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不同ADC药物相关间质性肺病发生率和管理策略比较
间质性肺病（ILD）是抗体药物偶联物（ADCs）治疗中一个重要的安全性问题，其发生率和管理策略因ADCs的种类、靶点、载荷、连接子以及患者的肿瘤类型和基线特征而异。以下将对不同ADC药物相关ILD的发生率进行比较，并总结当前的管理策略。
1. ADC药物相关间质性肺病的总体发生率与特异性药物关联
ADCs在癌症治疗中显示出创新潜力，然而，肺毒性是其独特的安全风险之一，其中ILD是临床上显著且可能致命的不良事件 。
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总体发生率:
- 一项对120项临床研究（涉及20,119名患者）的系统回顾和Meta分析显示，ADC相关ILD的总体发生率为4.40%（所有级别），其中≥3级ILD的发生率为2.35% 。
- 在FAERS数据库2014-2023年的分析中，共报告了1277例ADC诱导的ILD，其中曲妥珠单抗-德鲁替康（Trastuzumab deruxtecan, T-DXd）的报告频率最高，占38.4% 。
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特定ADC药物的ILD发生率:
- 曲妥珠单抗-德鲁替康（T-DXd）:
- T-DXd被广泛认为与ILD/肺炎的风险增加有关，是导致ADC相关ILD最常见的药物之一 。
- 一项对九项T-DXd单药治疗研究的汇总分析显示，经独立裁定委员会评估的药物相关ILD/肺炎的总体发生率为15.4%，其中5级事件占2.2% 。
- 在DESTINY-Breast03试验中，T-DXd组患者的ILD或肺炎发生率为10.5%，而曲妥珠单抗-美坦新（T-DM1）组为1.9%。T-DXd组的ILD事件均为1级或2级，无4级或5级事件 。
- 在DESTINY-Gastric04试验中，T-DXd组患者ILD或肺炎的发生率为13.9%（33例1级或2级，1例3级），而雷莫西尤单抗加紫杉醇组为1.3%（2例3级，1例5级） 。
- 在DESTINY-Breast01研究中，T-DXd相关ILD的发生率为13.6%（1级或2级占10.9%，3级或4级占0.5%，5级占2.2%） 。
- DESTINY-Breast12研究显示，无论患者是否存在脑转移，T-DXd治疗后的ILD/肺炎发生率分别为16%（≥3级为3%）和13%（≥3级为1%） 。
- DESTINY-Breast05研究中，T-DXd组的裁定药物相关ILD发生率高于T-DM1组（9.6% vs 1.6%），其中T-DXd组有两名患者死于ILD 。
- 一项针对HER2阳性晚期实体瘤患者的系统回顾显示，T-DXd诱导的ILD/肺炎总体发生率为11.40%（136/1193），其中大部分为1级或2级（78.69%），死亡率为10.66%（13/122） 。
- 另一项系统回顾（涵盖18项研究，3380名患者）报告T-DXd相关ILD/肺炎的总体发生率为12.40%，大多数为低级别，但仍需警惕ILD/肺炎相关的死亡风险 。
- 对乳腺癌患者的Meta分析显示，T-DXd治疗的ILD发生率为11.7%，其中接受6.4 mg/kg剂量T-DXd的患者ILD发生率显著高于接受5.4 mg/kg剂量的患者（22.7% vs 9.3%）。大多数ILD病例为轻度（1级或2级，80.2%），3级或4级ILD占13.4%，5级占6.4% 。
- 与T-DM1相比，T-DXd的严重不良事件如ILD和左心室功能障碍更为特殊 。
- T-DXd在非小细胞肺癌（NSCLC）中显示出优越疗效，但也有较高的≥3级治疗相关不良事件发生率（38.6% vs 22%） 。
- 曲妥珠单抗-美坦新（T-DM1）:
- T-DM1是HER2阳性转移性乳腺癌的标准治疗药物，ILD发生率相对较低。在DESTINY-Breast03和DESTINY-Breast05研究中，T-DM1组的ILD或肺炎发生率分别为1.9%和1.6% 。
- T-DM1常见的不良事件包括血小板减少症和丙氨酸转氨酶升高 。
- 在NSCLC中，T-DM1的疗效不显著，ILD发生率低 。
- 达妥昔单抗-德鲁替康（Datopotamab deruxtecan, Dato-DXd）:
- Dato-DXd是一种新型的靶向TROP2的ADC，正在多种实体瘤中进行研究。ILD/肺炎被确定为其特殊关注的不良事件（AESIs）之一，需要适当的预防、监测和管理 。
- Dato-DXd在NSCLC中显示出改善的客观缓解率（ORR）和无进展生存期（PFS），ILD是其主要关注的安全问题 。
- Sacituzumab govitecan (SG):
- SG主要不良事件包括中性粒细胞减少症、腹泻和恶心 。目前证据未突出SG与ILD的直接关联性，与T-DXd的ILD风险不同 。
- 其他ADCs:
- Mirvetuximab soravtansine和Tisotumab vedotin与眼部不良事件（如视力模糊、角膜病变）常见，Mirvetuximab soravtansine也与ILD有关 。
- Inotuzumab ozogamicin和Gemtuzumab ozogamicin与肝窦阻塞综合征相关 。
- Brentuximab vedotin和Polatuzumab vedotin与进行性多灶性白质脑病（PML）相关 。
- Enfortumab vedotin和Brentuximab vedotin可引起高血糖，甚至糖尿病酮症酸中毒 。
- 曲妥珠单抗-德鲁替康（T-DXd）:
2. 影响ILD发生率的因素
ADC相关ILD的发生率存在变异性，主要受ADCs特定组分驱动 。
- 肿瘤类型:
- 胃肠道癌症（12.81%）和肺癌（9.70%）患者的ILD发生率较高 。
- T-DXd在子宫癌（26.47%）和非小细胞肺癌（24.77%）患者中的ILD/肺炎发生率最高 。
- ADC组分:
- 连接子类型: 可裂解连接子（cleavable linkers）的ADCs表现出更高的ILD发生率，其中谷胱甘肽（GSH）连接子的ADCs最高 。T-DXd采用可裂解的四肽连接子 。
- 药物抗体比（DAR）值: 高DAR值的ADCs具有更高的ILD发生率 。
- 载荷类型: 载荷类型本身不显著影响发生率，但当特定载荷（如拓扑异构酶I抑制剂）与高DAR值或可裂解连接子结合时，ILD风险显著增加 。T-DXd和Dato-DXd均采用拓扑异构酶I抑制剂作为载荷 。
- 患者基线特征:
- 一项T-DXd的汇总分析确定了几个可能与ILD/肺炎风险增加相关的基线因素：年龄<65岁、日本患者、T-DXd剂量>6.4 mg/kg、血氧饱和度<95%、中度/重度肾功能损害、存在肺部合并症以及初次诊断时间>4年 。
- 剂量: T-DXd 6.4 mg/kg剂量组的ILD发生率显著高于5.4 mg/kg剂量组（22.7% vs 9.3%） 。
3. 间质性肺病的管理策略
鉴于ADC相关ILD的潜在致命后果，早期诊断、密切监测和及时管理至关重要 。目前虽然没有针对ADC相关ILD的特异性指南，但可以借鉴药物诱导和免疫治疗相关ILD的通用原则 。中国的专家小组也制定了关于HER2 ADC治疗相关ILD/肺炎识别和管理的战略方法及建议 。
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早期识别与监测:
- 患者应接受密切监测，以确保患者安全并优化治疗结果 。
- 临床医生应接受适当培训，以便识别和管理这种毒性效应 。
- ADC相关ILD的中位发病时间为51天（IQR 16-196天），急性呼吸窘迫综合征（ARDS）发病最早，中位时间为15天（IQR 6-52天） 。T-DXd相关ILD/肺炎的大多数事件（87.0%）在首次给药后12个月内发生，中位时间为5.4个月 。
- ILD/肺炎的症状可能与肺炎相似，导致呼吸衰竭和死亡 。
- 在无症状阶段（1级）识别T-DXd相关ILD可以通过监测和有效治疗，并可能继续治疗。然而，诊断和/或治疗延迟会导致毒性进展至2级或更高级别，并需要立即永久停止活性药物 。
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治疗中断/停药:
- 对于有症状的ILD，应停止ADC治疗 。
- 只有在无症状且完全缓解后，才能考虑重新引入ADC 。
- 一项对T-DXd治疗后1级ILD恢复的患者进行再治疗的汇总分析显示，ILD复发率为33.3%，所有复发事件均为1/2级，可根据现有治疗指南进行管理。这表明在1级ILD缓解后重新开始T-DXd治疗是安全的，并可能最大化治疗益处 。
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皮质类固醇治疗:
- 皮质类固醇是ILD治疗的基石，应根据事件的严重程度调整剂量 。
- 对于急性呼吸窘迫综合征，紧急治疗包括氧合、呼吸支持和皮质类固醇 。
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支持性护理:
- ILD/肺炎事件通常需要剂量中断或减少、治疗停药、皮质类固醇以及支持性护理 。
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多学科团队管理:
- 多学科方法，包括肿瘤内科医生、放射科医生、呼吸科医生和联合医疗专业人员之间的合作，对于主动识别和管理T-DXd相关ILD以及其他具有类似毒性特征的药物诱导ILD至关重要 。
- 加强ADC安全性的方法包括抗体工程、连接子设计和载荷选择的结构优化 。
总结
不同ADC药物相关ILD的发生率存在显著差异，其中T-DXd与ILD的关联性最强，其ILD发生率在临床试验中通常高于其他ADCs，但大多数病例为低级别。影响ILD发生率的因素包括肿瘤类型、ADC的组分（特别是可裂解连接子和高DAR值结合拓扑异构酶I抑制剂载荷）以及患者的基线特征。
管理策略的核心在于早期识别、密切监测、及时干预。对于有症状的ILD，应停止ADC治疗并考虑使用皮质类固醇。在某些情况下，如1级ILD完全缓解后，T-DXd的再治疗是可行的，且复发事件通常为可控的低级别。未来的研究需要进一步阐明ILD的风险因素和潜在病理生理机制，以开发更有效的预防和管理策略，最终改善患者的预后并扩大ADCs在癌症治疗中的安全应用范围 。
References
1Interstitial 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.
2Trastuzumab 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.).
3Interstitial 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.
4Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.PubMed
Javier Cortés, Sung-Bae Kim, Wei-Pang Chung, et al.
BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).
5Antibody-drug conjugate components in association with the incidence of ADC-related interstitial lung disease: A systematic review and meta-analysis.PubMed
Tianyu Shao, Jiayao Yang, Jialu Chen, et al.
BACKGROUND: Antibody-drug conjugates (ADCs) have emerged as an innovative approach in cancer therapy. Although the incidence of ADC-related interstitial lung disease (ILD) is low, it remains a clinically significant and potentially fatal adverse event. This study focuses on evaluating the incidence of ADC-related ILD and examining how specific ADC components contribute to the risk of ILD. METHODS: Five databases were conducted to identify clinical studies on ADC-related ILD published up to September 2024. The incidence of treatment-related adverse events was calculated by a random effects (RE) model. RESULTS: A total of 120 clinical studies involving 20,119 patients were included. The overall incidence of ADC-related ILD was 4.40 % (1215/20119) for all-grade and 2.35 % (603/20119) for grade ≥ 3 ILD. Among these, 2287 patients had hematologic tumors and 17,832 patients had solid tumors. Particularly, gastrointestinal cancers (12.81 %, 107/835), followed by lung cancer (9.70 %, 290/2991) were observed with a high incidence of ILD. A detailed subgroup analysis was performed, stratified by payload, drug-to-antibody ratio (DAR) value, linker type, and target. ADCs with cleavable linkers exhibited a higher incidence, notably, ADCs with glutathione (GSH) linkers were the highest. Furthermore, ADCs with high DAR had a higher incidence of ILD. Interestingly, payload type alone did not significantly affect the incidence, while a marked increase in ILD risk was observed when specific payloads (such as topoisomerase I inhibitors) were combined with high DAR values or cleavable linkers. CONCLUSION: This study reveals variability of ADC-related ILD incidence, largely driven by the specific components of the ADCs, offer valuable insights into potential ILD occurrence patterns and guide for optimizing ADC design.
6Pooled 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.
7Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: An expert consensus in China.PubMed
Chunwei Xu, Zhanhong Chen, Yuanli Xia, et al.
Antibody-drug conjugates (ADCs) have demonstrated effectiveness in treating various cancers, particularly exhibiting specificity in targeting human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Recent advancements in phase 3 clinical trials have broadened current understanding of ADCs, especially trastuzumab deruxtecan, in treating other HER2-expressing malignancies. This expansion of knowledge has led to the US Food and Drug Administration's approval of trastuzumab deruxtecan for HER2-positive and HER2-low breast cancer, HER2-positive gastric cancer, and HER2-mutant nonsmall cell lung cancer. Concurrent with the increasing use of ADCs in oncology, there is growing concern among health care professionals regarding the rise in the incidence of interstitial lung disease or pneumonitis (ILD/p), which is associated with anti-HER2 ADC therapy. Studies on anti-HER2 ADCs have reported varying ILD/p mortality rates. Consequently, it is crucial to establish guidelines for the diagnosis and management of ILD/p in patients receiving anti-HER2 ADC therapy. To this end, a panel of Chinese experts was convened to formulate a strategic approach for the identification and management of ILD/p in patients treated with anti-HER2 ADC therapy. This report presents the expert panel's opinions and recommendations, which are intended to guide the management of ILD/p induced by anti-HER2 ADC therapy in clinical practice.
8Trastuzumab 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.
9A 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.
10Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer.PubMed
Shanu Modi, Cristina Saura, Toshinari Yamashita, et al.
BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation. METHODS: In this two-part, open-label, single-group, multicenter, phase 2 study, we evaluated trastuzumab deruxtecan in adults with pathologically documented HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab emtansine. In the first part of the study, we evaluated three different doses of trastuzumab deruxtecan to establish a recommended dose; in the second part, we evaluated the efficacy and safety of the recommended dose. The primary end point was the objective response, according to independent central review. Key secondary end points were the disease-control rate, clinical-benefit rate, duration of response and progression-free survival, and safety. RESULTS: Overall, 184 patients who had undergone a median of six previous treatments received the recommended dose of trastuzumab deruxtecan (5.4 mg per kilogram of body weight). In the intention-to-treat analysis, a response to therapy was reported in 112 patients (60.9%; 95% confidence interval [CI], 53.4 to 68.0). The median duration of follow-up was 11.1 months (range, 0.7 to 19.9). The median response duration was 14.8 months (95% CI, 13.8 to 16.9), and the median duration of progression-free survival was 16.4 months (95% CI, 12.7 to not reached). During the study, the most common adverse events of grade 3 or higher were a decreased neutrophil count (in 20.7% of the patients), anemia (in 8.7%), and nausea (in 7.6%). On independent adjudication, the trial drug was associated with interstitial lung disease in 13.6% of the patients (grade 1 or 2, 10.9%; grade 3 or 4, 0.5%; and grade 5, 2.2%). CONCLUSIONS: Trastuzumab deruxtecan showed durable antitumor activity in a pretreated patient population with HER2-positive metastatic breast cancer. In addition to nausea and myelosuppression, interstitial lung disease was observed in a subgroup of patients and requires attention to pulmonary symptoms and careful monitoring. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast01 ClinicalTrials.gov number, NCT03248492.).
11Clinical 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.
12Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial.PubMed
Nadia Harbeck, Eva Ciruelos, Guy Jerusalem, et al.
Trastuzumab deruxtecan (T-DXd) intracranial activity has been observed in small or retrospective patient cohorts with human epidermal growth factor receptor 2-positive (HER2) advanced/metastatic breast cancer (mBC) and stable or active (untreated/previously treated and progressing) brain metastases (BMs). The phase 3b/4 DESTINY-Breast12 study investigated T-DXd in patients with HER2 mBC and is, to our knowledge, the largest prospective study of T-DXd in patients with BMs in this setting. Patients (stable/active BMs (n = 263) and no BMs (n = 241)) treated with one or more prior anti-HER2-based regimens received T-DXd (5.4 mg per kg). Primary endpoints were progression-free survival (PFS; BMs cohort) and objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (non-BMs cohort). Additional endpoints included central nervous system (CNS) PFS, ORR, time to second progression, CNS ORR (BMs cohort), incidence of new symptomatic CNS metastases (non-BMs cohort), time to progression, duration of response, overall survival and safety (both cohorts). No formal hypothesis testing was conducted for this single-arm, open-label study. In the BMs cohort, 12-month PFS was 61.6% (95% confidence interval (CI): 54.9-67.6), and 12-month CNS PFS was 58.9% (95% CI: 51.9-65.3). In the non-BMs cohort, ORR was 62.7% (95% CI: 56.5-68.8). Grade 3 or higher adverse events occurred in 51% (BMs cohort) and 49% (non-BMs cohort) of patients. Investigator-reported interstitial lung disease/pneumonitis occurred in 16% (grade ≥3: 3%) of patients with BMs and 13% (grade ≥3: 1%) of patients without BMs. These data show substantial and durable overall and intracranial activity for T-DXd, supporting its use in previously treated patients with HER2 mBC irrespective of stable/active baseline BMs. ClinicalTrials.gov identifier: NCT04739761 .
13Adverse events and impact on quality of life of antibody-drug conjugates in the treatment of metastatic breast cancer: A systematic review and meta-analysis.PubMed
Marta Perachino, Eva Blondeaux, Chiara Molinelli, et al.
BACKGROUND: Antibody-drug conjugates are novel effective therapies for metastatic breast cancer. Nevertheless, their toxicity profile can significantly affect patients' quality of life over time. METHODS: This is a systematic review and meta-analysis of randomized controlled trials of antibody-drug conjugates currently approved for the treatment of metastatic breast cancer [trastuzumab-emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab-govitecan (SG)] versus standard therapy to evaluate the risk of adverse events, discontinuation rate due to toxicity, impact on quality of life according to EORTC QLQ-C30 scale and subdomains. Relative risks (RR) and hazard ratios (HR) with 95% CIs were calculated using random effects models. RESULTS: Nine trials with a total of 5753 patients were included. The most common adverse events of any grade for T-DM1 included thrombocytopenia (RR 7.14, 95% CI 4.13-12.36) and increased alanine-transaminase (ALT) (RR 2.04, 95% CI 1.43-2.91), for T-DXd were nausea (RR 2.39, 95% CI 1.90-3.00) and anemia (RR 1.55, 95% CI 1.27-1.90), while for SG were neutropenia (RR 1.30, 95% CI 1.14-1.49), diarrhea (RR 3.62, 95% CI 2.97-4.42) and nausea (RR1.90, 95% CI 1.65-2.19). Severe adverse events such as interstitial lung disease and left ventricular dysfunction were peculiar of T-DXd. Antibody-drug conjugates significantly delayed clinical deterioration of global health status by EORTC QLQ-C30 (HR .71, 95% CI .59-.86), physical, emotional and social functioning, pain and fatigue symptoms. CONCLUSIONS: This meta-analysis offers consolidated data on adverse events associated with antibody-drug conjugates and their effects on patients' quality of life, emphasizing differences based on the specific agent. These findings underscore the critical need for effective strategies to prevent, diagnose and manage these toxicities.
14Efficacy and Safety of Antibody-Drug Conjugates for Lung Cancer Therapy: A Systematic Review of Randomized and Non-Randomized Clinical Trials.PubMed
Matteo Gallina, Anna Carollo, Anna Gallina, et al.
: Lung cancer is the leading cause of cancer-related deaths worldwide. Non-Small-Cell Lung Cancer (NSCLC) accounts for 80-90% of all lung cancers. Antibody-Drug Conjugates (ADCs) represent an expanding targeted therapy option for the treatment of NSCLC. The aim is to perform a systematic literature review to evaluate the efficacy and safety profiles of ADCs currently undergoing clinical trials for the treatment of NSCLC. : The study adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Literature searches were conducted in PubMed, ClinicalTrial.gov and Web of Science databases, covering the period from 2014 to 2024. Only randomized and non-randomized phase II-IV clinical trials focusing on ADC-based therapies for adult patients affected by NSCLC were selected. The Revised Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2.0) and the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) were used to evaluate the overall risk of bias in the included randomized and non-randomized studies, respectively. While GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology was used to assess the certainty of the evidence. Efficacy endpoints were categorized based on primary outcomes while safety was assessed through the frequency and severity of Treatment-Emergent Adverse Events (TEAEs), and a qualitative summary of the findings was conducted. : A total of seven studies, including three randomized, three non-randomized, and one without specific allocation, were included, comprising 1287 patients, with 693 (54%) men, and an average age of 63 years old. Two studies were deemed to have a low risk of bias, while six had a moderate risk or some concerns. Five ADCs were evaluated: trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), telisotuzumab vedotin, patritumab deruxtecan, and datopotamab deruxtecan (Dato-DXd). T-DXd demonstrated superior efficacy in HER2-overexpressing and HER2-mutant NSCLC, with an ORR of 52.9% and 49.0%, respectively. However, HER2-mutant patients exhibited a longer median DOR (16.8 vs. 6.2 months) but a higher incidence of grade ≥ 3 TEAEs (38.6% vs. 22%). T-DM1 showed modest efficacy, with an ORR of 20% in HER2-overexpressing NSCLC and 6.7% in HER2-mutant patients. Dato-DXd demonstrated improved ORR (26.4% vs. 12.8%) and PFS (4.4 vs. 3.7 months) compared to docetaxel. Patritumab deruxtecan achieved an ORR of 39% in EGFR-mutant NSCLC, while telisotuzumab vedotin exhibited limited activity in c-MET-positive NSCLC (ORR 9%, median DOR 7.5 months). Frequency and severity of TEAEs varied across ADCs, with ILD being a major concern, highlighting the need for strict patient monitoring and early intervention to mitigate severe adverse events. : ADCs represent a promising advancement in NSCLC treatment, offering targeted therapeutic options beyond conventional chemotherapy and immunotherapy. T-DXd has emerged as the most effective ADC for HER2-mutant NSCLC with manageable safety profile, whereas Dato-DXd provides a viable alternative for TROP2-expressing tumors. While ADCs offer significant clinical benefits, careful patient selection and proactive management of adverse events remain crucial. Ongoing and future trials will further refine the role of ADCs in personalized NSCLC treatment, potentially expanding their tumor-agnostic use to broader patient populations.
15Focusing on toxicity management: Challenges and strategies for HER2-targeted antibody-drug conjugates in breast cancer.PubMed
Xiaoyu Liu, Saige Yin, Xiyin Li, et al.
Antibody-drug conjugates (ADCs) targeting human epidermal growth factor receptor 2 (HER2) have revolutionized the treatment landscape of HER2-positive breast cancer, significantly improving patient survival. However, their growing clinical application has revealed a spectrum of serious adverse events (AEs) that can compromise quality of life, reduce treatment compliance, and, in some cases, lead to life-threatening outcomes or premature therapy discontinuation. This review provides a comprehensive overview of the toxicity profiles and underlying mechanisms of HER2-targeted ADCs, with a focus on representative agents such as trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). We examine the pathogenesis of common toxicities, including thrombocytopenia, interstitial lung disease, cardiotoxicity, and hepatotoxicity, and summarize clinical evidence for monitoring and intervention strategies. Emphasis is placed on the importance of early identification and standardized management to mitigate risk. Furthermore, we discuss emerging approaches to improve ADC safety through structural optimization, including advances in antibody engineering, linker design, and payload selection. This review aims to guide clinicians and researchers in improving the safety and clinical utility of HER2-targeted ADCs in breast cancer treatment.
16Incidence of interstitial lung disease and cardiotoxicity with trastuzumab deruxtecan in breast cancer patients: a systematic review and single-arm meta-analysis.PubMed
L R Soares, M Vilbert, V D L Rosa, et al.
BACKGROUND: Trastuzumab deruxtecan (T-DXd) has been shown to benefit progression-free survival and overall survival in patients with metastatic breast cancer (mBC) after progression on ≥1 human epidermal growth factor receptor 2 (HER2)-targeted therapies. However, interstitial lung disease (ILD) and cardiotoxicity are the most significant toxicities associated with T-DXd. Therefore, we conducted a systematic review and meta-analysis to assess the incidence and severity of these toxicities in mBC patients treated with T-DXd. MATERIALS AND METHODS: We searched PubMed, Cochrane, and Scopus databases, and conferences websites for randomized clinical trials and nonrandomized studies of intervention including HER2-low or HER2-positive mBC patients who received at least one dose of T-DXd. Statistical analysis was carried out using R software. RESULTS: We included 15 studies comprising 1970 patients with a mean follow-up of 13.3 months. Median age ranged from 53 to 59 years, 61.9% were non-Asian, and 67.4% had hormone receptor-positive mBC. In a pooled analysis, the incidence of ILD was 11.7% [222 patients; 95% confidence interval (CI) 9.1% to 15.0%]. Patients receiving T-DXd dose of 6.4 mg/kg developed a significantly higher rate of ILD (22.7%) compared to those receiving a dose of 5.4 mg/kg (9.3%) (P < 0.01). Most cases of ILD (80.2%; 174/217 patients) were mild (grade 1 or 2). Grade 3 or 4 ILD was reported in 29 patients (13.4%), and grade 5 in 14 patients (6.4%). The incidence of decreased left ventricular ejection fraction (LVEF) was 1.95% (95% CI 0.65% to 3.73%), and the QT interval (QTi) prolongation was 7.77% (95% CI 2.74% to 20.11%). Most patients were asymptomatic, but four had LV dysfunction and heart failure (0.26%). CONCLUSIONS: In this meta-analysis of 1970 patients with mBC, treatment with T-DXd was associated with a 11.7% incidence of ILD, 7.7% incidence of prolonged QTi, and 1.9% incidence of reduced LVEF. Early detection and management of T-DXd-related toxicity by a multidisciplinary team may ultimately improve patient outcomes.
17Antibody-Drug Conjugates: The Toxicities and Adverse Effects That Emergency Physicians Must Know.PubMed
Danna Michelle Markides, Angel Guido Hita, Jeffrey Merlin, et al.
Antibody-drug conjugates are novel antineoplastic agents whose use is expanding, both in terms of the number of drugs and the number of patients being treated. This article reviews the known toxicities and complications of antibody-drug conjugates that are currently approved for the treatment of cancer in the United States, with a focus on their emergency presentation and management. Similar to many other cancer therapies, most antibody-drug conjugates can cause diarrhea, nausea/vomiting, rash, peripheral neuropathy, and cytopenia, which are generally treated following standard-of-care. Interstitial lung disease, which may mimic pneumonia and cause respiratory failure and death, has been seen with trastuzumab deruxtecan and mirvetuximab soravtansine; emergency treatment of this condition includes oxygenation, ventilatory support, and corticosteroids. Inotuzumab ozogamicin and gemtuzumab ozogamicin are both associated with sinusoidal obstruction syndrome, a potentially fatal liver dysfunction that presents with weight gain, fluid overload, and jaundice. Abnormal liver function tests in patients who have been recently treated with these agents should be cautiously evaluated. Cardiac adverse events with antibody-drug conjugates are rare, but trastuzumab emtansine and trastuzumab deruxtecan may cause a decrease in cardiac contractility, and heart rate corrected QT interval prolongation is a rare effect of trastuzumab deruxtecan. Ocular adverse events, especially blurred vision, and keratopathy, are common with mirvetuximab soravtansine and tisotumab vedotin. Progressive multifocal leukoencephalopathy has been reported with brentuximab vedotin and polatuzumab vedotin. Tumor lysis syndrome may occur after treatment with gemtuzumab ozogamicin, polatuzumab vedotin, and brentuximab vedotin. Patients receiving enfortumab vedotin or brentuximab vedotin may develop hyperglycemia, sometimes presenting as diabetic ketoacidosis. Tisotumab vedotin and trastuzumab emtansine are associated with bleeding; although it is minor in most cases, severe bleeding and intracranial hemorrhage have occurred. Several antibody-drug conjugates can cause an anaphylactoid infusion-related reaction, which occurs most commonly during or soon after infusion but may be delayed up to 24 hours. Further research is needed to establish the real-world incidence of rare complications and how often patients with these complications present to the emergency department.
18Managing the Risk of Lung Toxicity with Trastuzumab Deruxtecan (T-DXd): A Canadian Perspective.PubMed
Jan-Willem Henning, Christine Brezden-Masley, Karen Gelmon, et al.
Ongoing advances in precision cancer therapy have increased the number of molecularly targeted and immuno-oncology agents for a variety of cancers, many of which have been associated with a risk of pulmonary complications, among the most concerning being drug-induced interstitial lung disease/pneumonitis (DI-ILD). As the number of patients undergoing treatment with novel anticancer agents continues to grow, DI-ILD is expected to become an increasingly significant clinical challenge. Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2 that is gaining widespread use in the metastatic breast cancer setting and is undergoing exploration for other oncologic indications. ILD/pneumonitis is an adverse event of special interest associated with T-DXd, which has potentially fatal consequences if left untreated and allowed to progress. When identified in the asymptomatic stage (grade 1), T-DXd-related ILD can be monitored and treated effectively with the possibility of treatment continuation. Delayed diagnosis and/or treatment, however, results in progression to grade 2 or higher toxicity and necessitates immediate and permanent discontinuation of this active agent. Strategies are, therefore, needed to optimize careful monitoring during treatment to ensure patient safety and optimize outcomes. Several guidance documents have been developed regarding strategies for the early identification and management of T-DXd-related ILD, although none have been within the context of the Canadian health care environment. A Canadian multidisciplinary steering committee was, therefore, convened to evaluate existing recommendations and adapt them for application in Canada. A multidisciplinary approach involving collaboration among medical oncologists, radiologists, respirologists, and allied health care professionals is needed to ensure the proactive identification and management of T-DXd-related ILD and DI-ILD associated with other agents with a similar toxicity profile.
19Trastuzumab Deruxtecan in Residual HER2-Positive Early Breast Cancer.PubMed
Sibylle Loibl, Yeon Hee Park, Zhiming Shao, et al.
BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer and residual disease after neoadjuvant therapy are at high risk for recurrence. METHODS: In a phase 3, open-label, international, randomized trial, we investigated postneoadjuvant trastuzumab deruxtecan (T-DXd; 5.4 mg per kilogram of body weight) as compared with trastuzumab emtansine (T-DM1; 3.6 mg per kilogram), the current standard treatment, in patients with HER2-positive breast cancer with residual invasive disease and node-positive disease at surgery or inoperable disease at diagnosis. The primary end point was invasive disease-free survival, and the key secondary end point was disease-free survival (including survival free from noninvasive breast cancers and second primary nonbreast cancers). Other end points included overall survival, distant recurrence-free interval, brain metastasis-free interval, and safety. RESULTS: A total of 1635 patients were randomly assigned (in a 1:1 ratio) to receive T-DXd (818 patients) or T-DM1 (817 patients). At the data-cutoff date, the median duration of follow-up was approximately 30 months in each group. Invasive-disease events or deaths were reported in 51 patients (6.2%) in the T-DXd group and 102 patients (12.5%) in the T-DM1 group (hazard ratio, 0.47; 95% confidence interval [CI], 0.34 to 0.66; P<0.001); 3-year invasive disease-free survival was 92.4% and 83.7%, respectively. Invasive-disease events, noninvasive-disease events, or deaths were reported in 52 patients (6.4%) in the T-DXd group and 103 patients (12.6%) in the T-DM1 group (hazard ratio, 0.47; 95% CI, 0.34 to 0.66; P<0.001); 3-year disease-free survival was 92.3% and 83.5%, respectively. The most common adverse events were nausea (71.3% of patients), constipation (32.0%), decreased neutrophil count (31.6%), and vomiting (31.0%) with T-DXd and increased liver-enzyme levels (aspartate aminotransferase [50.2%] and alanine aminotransferase [45.3%]) and decreased platelet count (49.8%) with T-DM1. The incidence of adjudicated drug-related interstitial lung disease was higher with T-DXd than with T-DM1 (9.6% vs. 1.6%). Two patients with interstitial lung disease in the T-DXd group died. CONCLUSIONS: In patients with high-risk, residual invasive HER2-positive breast cancer, postneoadjuvant T-DXd resulted in a significantly higher likelihood of invasive disease-free survival than T-DM1; toxic effects were mainly gastrointestinal and hematologic. An important identified risk of T-DXd is interstitial lung disease, which requires appropriate monitoring and management. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast05 ClinicalTrials.gov number, NCT04622319.).
20Pooled analysis of trastuzumab deruxtecan retreatment after recovery from grade 1 interstitial lung disease/pneumonitis.PubMed
H S Rugo, E Tokunaga, H Iwata, et al.
BACKGROUND: Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate treatment for multiple solid tumors, carries risk of interstitial lung disease/pneumonitis (ILD). Management guidelines generally mandate interrupting T-DXd treatment for grade 1 ILD, with possible retreatment following resolution of imaging findings. This pooled analysis examined T-DXd retreatment duration and ILD recurrence following recovery from grade 1 ILD. PATIENTS AND METHODS: Data were pooled from nine clinical trials of patients with various human epidermal growth factor receptor 2 (HER2)-positive, HER2-low, or HER2 (ERBB2)-mutant solid tumors treated with T-DXd (5.4-8.0 mg/kg). ILD events were reported and graded by investigators and confirmed as drug related by an independent ILD adjudication committee. Patients who recovered from a first investigator-assessed grade 1 and adjudication committee-confirmed drug-related ILD event (ILD1) could receive T-DXd retreatment. Patients were evaluated until disease progression or data cut-off. RESULTS: Among 2145 pooled patients, 9% (193/2145) had grade 1 ILD1, of which 23.3% (45/193) were retreated with T-DXd. Median retreatment duration was 85 days (range 1-848 days); 17.8% (8/45) of patients received T-DXd retreatment for ≥1 year. ILD recurrence (ILD2) occurred in 33.3% (15/45) of retreated patients; median time to ILD2 from T-DXd retreatment was 64 days (range, 22-391 days) and were low-grade events (grade 1, n = 6; grade 2, n = 9; no grade ≥3 or fatal events). Reasons for T-DXd retreatment discontinuation were disease progression [33.3% (15/45)]; ILD recurrence [20% (9/45)]; non-ILD adverse events [17.8% (8/45)]; and physician's decision [4.4% (2/45)]. At the analysis cut-off, 24.4% (11/45) of retreated patients were still receiving treatment, and most patients with ILD2 [60% (9/15)] had recovered with/without sequelae. CONCLUSIONS: This first large-scale pooled analysis demonstrates the safety of T-DXd retreatment after recovery from grade 1 ILD. ILD recurred in one-third of patients; all recurrence events were grade 1/2 and manageable using existing treatment guidelines. T-DXd retreatment following resolution of grade 1 drug-related ILD has potential to maximize therapeutic benefit.