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  5. ADC相关间质性肺病：风险、识别、预防与管理的研究缺口

ADC相关间质性肺病：风险、识别、预防与管理的研究缺口

文献检索Suppr助手发表于 2026年05月20日 11:5110阅读
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抗体偶联药物相关间质性肺病的风险因素、早期识别、预防策略和管理路径有哪些研究空白

Interstitial lung disease (ILD) associated with antibody-drug conjugates (ADCs) is a significant concern in oncology, presenting challenges in risk factor identification, early detection, prevention, and management. Despite considerable research, several gaps remain, particularly regarding ADC-related ILD (ADC-ILD) .

Research Gaps in Risk Factors for ADC-ILD

While some potential risk factors for ADC-ILD have been identified, further investigation is needed for definitive understanding and clinical application .

1. Comprehensive Identification and Validation of Patient-Specific Risk Factors:

  • Respiratory Comorbidities and Baseline Lung Function: Although respiratory comorbidities are emerging as potential risk factors for ADC-ILD, a comprehensive understanding of which specific conditions and their severity contribute most to risk is lacking . Detailed baseline lung function assessments (e.g., pulmonary function tests, diffusing capacity of the lung for carbon monoxide [DLCO]) before initiating ADC therapy are not universally standardized, and their predictive value needs further validation in large-scale prospective studies. This includes exploring the impact of pre-existing subclinical lung injury or fibrosis .
  • Renal Impairment: Renal insufficiency has been identified as a possible risk factor . However, the specific degrees of renal impairment and their impact on ADC pharmacokinetics and subsequent ILD risk require more detailed analysis. Understanding how different levels of renal dysfunction might necessitate dose adjustments or increased monitoring for various ADCs is an area for further research.
  • Age: While a pooled analysis of trastuzumab deruxtecan (T-DXd) studies suggested age <65 years as a potential risk factor , this finding needs further confirmation across different ADCs and patient populations. More granular age-related risk profiles are needed, considering the diverse patient demographics receiving ADCs.
  • Genetic Predisposition: The role of genetic susceptibility in ADC-ILD is largely unexplored. Research into specific genetic polymorphisms or mutations that might predispose patients to developing ILD in response to ADCs could provide crucial insights for personalized risk assessment. This includes investigating genetic markers related to drug metabolism, immune response, or lung tissue repair.
  • Racial and Ethnic Differences: The pooled analysis of T-DXd studies identified "enrollment in Japan" as a potential risk factor, suggesting a possible racial or ethnic predisposition to ILD . This observation warrants further investigation to determine if specific genetic or environmental factors prevalent in certain populations contribute to a higher risk of ADC-ILD.
  • Time Since Initial Cancer Diagnosis: Longer time since initial diagnosis (>4 years) was also identified as a potential risk factor for T-DXd-related ILD . The biological basis for this association is unclear and requires further mechanistic and clinical investigation.

2. ADC-Specific Risk Factors and Characteristics:

  • Linker-Payload Properties: The incidence of drug-induced ILD is not directly correlated with target antigen expression levels, suggesting that factors beyond antigen expression, such as the cytotoxic payload and linker characteristics of ADCs, play a crucial role . While it is recognized that deruxtecan-based ADCs (e.g., T-DXd, datopotamab deruxtecan [Dato-DXd], patritumab deruxtecan) are associated with a higher incidence of ILD compared to other ADCs like sacituzumab govitecan or tusamitamab ravtansine, the precise mechanisms linking specific linker-payload combinations to pulmonary toxicity are not fully elucidated . Further research is needed to:
    • Payload Toxicity Mechanisms: Understand how different cytotoxic payloads (e.g., topoisomerase I inhibitors like deruxtecan, microtubule inhibitors like MMAE/MMAF) exert their specific toxic effects on lung tissue and alveolar epithelial cells . This includes investigating the role of bystander effect (where the payload is released and affects neighboring cells, including healthy ones) and off-target effects .
    • Linker Stability and Release Kinetics: Delve deeper into how the stability and cleavage mechanisms of different linkers (e.g., cleavable vs. non-cleavable) influence the systemic exposure of the cytotoxic payload to lung tissue and contribute to ILD development . Optimizing linker properties is identified as a critical area for ADC development to mitigate this adverse effect .
    • Drug-to-Antibody Ratio (DAR): The impact of varying DARs on lung toxicity needs more systematic investigation. How does increasing the DAR affect the amount of payload delivered to both tumor and healthy lung tissue, and subsequently the risk of ILD? T-DXd, for example, has a high DAR, which contributes to its potency but may also influence its safety profile .
  • Target Antigen Expression in Normal Lung Tissue: Although the initial study suggested no direct correlation between target antigen expression levels and D-ILD incidence , further nuanced investigation is warranted. It is possible that low-level, heterogeneous expression of target antigens (like HER2, TROP2, EGFR, HER3) in specific lung cell populations, or even transient upregulation under stress, could contribute to off-target toxicity. More sensitive and localized measurement techniques for antigen expression in various lung cell types are needed .

3. Combination Therapies:

  • ADC and Immunotherapy Combinations: Current studies are exploring combinations of ADCs with immunotherapy, but data on their combined pulmonary toxicity profiles are limited . Understanding the synergistic or additive effects on ILD risk when ADCs are combined with immune checkpoint inhibitors (ICIs) is a significant gap. Both classes of drugs can induce ILD independently, raising concerns about potential exacerbation or unique forms of ILD with combination therapy . Research needs to focus on identifying specific combinations that carry higher risk and developing appropriate monitoring strategies.

Research Gaps in Early Identification of ADC-ILD

Early identification of ADC-ILD is crucial for effective management and preventing severe outcomes, but it is often challenging due to non-specific symptoms and delayed diagnosis .

1. Biomarkers for Early Detection:

  • Circulating Cell-Free DNA (cfDNA): While a proof-of-concept study showed that lung-specific methylation markers in cfDNA could detect and monitor T-DXd-related ILD , this needs further validation in larger cohorts and across different ADCs. Research should focus on:
    • Sensitivity and Specificity: Determining the optimal cut-off points and the sensitivity and specificity of cfDNA markers for detecting early, subclinical ILD across various ADC types.
    • Predictive Value: Investigating if cfDNA levels can predict who will develop severe ILD or if they can identify patients at risk before clinical symptoms manifest.
    • Standardization: Developing standardized assays and protocols for cfDNA analysis to ensure reproducibility and widespread clinical applicability.
  • Other Blood-Based Biomarkers: Exploration of novel blood-based biomarkers (e.g., inflammatory cytokines, chemokines, extracellular vesicles, microRNAs) that are specific to lung injury and inflammation induced by ADCs is a critical area. Identifying a panel of biomarkers that can differentiate ADC-ILD from other lung pathologies would be highly valuable.
  • Imaging Biomarkers and AI-Assisted Tools:
    • Refined Radiographic Features: While chest CT is used, more precise and early radiographic markers specific to ADC-ILD need to be identified and validated. This includes exploring quantitative imaging techniques to detect subtle changes before overt symptomatic ILD .
    • Artificial Intelligence (AI) for Image Analysis: Emerging AI-assisted tools for earlier detection and risk stratification based on imaging data are promising but require extensive development and validation using large real-world datasets . This involves training AI models to recognize subtle patterns indicative of impending ILD that might be missed by human interpretation.

2. Improved Monitoring Strategies:

  • Symptom Recognition Training: Symptoms of ILD can be nonspecific, leading to delayed diagnosis . There is a need for enhanced patient and provider understanding of ADC-ILD symptoms and comprehensive training programs to improve early symptom identification . This includes developing clear, actionable checklists and educational materials.
  • Standardized Monitoring Protocols: While guidelines for T-DXd-related ILD/pneumonitis exist, including proactive monitoring , a universally standardized, validated, and ADC-agnostic monitoring protocol across all ADC types is lacking. This includes defining optimal frequency and type of clinical assessments (e.g., physical exams, oxygen saturation, spirometry), laboratory tests, and imaging.
  • Integration of Multidisciplinary Teams: While multidisciplinary guidelines are being developed , further research is needed on optimizing the integration of pulmonologists, radiologists, and oncologists into a cohesive team for proactive monitoring and rapid response to suspected ILD. Understanding the most effective communication and referral pathways is crucial.

Research Gaps in Prevention Strategies for ADC-ILD

Currently, robust preventative strategies for ADC-ILD are limited, and research is needed to move beyond reactive management .

1. Patient Selection and Stratification:

  • Pre-treatment Risk Assessment Tools: Developing validated risk prediction models that integrate multiple identified risk factors (e.g., respiratory comorbidities, renal function, ADC type, patient demographics) to identify high-risk patients who might benefit from alternative treatments or intensified monitoring.
  • Biomarker-Guided Patient Selection: Research into biomarkers that could identify patients highly susceptible to ADC-ILD before treatment initiation would be transformative. This could involve genetic markers, specific inflammatory profiles, or lung-specific cfDNA patterns.

2. Dose Optimization and Modification:

  • Individualized Dosing Strategies: Current dosing strategies are often based on body weight, but personalized dosing based on individual risk factors, pharmacogenomics, or real-time biomarker monitoring might reduce ILD incidence while maintaining efficacy.
  • Prophylactic Treatments: Exploration of prophylactic pharmacologic interventions (e.g., low-dose corticosteroids, antifibrotic agents) in high-risk patients prior to or during ADC treatment, although this requires careful consideration of potential side effects and impact on anti-tumor efficacy.
  • Optimization of ADC Design: The call for optimizing linker and payload properties to mitigate adverse effects like D-ILD is a critical research area . This includes:
    • Targeted Delivery Mechanisms: Developing ADCs with even more precise tumor targeting to reduce off-target accumulation in healthy lung tissue.
    • Reduced Bystander Effect: Designing payloads or linkers that minimize the release of cytotoxic agents into the microenvironment, thereby reducing damage to surrounding healthy cells.
    • Tissue-Specific Linker Cleavage: Exploring linkers that are selectively cleaved only within the tumor microenvironment to further reduce systemic payload exposure.

Research Gaps in Management Pathways for ADC-ILD

While general principles for managing drug-induced ILD exist, specific, evidence-based guidelines for ADC-ILD are still evolving .

1. Standardized Diagnostic Criteria and Grading:

  • ADC-Specific ILD Subtypes: Understanding if ADC-ILD presents with distinct clinical, radiological, or pathological features compared to ILD induced by other cancer therapies (e.g., targeted therapies, ICIs) . This could lead to more accurate diagnosis and tailored treatment.
  • Harmonized Grading System: While common terminology criteria for adverse events (CTCAE) are used, developing a more specific and sensitive grading system for ADC-ILD that accounts for its unique characteristics could improve reporting and management consistency.

2. Treatment Algorithms and Efficacy of Interventions:

  • Corticosteroid Regimens: Corticosteroids are the cornerstone of ILD treatment, and dosing should be adapted to severity . However, optimal dosing, duration, and tapering schedules for different grades of ADC-ILD need more rigorous investigation. Studies comparing different corticosteroid regimens and their impact on outcomes, including resolution rates and recurrence, are lacking.
  • Role of Additional Treatments: The role of additional treatments beyond corticosteroids (e.g., immunosuppressants like mycophenolate mofetil, cyclophosphamide, or anti-fibrotic agents) in refractory or severe ADC-ILD needs further evaluation . Data on their efficacy, safety in oncology patients, and optimal timing of initiation are limited.
  • Rechallenge Strategies: Guidelines suggest reintroduction of ADCs only in asymptomatic cases after complete resolution of ILD . However, precise criteria for safe rechallenge, identifying patients who can tolerate it, and the long-term outcomes of rechallenge are not fully established.
  • Management of Specific ADC-ILD Types: Some ADCs, particularly deruxtecan-based ones, are associated with an elevated incidence of ILD . Research is needed to determine if the management of deruxtecan-induced ILD requires unique approaches compared to ILD caused by other ADCs or drug classes.

3. Long-term Outcomes and Follow-up:

  • Longitudinal Studies: Data on the long-term pulmonary consequences of ADC-ILD, including the risk of chronic lung impairment, fibrosis progression, and impact on quality of life, are scarce. Longitudinal studies are needed to track patients for extended periods after ILD resolution.
  • Impact on Cancer Treatment Trajectory: How ADC-ILD affects the overall cancer treatment plan, including dose reductions, discontinuations, and subsequent therapeutic choices, and its ultimate impact on patient survival, requires further analysis.

4. Multidisciplinary Clinical Guidance Refinement:

  • Living Guidelines: The rapid evolution of ADCs and emerging data on ILD necessitate "living guidelines" that are regularly updated based on new evidence . Research needs to support the continuous refinement of these guidelines through robust clinical trials and real-world data collection.
  • Real-World Data (RWD) and Multi-omics Approaches: Incorporating real-world evidence and multi-omics approaches (genomics, proteomics, metabolomics) can provide valuable insights into ADC-ILD mechanisms, risk stratification, and personalized management strategies . Current evidence is limited by a predominance of retrospective studies and case reports .

In conclusion, while ADCs represent a promising avenue for cancer treatment, the risk of D-ILD necessitates a balanced approach in ADC development and clinical practice . Addressing these research gaps through comprehensive, prospective studies will be crucial for improving the safety profile of ADCs, enabling earlier detection, optimizing prevention strategies, and refining management pathways, ultimately ensuring the safe and effective use of these transformative agents in clinical practice .

References

1Association of Antibody-Drug Conjugate (ADC) Target Expression and Interstitial Lung Disease (ILD) in Non-Small-Cell Lung Cancer (NSCLC): Association or Causation or Neither?PubMed

Aakash Desai, Vivek Subbiah, Sinchita Roy-Chowdhuri, et al.
INTRODUCTION: Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, despite advances in immune checkpoint inhibitors and targeted therapies. Antibody-drug conjugates (ADCs) represent a promising therapeutic approach by delivering cytotoxic agents specifically to cancer cells, potentially reducing harm to healthy tissues. This study aims to explore the effectiveness and challenges associated with ADCs in NSCLC, with a focus on drug-induced interstitial lung disease (D-ILD). METHODS: A comprehensive literature review was conducted across MEDLINE (Ovid), Embase (Elsevier), CENTRAL (Cochrane Library), and other sources up to March 2023, to identify ADCs used in NSCLC treatment and their associated risk of D-ILD. The incidence of ILD was analyzed from clinical trial data, while ADC target expression was examined through RNA and protein levels in normal and tumor lung tissues. DISCUSSION: Our findings highlight the therapeutic potential of ADCs in NSCLC, as evidenced by significant clinical outcomes. However, the occurrence of D-ILD presents a notable challenge, as its incidence was not directly correlated with the expression levels of the target antigens. This suggests that D-ILD may result from factors beyond antigen expression, including the cytotoxic payload and linker characteristics of ADCs. CONCLUSION: ADCs offer a promising avenue for NSCLC treatment. Nonetheless, the risk of D-ILD necessitates a balanced approach in ADC development, focusing on optimizing linker and payload properties to mitigate this adverse effect. Further research is essential to better understand and manage D-ILD, ensuring the safe and effective use of ADCs in clinical practice.

2Clinical applications of antibody-drug conjugates in advanced non-small cell lung cancer.PubMed

Hai Guo, Zhongcai Xu, Kaidi Li, et al.
Lung cancer remains the leading cause of cancer-related incidence and mortality worldwide, with non-small cell lung cancer (NSCLC) constituting the majority of cases. Current treatment modalities are constrained by significant limitations: conventional chemotherapy exhibits poor tumor selectivity and systemic toxicity, while monoclonal antibodies frequently demonstrate inadequate therapeutic efficacy. Antibody-drug conjugates (ADCs)-engineered biotherapeutics comprising tumor-targeting antibodies conjugated to potent cytotoxic agents through optimized linkers-have emerged as a transformative strategy to address these therapeutic challenges in advanced NSCLC. This review systematically examines the structural architecture, developmental evolution, and mechanistic foundations of ADCs, with a focused evaluation of clinical evidence supporting ADCs targeting HER2, TROP2, c-MET, HER3, CEACAM5, and B7-H3 in advanced NSCLC. We critically assess efficacy outcomes, safety profiles, predictive biomarkers, and toxicity management strategies-particularly regarding interstitial lung disease, hematologic toxicities, and neuropathic adverse events. Key clinical challenges including tumor heterogeneity, therapeutic resistance, biomarker heterogeneity, and patient stratification are analyzed. Furthermore, we highlight emerging therapeutic approaches such as next-generation ADC design, novel linker-payload systems, bispecific platforms, and rational combination strategies with targeted and immunotherapeutic agents. Collectively, these developments position ADCs as promising precision oncology tools capable of reshaping treatment paradigms and improving clinical outcomes in advanced NSCLC.

3BL-B01D1, a first-in-class EGFR-HER3 bispecific antibody-drug conjugate, in patients with locally advanced or metastatic solid tumours: a first-in-human, open-label, multicentre, phase 1 study.PubMed

Yuxiang Ma, Yan Huang, Yuanyuan Zhao, et al.
BACKGROUND: Antibody-drug conjugates have promising clinical activity in the treatment of solid tumours. BL-B01D1 is a first-in-class EGFR-HER3 bispecific antibody-drug conjugate. We aimed to assess the safety and preliminary antitumour activity of BL-B01D1 in patients with locally advanced or metastatic solid tumours. METHODS: This first-in-human, open-label, multicentre, dose-escalation and dose-expansion phase 1 trial was conducted in seven hospitals in China, enrolling patients aged 18-75 years (dose escalation; phase 1a) or older than 18 years (dose expansion; phase 1b), with a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, and histologically or cytologically confirmed locally advanced or metastatic solid tumours that had progressed on current standard treatment. In the phase 1a i3+3 design, patients received intravenous BL-B01D1 at three different schedules: 0·27 mg/kg, 1·5 mg/kg, and 3·0 mg/kg weekly; 2·5 mg/kg, 3·0 mg/kg, and 3·5 mg/kg on days 1 and 8 of each cycle every 3 weeks; or 5·0 mg/kg and 6·0 mg/kg on day 1 of each cycle every 3 weeks. The primary objectives of phase 1a were to identify the safety, maximum tolerated dose, and dose-limiting toxicity. In phase 1b, patients were treated in two schedules: 2·5 and 3·0 mg/kg on days 1 and 8 every 3 weeks, or 4·5, 5·0, and 6·0 mg/kg on day 1 every 3 weeks. The primary objectives of phase 1b were to assess the safety and recommended phase 2 dose of BL-B01D1, and objective response rate was a key secondary endpoint. Safety was analysed in all patients with safety records who received at least one dose of BL-B01D1. Antitumour activity was assessed in the activity analysis set which included all patients who received at least one dose of BL-B01D1 every 3 weeks. This trial is registered with China Drug Trials, CTR20212923, and ClinicalTrials.gov, NCT05194982, and recruitment is ongoing. FINDINGS: Between Dec 8, 2021, and March 13, 2023, 195 patients (133 [65%] men and 62 [32%] women; 25 in phase 1a and 170 in phase 1b) were consecutively enrolled, including 113 with non-small-cell lung cancer, 42 with nasopharyngeal carcinomas, 13 with small-cell lung cancer, 25 with head and neck squamous cell carcinoma, one with thymic squamous cell carcinoma, and one with submandibular lymphoepithelioma-like carcinoma. In phase 1a, four dose-limiting toxicities were observed (two at 3·0 mg/kg weekly and two at 3·5 mg/kg on days 1 and 8 every 3 weeks; all were febrile neutropenia), thus the maximum tolerated dose was reached at 3·0 mg/kg on days 1 and 8 every 3 weeks and 6·0 mg/kg on day 1 every 3 weeks. Grade 3 or worse treatment-related adverse events occurred in 139 (71%) of 195 patients; the most common of which were neutropenia (91 [47%]), anaemia (76 [39%]), leukopenia (76 [39%]), and thrombocytopenia (63 [32%]). 52 (27%) patients had a dose reduction and five (3%) patients discontinued treatment due to treatment-related adverse events. One patient was reported as having interstitial lung disease. Treatment-related deaths occurred in three (2%) patients (one due to pneumonia, one due to septic shock, and one due to myelosuppression). In 174 patients evaluated for activity, median follow-up was 6·9 months (IQR 4·5-8·9) and 60 (34%; 95% CI 27-42) patients had an objective response. INTERPRETATION: Our results suggest that BL-B01D1 has preliminary antitumour activity in extensively and heavily treated advanced solid tumours with an acceptable safety profile. Based on the safety and antitumour activity data from both phase 1a and 1b, 2·5 mg/kg on days 1 and 8 every 3 weeks was selected as the recommended phase 2 dose in Chinese patients. FUNDING: Sichuan Baili Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

4Multidisciplinary 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.

5Interstitial 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.

6[Diffuse interstitial lung disease induced by antibody-drug conjugates].PubMed

L Maurier, A-L Chéné, P Hulo, et al.
INTRODUCTION: Antibody-drug conjugates (ADCs) represent a promising new therapeutic class in non-small-cell lung cancer (NSCLC) patients. Studies assessing ADC have highlighted a pulmonary toxicity profile in the form of interstitial lung disease (ILD). STATE OF THE ART: Several ADCs for NSCLC are currently being developed. In studies evaluating Trastuzumab-Deruxtecan (Her-2 target), incidence of drug-induced ILD ranged from 10.7 to 26.0%, and from 3.6 to 25.0% in those evaluating Datopotamab-Deruxtecan (TROP-2 target). Incidence of 9.9 and 5% of ILD was observed with Telisotuzumab-Vedotin (c-MET target) and Patritumab-Deruxtecan (Her-3 target), respectively. No cases of ILD have been reported with Sacituzumab-Govitecan (TROP-2 target) or Tusamitamab-Ravtansine (CEACAM5 target). PERSPECTIVES: Several risk factors for ADC-induced ILD seem to emerge, including respiratory comorbidities, renal insufficiency, or type and dosage of ADC. Current studies are focusing on the combination of ADC and immunotherapy, although there are few data now available on pulmonary toxicity profiles. CONCLUSION: Among the many ADCs being developed, several can cause ILD of varying grades and intensity. Knowledge of their risks, diagnostic and therapeutic modalities is required in order to quickly detect and treat ADC-induced ILD.

7Bronchioalveolar organoids: A preclinical tool to screen toxicity associated with antibody-drug conjugates.PubMed

Tara N McCray, Vy Nguyen, Jake S Heins, et al.
Despite extensive preclinical testing, cancer therapeutics can result in unanticipated toxicity to non-tumor tissue in patients. These toxicities may pass undetected in preclinical experiments due to modeling limitations involving poor biomimicry of 2-dimensional in vitro cell cultures and due to lack of interspecies translatability in in vivo studies. Instead, primary cells can be grown into miniature 3-dimensional structures that recapitulate morphological and functional aspects of native tissue, termed "organoids." Here, human bronchioalveolar organoids grown from primary alveolar epithelial cells were employed to model lung epithelium and investigate off-target toxicities associated with antibody-drug conjugates (ADCs). ADCs with three different linker-payload combinations (mafodotin, vedotin, and deruxtecan) were tested in bronchioalveolar organoids generated from human, rat, and nonhuman primate lung cells. Organoids demonstrated antibody uptake and changes in viability in response to ADC exposure that model in vivo drug sensitivity. RNA sequencing identified inflammatory activation in bronchioalveolar cells in response to deruxtecan. Future studies will explore specific cell populations involved in interstitial lung disease and incorporate immune cells to the culture.

8Detection of antibody-drug conjugate-induced interstitial lung disease using circulating cell-free DNA.PubMed

A Grinshpun, A Zick, T Perri, et al.
BACKGROUND: The increasing use and anticipated future adoption of antibody-drug conjugates (ADCs) present a significant challenge in identifying and monitoring patients for the development of potentially fatal drug-induced interstitial lung disease (ILD). We sought to apply a tissue-specific methylation analysis of circulating cell-free DNA (cfDNA) to measure lung damage in patients with trastuzumab deruxtecan (T-DXd)-related ILD. PATIENTS AND METHODS: We describe a patient with metastatic human epidermal growth factor receptor 2 (HER2)-positive endometrial cancer who developed ILD during T-DXd treatment. Blood samples collected at the time of ILD diagnosis, after recovery, and following rechallenge were studied for lung damage using lung-specific methylation markers in cfDNA. To validate the findings, we also tested plasma samples from an additional cohort of patients with HER2-positive metastatic breast cancer treated with T-DXd. RESULTS: In patients with HER2-positive metastatic cancer treated with T-DXd, the presence of an active ILD, as assessed clinically and using chest computed tomography, was associated with increased levels of lung-derived cfDNA. CONCLUSIONS: This proof-of-concept study demonstrates that liquid biopsy can be developed as a valuable tool for detecting and monitoring ADC-related ILD. Its low cost and simplicity make it a potential alternative to current imaging methods, warranting further clinical development.

9Another power of antibody-drug conjugates: immunomodulatory effect and clinical applications.PubMed

Ruotong Shi, Lin Jia, Zheng Lv, et al.
Antibody-drug conjugates (ADCs) enhance tumour immunogenicity through multidimensional immune modulation beyond targeted cytotoxicity. The immune remodelling of the tumour microenvironment (TME) suggests potential synergistic mechanisms with immune checkpoint inhibitors (ICIs): ICIs amplify antitumour immune responses by blocking inhibitory signals. Preclinical studies and preliminary clinical evidence demonstrate their synergistic efficacy; however, mechanistic synergy requires further experimental validation. Current challenges encompass the impact of heterogeneous TME on therapeutic outcomes and toxicity risks including interstitial lung disease. Advancing the translational potential of combination therapies necessitates optimised linker designs, development of immunostimulatory payloads, and establishment of precise biomarker frameworks. This review investigates the immunomodulatory mechanisms of ADCs, providing a theoretical foundation and novel directions for antitumour combination therapies and next-generation ADC development.

10Targeted 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.

11Cancer 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.

12Management of trastuzumab deruxtecan-related adverse events in breast cancer: Italian expert panel recommendations.PubMed

Giampaolo Bianchini, Alessandra Fabi, Valentina Guarneri, et al.
Trastuzumab deruxtecan (T-DXd) - antibody - drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) - has demonstrated high efficacy in clinical studies, with high rates of durable responses and improved outcomes in HER2-positive and HER2-low metastatic breast cancer (mBC) patients. T-DXd has demonstrated a generally manageable safety profile across the DESTINY trials, but there is an emerging unmet need for additional real-world clinical practice information. Italian experts conducted a Delphi panel and several roundtables to develop recommendations for the prevention and practical management of T-DXd-related AEs and toxicities, including nausea and vomiting (N/V), neutropenia, anemia, cardiovascular events, interstitial lung disease/pneumonitis (ILD/P), and treatment safety. ILD/P and N/V are the most challenging AEs associated with T-DXd. Being T-DXd now classified as a Highly Emetogenic Chemotherapy, Italian experts recommend pre-treatment with the triplet (NK1 RA + 5-HT3 RA + dexamethasone) in all patients to prevent acute N/V. Patients must be monitored early on treatment for signs/symptoms of ILD/P and any clinical suspicion should be promptly investigated and managed according to guidelines. These recommendations and proactive surveillance may substantially improve the management of T-DXd-related AEs, maximizing the benefit of this treatment for HER2-positive and HER2-low mBC, and potentially increasing treatment acceptance.

13Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies.PubMed

C A Powell, S Modi, H Iwata, et al.
INTRODUCTION: This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd. METHODS: Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized. RESULTS: The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years. CONCLUSIONS: In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit-risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all.

14Current Management and Future Perspectives in Metastatic HER2-Positive Breast Cancer.PubMed

Luisa Sánchez-Lorenzo, Alejandra Bachiller, Claudia Gea, et al.
OBJECTIVE: Metastatic HER2-positive breast cancer remains a significant clinical challenge with a poor prognosis. The introduction of anti-HER2 therapies has significantly improved survival in early and advanced stages. However, patients with metastatic HER2-positive breast cancer eventually experience progression due to de novo or acquired resistance. This review article comprehensively analyzes the current management of metastatic HER2-positive breast cancer, addressing the complexities in determining the optimal HER2-targeted therapy sequence. DATA SOURCES: Discussion of selected peer-reviewed articles and expert opinion. CONCLUSIONS: We explore the actual standard of care and the emerging therapeutic options that hold promise for further improving patient care and survival in this aggressive breast cancer subtype. This article highlights vital toxicities linked to anti-HER2 therapies, emphasizing their recognition across treatments as interstitial lung disease, diarrhea, or left ventricular dysfunction. IMPLICATIONS FOR NURSING PRACTICES: Oncology nurses have a key role to play in detecting potential adverse effects of anti-HER2 therapies. The development of new drugs, as antibody-drug conjugates, with a distinct toxicity profile makes it necessary for us to be updated on the management of these new toxicities.

15Trastuzumab 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.

16Clinical 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.

17Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer.PubMed

H S Rugo, G Bianchini, J Cortes, et al.
INTRODUCTION: The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) targets human epidermal growth factor receptor 2 (HER2) and has been evaluated in patients with HER2-positive unresectable/metastatic breast cancer in the phase II DESTINY-Breast01 trial (NCT03248492; DS8201-A-U201) and the randomized phase III DESTINY-Breast03 trial (NCT03529110; DS8201-A-U302). Approximately 20 additional studies are ongoing in breast cancer, including HER2-low breast cancer, and other solid tumor types within the DESTINY trial program. T-DXd has demonstrated a generally manageable safety profile, with low-grade hematologic and gastrointestinal adverse events (AEs) among the most common; interstitial lung disease (ILD)/pneumonitis has been observed in patients receiving T-DXd and can be severe. This review discusses the management of common AEs and AEs of special interest in patients with HER2-positive unresectable/metastatic breast cancer, including nausea and vomiting, neutropenia, infusion-related reactions, alopecia, fatigue, ILD/pneumonitis, and left ventricular dysfunction. METHODS: Expert opinions, institutional protocols, and strategies to help optimize AE management and maximize the potential benefits of T-DXd in patients with breast cancer from five oncologists treating patients with T-DXd in North America and Europe are discussed. RESULTS: Prophylaxis for nausea and vomiting and proactive management of ILD/pneumonitis are especially important in treating patients with T-DXd. Management strategies for other T-DXd-related AEs of interest (e.g. neutropenia, infusion-related reactions, alopecia, fatigue, and left ventricular dysfunction) are also discussed. CONCLUSIONS: This review provides context for understanding the usage, monitoring, and management practices of other health care providers and institutions with experience using T-DXd to help with safe and effective management of T-DXd-related AEs, particularly since the duration of T-DXd treatment may be quite long. Proper management of T-DXd-related AEs will allow optimal exposure and benefit from T-DXd and will help avoid premature discontinuation or improper dose reductions.

18Antibody-Drug Conjugates in Gynecologic Oncology: Advances, Challenges, and Future Directions.PubMed

Taliya Lantsman, Ursula A Matulonis
Antibody-drug conjugates (ADCs) have emerged as an efficacious and promising treatment for advanced gynecologic cancers. These agents are an innovative treatment strategy that combines a monoclonal antibody, a linker, and a cytotoxic payload. Currently, three ADCs have received Food and Drug Administration (FDA) approval for use in gynecologic malignancies: mirvetuximab soravtansine, tisotumab vedotin, and trastuzumab deruxtecan. The demonstrable efficacy of these therapeutic agents has catalyzed rapid advancements in the field, prompting investigations into novel antigen targets such as cadherin-6 and B7H4, varying payloads, and innovative construction designs in both preclinical and clinical settings. While enthusiasm for ADCs is substantial, their clinical utility is tempered by significant side effects, such as ocular toxicities and pneumonitis, that necessitate specialized management expertise. Furthermore, the inherent complexities of these drugs and their mechanisms of action underscore the need for further research into the relevance of biomarkers, methods of therapy resistance, and the potential for re-utilization of payloads and targets later in the disease course. This review focuses on the mechanisms of action of ADCs, their developmental trajectory, successes in gynecologic cancers, emerging areas of investigation, the prospective landscape, and current challenges in the field.

19Real-World Perspectives and Practices for Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use in Human Epidermal Growth Factor Receptor 2-Expressing Metastatic Breast Cancer.PubMed

Hope S Rugo, Christine L Crossno, Yaron B Gesthalter, et al.
Trastuzumab deruxtecan (T-DXd) is an antibody drug conjugate with a topoisomerase I payload that targets the human epidermal growth factor receptor 2 (HER2). T-DXd is approved for patients with previously treated HER2-positive or HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-) metastatic/unresectable breast cancer (BC). In a second-line HER2-positive metastatic BC (mBC) population (DESTINY-Breast03 [ClinicalTrials.gov identifier: NCT03529110]), T-DXd demonstrated significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (12-month rate: 75.8% 34.1%; hazard ratio, 0.28; < .001), and in patients with HER2-low mBC treated with one prior line of chemotherapy (DESTINY-Breast04 [ClinicalTrials.gov identifier: NCT03734029]), T-DXd demonstrated significantly longer PFS and overall survival than physician's choice chemotherapy (10.1 5.4 months; hazard ratio, 0.51; < .001, and 23.4 16.8 months; hazard ratio, 0.64; < .001, respectively).Interstitial lung disease (ILD) is an umbrella term used for a group of diseases characterized by lung injury including pneumonitis, which can lead to irreversible lung fibrosis. ILD is a well-described adverse event associated with certain anticancer therapies, including T-DXd. An important part of T-DXd therapy for mBC consists of monitoring for and managing ILD. Although information on ILD management strategies is included in the prescribing information, additional information on patient selection, monitoring, and treatment can be beneficial in routine clinical practice. The objective of this review is to describe real-world, multidisciplinary clinical practices and institutional protocols used for patient selection/screening, monitoring, and management related to T-DXd-associated ILD.

20Trastuzumab 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.
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