high drug-to-antibody ratio, potent topoisomerase I inhibitor payload, and membrane-permeable design enabling a bystander effect. METHODS: We reviewed clinical and translational evidence for T-DXd in non-breast solid tumors, focusing on efficacy, safety, biomarkers, and resistance mechanisms. Key data were derived from the DESTINY trial program, basket studies, and recent regulatory submissions. RESULTS: Across tumor types, T-DXd has demonstrated clinically meaningful response rates: ∼55 % in HER2-mutant NSCLC, 42-51 % in gastric cancer, 37-45 % in colorectal cancer, 57 % in endometrial cancer, and ∼60 % in salivary duct carcinoma. Durable responses have also been observed in biliary and urothelial cancers. The most frequent adverse events are gastrointestinal and hematologic, while interstitial lung disease remains the most significant toxicity, occurring in ∼10-15 % of patients, with rare fatal cases. Predictive biomarkers vary by histology: HER2 mutation is most relevant in NSCLC, whereas amplification and overexpression define benefit in gastrointestinal and gynecologic malignancies. Resistance mechanisms include HER2 downregulation, bypass signaling activation, and impaired payload release. CONCLUSIONS: T-DXd has emerged as a transformative therapy across HER2-driven malignancies, leading to histology-specific and tissue-agnostic approvals. Vigilant ILD monitoring is essential, and further research is warranted to refine biomarkers, address resistance, and explore rational drug combinations. T-DXd exemplifies the paradigm shift of antibody-drug conjugates toward pan-cancer precision oncology.
14Cancer therapy-related interstitial lung disease.PubMed
Chengzhi Zhou, Haiyi Deng, Yilin Yang, et al.
With the increasing utilization of cancer therapy, the incidence of lung injury associated with these treatments continues to rise. The recognition of pulmonary toxicity related to cancer therapy has become increasingly critical, for which interstitial lung disease (ILD) is a common cause of mortality. Cancer therapy-related ILD (CT-ILD) can result from a variety of treatments including chemotherapy, targeted therapy, immune checkpoint inhibitors, antibody-drug conjugates, and radiotherapy. CT-ILD may progress rapidly and even be life-threatening; therefore, prompt diagnosis and timely treatment are crucial for effective management. This review aims to provide valuable information on the risk factors associated with CT-ILD; elucidate its underlying mechanisms; discuss its clinical features, imaging, and histological manifestations; and emphasize the clinical-related views of its diagnosis. In addition, this review provides an overview of grading, typing, and staging treatment strategies used for the management of CT-ILD.
15Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan.PubMed
Rebecca S Heist, Jacob Sands, Aditya Bardia, et al.
Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials.
16Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management.PubMed
Sandra M Swain, Mizuki Nishino, Lisa H Lancaster, et al.
Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd-related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd-related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms. SEARCH STRATEGY AND SELECTION CRITERIA: References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors' own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.
17Lung cancer research and treatment: global perspectives and strategic calls to action.PubMed
M-L Meyer, S Peters, T S Mok, et al.
BACKGROUND: Lung cancer remains a critical public health issue, presenting multifaceted challenges in prevention, diagnosis, and treatment. This article aims to review the current landscape of lung cancer research and management, delineate the persistent challenges, and outline pragmatic solutions. MATERIALS AND METHODS: Global experts from academia, regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), the National Cancer Institute (NCI), professional societies, the pharmaceutical and biotech industries, and patient advocacy groups were gathered by the New York Lung Cancer Foundation to review the state of the art in lung cancer and to formulate calls to action. RESULTS: Improving lung cancer management and research involves promoting tobacco cessation, identifying individuals at risk who could benefit from early detection programs, and addressing treatment-related toxicities. Efforts should focus on conducting well-designed trials to determine the optimal treatment sequence. Research into innovative biomarkers and therapies is crucial for more personalized treatment. Ensuring access to appropriate care for all patients, whether enrolled in clinical trials or not, must remain a priority. CONCLUSIONS: Lung cancer is a major health burden worldwide, and its treatment has become increasingly complex over the past two decades. Improvement in lung cancer management and research requires unified messaging and global collaboration, expanded education, and greater access to screening, biomarker testing, treatment, as well as increased representativeness, participation, and diversity in clinical trials.