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德曲妥珠单抗相关间质性肺病/肺炎的发生率、严重程度、死亡率、危险因素和临床管理建议的文献证据
德曲妥珠单抗 (Trastuzumab deruxtecan, T-DXd) 是一种新型的抗ERBB2（也称HER2）抗体偶联药物（ADC），在治疗多种晚期实体瘤中显示出疗效，但与间质性肺病/肺炎（ILD/pneumonitis）的发生风险增加有关。ILD/pneumonitis是T-DXd治疗中一个已充分描述的、严重的、可能危及生命的副作用。
以下是关于T-DXd相关ILD/pneumonitis的发生率、严重程度、死亡率、危险因素和临床管理建议的文献证据：
1. 发生率
T-DXd相关ILD/pneumonitis的总体发生率在不同研究中有所报告：
- 一项纳入14项研究共1193名患者的系统评价显示，独立委员会裁定的所有级别ILD/pneumonitis的总体发生率为11.40%（1193名患者中有136例）。
- 一项对FAERS数据库中ADC相关ILD报告的分析（2014-2023年）显示，T-DXd是报告最频繁的药物（占38.4%）。
- 一项对九项T-DXd单药研究的汇总分析，涉及1150名患者，裁定的药物相关ILD/pneumonitis总体发生率为15.4%。
- 另一项纳入13篇文章共1428名患者的荟萃分析显示，所有级别ILD/pneumonitis的发生率为12.5%。
- 一项纳入18项研究共3380名患者的系统评价显示，裁定的药物相关ILD/pneumonitis总体发生率为12.40%。
- 在HER2-低转移性乳腺癌患者的DESTINY-Breast04试验中，T-DXd组裁定的药物相关ILD/pneumonitis发生率为12.1%，其中0.8%为5级事件。
- 在DESTINY-Breast06试验中，HER2-低或HER2-超低转移性乳腺癌患者接受T-DXd治疗，裁定ILD/pneumonitis发生率为11.3%，其中3例为5级事件。
- 在DESTINY-Breast03试验中，HER2阳性转移性乳腺癌患者接受T-DXd治疗，裁定的药物相关ILD/pneumonitis发生率为10.5%，与曲妥珠单抗恩美坦辛组的1.9%相比更高，但T-DXd组无4或5级事件。该试验的更新结果显示，T-DXd组ILD/pneumonitis发生率为15%，但无4或5级事件。
- 一项针对乳腺癌患者的系统评价和单臂荟萃分析显示，T-DXd治疗的ILD发生率为11.7%（222/1970名患者）。
- 在HER2阳性转移性胃癌或胃食管连接腺癌患者的DESTINY-Gastric04试验中，T-DXd组裁定的药物相关ILD/pneumonitis发生率为13.9%（33例1或2级，1例3级）。
- 针对非小细胞肺癌（NSCLC）的药物警戒分析显示，T-DXd的ILD信号报告比值比（ROR）为3.14（95% CI 2.29-4.30）。在NSCLC患者中，T-DXd在HER2过表达和HER2突变型NSCLC中显示出优越疗效，但HER2突变患者的3级以上TEAE发生率更高（38.6% vs 22%），ILD是主要关注点。
- 在DESTINY-Breast09试验中，一线治疗HER2阳性晚期或转移性乳腺癌患者中，T-DXd联合帕妥珠单抗组裁定的药物相关ILD/pneumonitis发生率为12.1%（44例1或2级，2例5级死亡），而紫杉烷、曲妥珠单抗和帕妥珠单抗（THP）组为1.0%。
2. 严重程度
T-DXd相关ILD/pneumonitis的严重程度通常较低，但重度事件（包括死亡）仍有发生：
- 在所有裁定的T-DXd相关ILD/pneumonitis病例中，大多数（78.69%，n=96）为1或2级。
- 一项汇总分析显示，77.4%的患者经历了低级别事件（1或2级）。
- 一项针对乳腺癌患者的荟萃分析显示，大多数ILD病例（80.2%；174/217名患者）为轻度（1或2级），3或4级ILD报告发生率为13.4%。
- 在DESTINY-Breast04试验中，12.1%的ILD/pneumonitis事件中，0.8%为5级事件。
- 在DESTINY-Breast06试验中，ILD/pneumonitis发生率为11.3%，其中3例为5级事件。
- 在DESTINY-Breast03试验中，T-DXd组ILD/pneumonitis发生率为10.5%，均无4或5级事件。更新结果中T-DXd组ILD/pneumonitis发生率为15%，仍无4或5级事件。
- 在DESTINY-Gastric04试验中，T-DXd组的ILD/pneumonitis事件中，33例为1或2级，1例为3级，显示主要为低级别事件。
- DESTINY-Breast09试验中，T-DXd联合帕妥珠单抗组的ILD/pneumonitis中，44例为1或2级，2例为5级（死亡）。
3. 死亡率
T-DXd相关ILD/pneumonitis导致的死亡率是一个重要关注点：
- 一项系统评价报告，在122名ILD/pneumonitis患者中，有13人死亡（10.66%）。
- FAERS数据库分析显示，超过26%的ADC相关ILD病例导致死亡，其中急性呼吸窘迫综合征（ARDS）的死亡率最高，为65.0%。
- 一项汇总分析报告，裁定的药物相关ILD/pneumonitis中有2.2%为5级（死亡）。
- 一项针对乳腺癌患者的荟萃分析显示，6.4%的ILD病例为5级（死亡），共14名患者。
- 在DESTINY-Breast04试验中，0.8%的ILD/pneumonitis事件为5级。
- 在DESTINY-Breast06试验中，3例ILD/pneumonitis事件为5级死亡。
- 虽然DESTINY-Breast03试验的早期和更新结果均未报告T-DXd组有4或5级ILD/pneumonitis事件，但其他试验仍报告了死亡病例。
- DESTINY-Gastric04试验中，T-DXd组未报告5级ILD/pneumonitis事件，但对照组有1例5级事件。
- DESTINY-Breast09试验中，T-DXd联合帕妥珠单抗组有2例5级（死亡）ILD/pneumonitis事件。
- 尽管大多数ILD/pneumonitis病例是低级别，但ILD/pneumonitis相关的死亡风险不应被忽视。
4. 危险因素
目前仍需进一步研究以识别T-DXd相关ILD/pneumonitis的风险因素，但一些研究已初步探索了潜在因素：
- 一项汇总分析通过逐步Cox回归识别出几个可能与裁定的药物相关ILD/pneumonitis风险增加相关的基线因素：年龄<65岁、在日本入组、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诊时间>4年。
- 一项针对乳腺癌患者的荟萃分析发现，接受6.4 mg/kg T-DXd剂量的患者ILD发生率显著高于接受5.4 mg/kg剂量的患者（22.7% vs 9.3%，P < 0.01）。
- FAERS数据库分析发现，非小细胞肺癌患者中，老年、男性和体重较低是影响ILD的因素，而体重较低、男性和同时服用药物数量较多与死亡率增加相关。
- 需要进一步研究以确认ILD/pneumonitis的风险因素。识别高风险患者、诊断和定制治疗仍然具有挑战性，关于患者选择的额外信息通常不完全明确。
- 建议对具有ILD风险因素的患者进行预测性生物标志物评估。
5. 临床管理建议
T-DXd相关ILD/pneumonitis的有效管理对于改善患者预后至关重要，包括早期诊断、密切监测和及时干预：
-
诊断：
- ILD/pneumonitis的诊断是排除性诊断，必须排除其他可能的肺损伤/影像学发现原因，才能做出准确诊断。
- 症状可能不特异，早期症状识别具有挑战性，因此诊断常被延迟。
- 诊断标准包括新发现的肺部混浊、症状发作与用药开始的关系以及排除其他ILD原因。
- 诊断过程的重要组成部分包括体格检查和仔细的病史采集、生命体征测量（特别是呼吸频率和动脉血氧饱和度）、相关实验室检查、肺功能测试（肺活量测定和一氧化碳弥散能力）以及计算机断层扫描/影像学检查。
- 由于ILD的临床和放射学表现常与肺炎或其他间质性肺病相似，鉴别诊断很重要，包括微生物和血清学检测以排除或确认感染原因。
-
监测：
- 所有患者都需要密切监测和积极管理ILD/pneumonitis。鉴于药物暴露时间延长，对T-DXd引起的ILD/pneumonitis进行仔细监测和管理至关重要。
- 在治疗的第一个月内进行监测尤为重要，因为48.59%的ILD事件发生在一个月内。
- 应增加患者对ILD症状的认识，确保密切关注并及时报告，以改善患者预后。
- 需要对患者进行主动监测、早期诊断和有效管理。
-
治疗：
- 在大多数情况下，ILD的管理需要停用抗肿瘤药物并给予短期类固醇。
- 类固醇的逐渐减量必须缓慢进行，以防止ILD复发。
- 有症状的ILD应停用ADC，无症状病例在完全消退后可考虑重新引入。
- 糖皮质激素是ILD治疗的基石，剂量应根据事件的严重程度进行调整。
- 对于3级和4级（严重和非常严重）ILD患者，需要住院治疗，并常需要氧气和无创通气。
- 关于有创通气的决定应考虑患者的癌症预后。
- 管理策略包括剂量中断或减少、治疗停止、糖皮质激素和支持性护理。
- 多学科团队的早期发现和管理T-DXd相关毒性最终可能改善患者预后。
- 为了优化副作用管理并最大限度地发挥T-DXd的潜在益处，预防恶心呕吐和积极管理ILD/pneumonitis尤为重要。
- 适当管理T-DXd相关的副作用将有助于实现最佳药物暴露和益处，并避免过早停药或不当剂量减少。
总结
T-DXd相关ILD/pneumonitis是一个重要的不良事件，其总体发生率约为11-15%，多数为低级别（1或2级）。然而，3级及以上事件和死亡病例均有报告，死亡率可达约10%或更高，特别是在出现ARDS等严重表现时。年龄、入组地点、剂量、血氧饱和度、肾功能、肺部合并症和疾病诊断时间等因素可能与风险增加相关，高剂量T-DXd（6.4mg/kg）显示出更高的ILD发生率。
临床实践中，应加强对ILD/pneumonitis的预防、主动监测、早期诊断和有效管理。诊断应通过排除其他肺部疾病，并结合患者病史、体格检查、影像学和肺功能检查。一旦确诊，通常需要停用T-DXd，并根据严重程度给予糖皮质激素和支持性护理，同时注意类固醇的缓慢减量以防复发。多学科团队的协作对于优化患者管理和改善预后至关重要。未来的研究需要进一步阐明ILD/pneumonitis的风险因素和潜在机制，以开发更有效的预防和管理策略。
References
1Trastuzumab 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.
2Interstitial lung disease with antibody-drug conjugates: a real-world pharmacovigilance study based on the FAERS database during the period 2014-2023.PubMed
Jing Shi, Xinya Liu, Li Wu, et al.
BACKGROUND: Antibody-drug conjugates (ADCs) combine the targeted nature of monoclonal antibodies with the potent efficacy of small-molecule cytotoxic drugs. However, they also carry unique safety risks, including lung toxicity. OBJECTIVE: To conduct a systematic review and analysis of ADC-related interstitial lung disease (ILD) incidence, characteristics, and risk factors to optimize safe and effective clinical use. DESIGN: ADC-related ILD reports from the FDA Adverse Event Reporting System (FAERS) database between January 2014 and March 2023 were analyzed. METHODS: ADC-related ILD reports were retrieved from the FAERS database. Statistical analyses were conducted using reporting odds ratio (ROR) and information components (ICs). The lower limit of the 95% confidence interval (CI) was set for ROR (ROR025) >1 or IC (IC025) >0, and statistical significance was determined based on a minimum of three reports. RESULTS: The study analyzed the statistical data on ADC-induced ILDs (1277 cases). Trastuzumab deruxtecan was reported to be the most frequent (38.4%). Among the 33 preferred terms (PTs) in standardized MedDRA queries (SMQ) = "Interstitial lung disease," the three most common were as follows: ILD (40.6%), pneumonitis (27.9%), and acute respiratory distress syndrome (ARDS) (7.6%). Trastuzumab deruxtecan showed the strongest association with ILD (PT) and pneumonitis, whereas ARDS was associated with four different drugs. The median time to onset of ADC-related ILDs was 51 days (interquartile range (IQR), 16-196), with ARDS having the earliest median time to onset at 15 days (IQR, 6-52). The onsets of pneumonitis, ILD, lung infiltration, and pulmonary toxicity were similar. More than 26% of ADC-related ILD cases result in death, with ARDS having the highest mortality rate of 65.0%. CONCLUSION: ADCs are associated with an increased risk of pulmonary adverse events, such as ILDs, with significant differences between drugs and varying mortality rates for different adverse events, necessitating distinct monitoring and appropriate management.
3Pooled 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.
4Clinical 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.
5Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer.PubMed
Shanu Modi, William Jacot, Toshinari Yamashita, et al.
BACKGROUND: Among breast cancers without human epidermal growth factor receptor 2 (HER2) amplification, overexpression, or both, a large proportion express low levels of HER2 that may be targetable. Currently available HER2-directed therapies have been ineffective in patients with these "HER2-low" cancers. METHODS: We conducted a phase 3 trial involving patients with HER2-low metastatic breast cancer who had received one or two previous lines of chemotherapy. (Low expression of HER2 was defined as a score of 1+ on immunohistochemical [IHC] analysis or as an IHC score of 2+ and negative results on in situ hybridization.) Patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival in the hormone receptor-positive cohort. The key secondary end points were progression-free survival among all patients and overall survival in the hormone receptor-positive cohort and among all patients. RESULTS: Of 557 patients who underwent randomization, 494 (88.7%) had hormone receptor-positive disease and 63 (11.3%) had hormone receptor-negative disease. In the hormone receptor-positive cohort, the median progression-free survival was 10.1 months in the trastuzumab deruxtecan group and 5.4 months in the physician's choice group (hazard ratio for disease progression or death, 0.51; P<0.001), and overall survival was 23.9 months and 17.5 months, respectively (hazard ratio for death, 0.64; P = 0.003). Among all patients, the median progression-free survival was 9.9 months in the trastuzumab deruxtecan group and 5.1 months in the physician's choice group (hazard ratio for disease progression or death, 0.50; P<0.001), and overall survival was 23.4 months and 16.8 months, respectively (hazard ratio for death, 0.64; P = 0.001). Adverse events of grade 3 or higher occurred in 52.6% of the patients who received trastuzumab deruxtecan and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. CONCLUSIONS: In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).
6Interstitial lung disease associated with novel anticancer agents in non-small cell lung cancer: a pharmacovigilance analysis using the FAERS database.PubMed
Yunfei Zhu, Jingjing Sun, Shuyun Xu
BACKGROUND: Some novel anticancer agents are associated with drug-induced interstitial lung disease (ILD), a critical and potentially fatal adverse event. Lung cancer patients appear particularly susceptible, yet the risk and clinical characteristics remain incompletely analyzed. OBJECTIVES: To comprehensively evaluate ILD risk and characteristics induced by novel anticancer agents in non-small cell lung cancer (NSCLC) using large-scale real-world data. DESIGN: A retrospective pharmacovigilance study based on spontaneous adverse event reports. METHODS: Data from 2014 to 2024 were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS). Reports of NSCLC patients who developed ILD during treatment with FDA-approved novel anticancer agents (immune checkpoint inhibitors, targeted therapies, antibody-drug conjugates). The reporting odds ratio (ROR) was used to assess the disproportionate reporting signals for each drug. Statistical significance was defined when the lower 95% confidence interval (CI) exceeded 1 with at least three reports. RESULTS: A total of 4712 NSCLC cases were analyzed. Eight agents were identified with positive signals for ILD: ROR and 95% CI for nivolumab was 1.28 (1.20-1.38), pembrolizumab 1.47 (1.36-1.59), durvalumab 7.38 (6.90-7.89), atezolizumab 1.25 (1.12-1.39), ipilimumab 1.96 (1.74-2.21), tremelimumab 3.58 (1.97-6.50), trastuzumab-deruxtecan 3.14 (2.29-4.30), osimertinib 1.12 (1.03-1.23). The median onset time was 33 days, with 48.59% of ILD events occurring within the first month. The fatal cases experienced a significantly shorter onset time than non-fatal cases. Older age, male sex, and lower body weight were identified as factors affecting ILD, whereas lower body weight, male sex, and a higher number of concomitant drugs were linked to increased mortality. CONCLUSION: Our study identifies positive signals for ILD with eight novel antineoplastic agents in NSCLC, including nivolumab, pembrolizumab, durvalumab, atezolizumab, ipilimumab, tremelimumab, trastuzumab-deruxtecan, and osimertinib, highlights the importance of monitoring during the first month of therapy, and identifies older male patients with lower body weight as a high-risk group.
7Drug-induced interstitial lung disease during cancer therapies: expert opinion on diagnosis and treatment.PubMed
P Conte, P A Ascierto, G Patelli, et al.
BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a form of interstitial lung disease resulting from exposure to drugs causing inflammation and possibly interstitial fibrosis. Antineoplastic drugs are the primary cause of DIILD, accounting for 23%-51% of cases, with bleomycin, everolimus, erlotinib, trastuzumab-deruxtecan and immune checkpoint inhibitors being the most common causative agents. DIILD can be difficult to identify and manage, and there are currently no specific guidelines on the diagnosis and treatment of DIILD caused by anticancer drugs. OBJECTIVE: To develop recommendations for the diagnosis and management of DIILD in cancer patients. METHODS: Based on the published literature and their clinical expertise, a multidisciplinary group of experts in Italy developed recommendations stratified by DIILD severity, based on the Common Terminology Criteria for Adverse Events. RESULTS: The recommendations highlight the importance of multidisciplinary interaction in the diagnosis and management of DIILD. Important components of the diagnostic process are physical examination and careful patient history-taking, measurement of vital signs (particularly respiratory rate and arterial oxygen saturation), relevant laboratory tests, respiratory function testing with spirometry and diffusing capacity of the lung for carbon monoxide and computed tomography/imaging. Because the clinical and radiological signs of DIILD are often similar to those of pneumonias or interstitial lung diseases, differential diagnosis is important, including microbial and serological testing to exclude or confirm infectious causes. In most cases, management of DIILD requires the discontinuation of the antineoplastic agent and the administration of short-term steroids. Steroid tapering must be undertaken slowly to prevent reactivation of DIILD. Patients with severe and very severe (grade 3 and 4) DIILD will require hospitalisation and often need oxygen and non-invasive ventilation. Decisions about invasive ventilation should take into account the patient's cancer prognosis. CONCLUSIONS: These recommendations provide a structured step-by-step diagnostic and therapeutic approach for each grade of suspected cancer-related DIILD.
8Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.PubMed
Aditya Bardia, Xichun Hu, Rebecca Dent, et al.
BACKGROUND: Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. METHODS: We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. RESULTS: Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. CONCLUSIONS: Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).
9Incidence 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.
10Interstitial 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.
11Trastuzumab 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.).
12The safety of trastuzumab deruxtecan (DS-8201) with a focus on interstitial lung disease and/or pneumonitis: A systematic review and single-arm meta-analysis.PubMed
Ruijuan Li, Manqi Hua, Jiulong Li, et al.
BACKGROUND: Previous studies involving risk-benefit analysis of trastuzumab deruxtecan (DS-8201) have indicated the benefit of this treatment, although it may increase the risk of interstitial lung disease (ILD) and/or pneumonitis in certain patients. This study aimed to assess the safety of DS-8201. METHODS: A search was done for relevant articles in four electronic databases: PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. All reports published up until November 2, 2022, were included, and study types were restricted to clinical trials; the last search was then updated to January 10, 2023. We also assessed the quality of the literature with the Cochrane Handbook for Systematic Reviews of Interventions and the Methodological Index for Non-Randomized Studies tool, and then performed a meta-analysis with R version 4.2.1. RESULTS: A total of 1428 patients reported in 13 articles were included in this study. The analysis revealed that the most common all-grade treatment-emergent adverse events (TEAEs) were nausea and fatigue. The most common TEAE of grade 3 or above (grade ≥3) was neutropenia. The incidences of ILD and/or pneumonitis for all-grade and grade ≥3 TEAEs were 12.5% and 2.2%, respectively. CONCLUSIONS: This comprehensive summary of the incidence of TEAEs associated with DS-8201 in clinical trials provides an important guide for clinicians. The most common TEAEs were gastrointestinal reactions and fatigue; meanwhile, the most common grade ≥3 TEAE was hematological toxicity. ILD and/or pneumonitis were specific adverse drug reactions associated with DS-8201, of which physicians should be particularly aware for their higher morbidity and rates of grade ≥3 TEAEs.
13Multidisciplinary clinical guidelines in proactive monitoring, early diagnosis, and effective management of trastuzumab deruxtecan (T-DXd)-induced interstitial lung disease (ILD) in breast cancer patients.PubMed
D Wekking, M Porcu, B Pellegrino, et al.
Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate (ADC), has altered the treatment landscape in breast cancer (BC), irrespective of the HR-receptor status. The use of the agent is increasing, despite the finding that exposure to T-DXd increases the risk of interstitial lung disease (ILD), particularly in BC patients. Although T-DXd-related ILD can be potentially severe and life-threatening, most low-grade cases can be treated safely using a multidisciplinary approach comprising early and accurate diagnosis, effective management, close monitoring, and the prompt administration of steroids. Additionally, increasing patients' education on ILD symptoms ensures close attention and enables prompt reporting, enhancing patient outcomes. It is recommended that predictive biomarkers are assessed in patients with risk factors for developing ILD. Currently, diagnostic criteria comprise newly identified pulmonary opacities, the relation of symptom onset to medication initiation, and the exclusion of other causes of ILD. The general condition of patients is weakened during the management of ILD (BC progression and corticosteroid treatment). Consequently, BC chemotherapy might be attenuated. This highlights the importance of preventing (high-grade) ILD, especially since its use is expanded. Identifying high-risk patients, diagnosing, and customizing treatment is, however, challenging and additional information on patient selection is often not fully clarified. In this paper, we provide updated multidisciplinary clinical guidance for patient selection, proactive monitoring, early diagnosis, and effectively management of T-DXd-induced ILD in HER2-positive BC patients. We describe the risk factors for developing ILD, patients' characteristics of ILD, and the histopathological and radiographic characteristics of ILD, including real-world clinical practice reports. These recommendations provide a structured step-by-step approach for managing each suspected BC-related ILD grade.
14Multidisciplinary 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.
15Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial.PubMed
Sara A Hurvitz, Roberto Hegg, Wei-Pang Chung, et al.
BACKGROUND: An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. METHODS: This open-label, randomised, multicentre, phase 3 trial was done in 169 study centres in North America, Asia, Europe, Australia, and South America. Eligible patients were aged 18 or older, had HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, had an Eastern Cooperative Oncology Group performance status 0-1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumours version 1.1. Patients were randomly assigned (1:1) to receive trastuzumab deruxtecan 5·4 mg/kg or trastuzumab emtansine 3·6 mg/kg, both administered by intravenous infusion every 3 weeks. Randomisation was stratified by hormone receptor status, previous treatment with pertuzumab, and history of visceral disease, and was managed through an interactive web-based system. Within each stratum, balanced block randomisation was used with a block size of four. Patients and investigators were not masked to the treatment received. The primary endpoint was progression-free survival by blinded independent central review. The key secondary endpoint was overall survival and this prespecified second overall survival interim analysis reports updated overall survival, efficacy, and safety results. Efficacy analyses were performed using the full analysis set. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03529110. FINDINGS: Between July 20, 2018, and June 23, 2020, 699 patients were screened for eligibility, 524 of whom were enrolled and randomly assigned to receive trastuzumab deruxtecan (n=261) or trastuzumab emtansine (n=263). Median duration of study follow-up was 28·4 months (IQR 22·1-32·9) with trastuzumab deruxtecan and 26·5 months (14·5-31·3) with trastuzumab emtansine. Median progression-free survival by blinded independent central review was 28·8 months (95% CI 22·4-37·9) with trastuzumab deruxtecan and 6·8 months (5·6-8·2) with trastuzumab emtansine (hazard ratio [HR] 0·33 [95% CI 0·26-0·43]; nominal p<0·0001). Median overall survival was not reached (95% CI 40·5 months-not estimable), with 72 (28%) overall survival events, in the trastuzumab deruxtecan group and was not reached (34·0 months-not estimable), with 97 (37%) overall survival events, in the trastuzumab emtansine group (HR 0·64; 95% CI 0·47-0·87]; p=0·0037). The number of grade 3 or worse treatment-emergent adverse events was similar in patients who received trastuzumab deruxtecan versus trastuzumab emtansine (145 [56%] patients versus 135 [52%] patients). Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 39 (15%) patients treated with trastuzumab deruxtecan and eight (3%) patients treated with trastuzumab emtansine, with no grade 4 or 5 events in either group. INTERPRETATION: Trastuzumab deruxtecan showed a significant improvement in overall survival versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer, as well as the longest reported median progression-free survival, reaffirming trastuzumab deruxtecan as the standard of care in the second-line setting. A manageable safety profile of trastuzumab deruxtecan was confirmed with longer treatment duration. FUNDING: Daiichi Sankyo and AstraZeneca.
16A 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.
17Trastuzumab 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.).
18Optimizing 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.
19Trastuzumab Deruxtecan plus Pertuzumab for HER2-Positive Metastatic Breast Cancer.PubMed
Sara M Tolaney, Zefei Jiang, Qingyuan Zhang, et al.
BACKGROUND: Trastuzumab deruxtecan has shown efficacy in patients with previously treated human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic breast cancer. The efficacy and safety of trastuzumab deruxtecan in patients with no previous therapy for HER2-positive advanced or metastatic breast cancer are unclear. METHODS: We conducted a phase 3 trial involving patients with HER2-positive advanced or metastatic breast cancer and no previous chemotherapy or HER2-directed therapy for metastatic disease. Patients were randomly assigned in a 1:1:1 ratio to receive trastuzumab deruxtecan plus pertuzumab; trastuzumab deruxtecan plus placebo; or a taxane, trastuzumab, and pertuzumab (THP). The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included objective response, duration of response, and safety. RESULTS: For this prespecified interim analysis, data for trastuzumab deruxtecan plus pertuzumab and for THP are reported; data for trastuzumab deruxtecan plus placebo remain blinded until the final analysis of progression-free survival. At the data-cutoff date (February 26, 2025), the median progression-free survival was 40.7 months with trastuzumab deruxtecan plus pertuzumab (383 patients) and 26.9 months with THP (387 patients) (hazard ratio for progression or death, 0.56; 95% confidence interval [CI], 0.44 to 0.71; P<0.00001 [P-value boundary for superiority, 0.00043]). The incidence of a confirmed response was 85.1% with trastuzumab deruxtecan plus pertuzumab and 78.6% with THP (complete responses in 15.1% and 8.5%, respectively), with a median duration of response of 39.2 months and 26.4 months. Safety was consistent with the known profiles of the individual treatments. The incidence of grade 3 or higher adverse events was 63.5% with trastuzumab deruxtecan plus pertuzumab and 62.3% with THP; the most common were neutropenia, hypokalemia, and anemia with trastuzumab deruxtecan plus pertuzumab and neutropenia, leukopenia, and diarrhea with THP. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 12.1% of patients receiving trastuzumab deruxtecan plus pertuzumab (grade 1 or 2 in 44 patients and grade 5 [death] in 2 patients) and in 1.0% of those receiving THP (all grade 1 or 2). CONCLUSIONS: Trastuzumab deruxtecan plus pertuzumab led to a significantly lower risk of progression or death than THP when used as first-line treatment for HER2-positive advanced or metastatic breast cancer, with no new safety signals. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast09 ClinicalTrials.gov number, NCT04784715.).
20Efficacy 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.