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Abstract：
Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab.
In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.
Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).
Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.
Bayer Healthcare Pharmaceuticals.
In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed.
Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia).
Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma.
Bayer Healthcare Pharmaceuticals.
摘要：
对于恶性胸膜间皮瘤的二线治疗，很少有治疗选择。我们旨在评估不可切除的局部晚期或转移性疾病过度表达间皮素的患者的抗体-药物偶联物anetumabravtansine与长春瑞滨的比较，这些患者在有或没有贝伐单抗的一线铂-培美曲塞化疗中进展。
在这个阶段2，随机，开放标签研究，在14个国家的76家医院，我们招募了患有不可切除的局部晚期或转移性恶性胸膜间皮瘤的成人（年龄≥18岁），东部肿瘤协作组的表现状态为0-1,在铂类-培美曲塞一线化疗加或不加贝伐单抗治疗后进展.参与者前瞻性筛选间皮素过表达（通过免疫组织化学定义为至少30％的活肿瘤细胞上的2或3间皮素膜染色强度），并随机分配（2：1），使用赞助商提供的交互式语音和网络响应系统，接受静脉内Anetumabravtansine（每个21天周期的第1天6·5mg/kg）或静脉内长春瑞滨（每周一次30mg/m2）直至进展，毒性,或死亡。主要终点是无进展生存期，根据盲法中心放射学综述，在意向治疗人群中评估，在接受任何研究治疗的所有参与者中进行安全性评估。这项研究在ClinicalTrials.gov注册，NCT02610140，现已完成。
2015年12月3日至2017年5月31日，589名患者入选，248例间皮素过表达患者被随机分配到两个治疗组（166名患者被随机分配接受阿尼单抗ravtansine，82名患者被随机分配接受长春瑞滨）。166例接受anetumabravtansine治疗的患者中有105例（63％）（中位随访时间4·0个月[IQR1·4-5·5]）与接受长春瑞滨治疗的82例患者（3·9个月[1·4-5·4]）中有43例（52％）疾病进展或死亡（中位无进展生存期4·3个月[95％CI4·1·5最常见的3级或更严重的不良事件是中性粒细胞减少症（163例患者中的1例[1％]使用阿尼单抗ravtansine，72例患者中的28例[39％]使用长春瑞滨），肺炎（七[4%]对五[7%]），中性粒细胞计数减少（2[1%]vs12[17%]），和呼吸困难（9[6%]vs3[4%]）。12例（7％）使用Anetumabravtansine治疗的患者和11例（15％）使用长春瑞滨治疗的患者发生了严重的药物相关治疗引起的不良事件。使用anetumabravtansine发生了10例（6％）治疗紧急死亡：肺炎（3[2％]），呼吸困难（两个[1%]），败血症（两个[1%]），心房颤动（1[1%]），物理退化（1[1%]），肝功能衰竭（1[1%]），间皮瘤（1[1%]），和肾功能衰竭（1例[1%]；1例患者有3例事件）。长春瑞滨组（肺炎）发生了1例（1％）因治疗引起的死亡。
Anetumabravtansine显示出可控的安全性，并不优于长春瑞滨。需要进一步的研究来确定复发性表达间皮素的恶性胸膜间皮瘤的积极治疗。
拜耳医疗制药。
在这个阶段2，随机，开放标签研究，在14个国家的76家医院，我们招募了患有不可切除的局部晚期或转移性恶性胸膜间皮瘤的成人（年龄≥18岁），东部肿瘤协作组的表现状态为0-1,在铂类-培美曲塞一线化疗加或不加贝伐单抗治疗后进展.参与者前瞻性筛选间皮素过表达（通过免疫组织化学定义为至少30％的活肿瘤细胞上的2或3间皮素膜染色强度），并随机分配（2：1），使用赞助商提供的交互式语音和网络响应系统，接受静脉内Anetumabravtansine（每个21天周期的第1天6·5mg/kg）或静脉内长春瑞滨（每周一次30mg/m2）直至进展，毒性,或死亡。主要终点是无进展生存期，根据盲法中心放射学综述，在意向治疗人群中评估，在接受任何研究治疗的所有参与者中进行安全性评估。这项研究在ClinicalTrials.gov注册，NCT02610140，现已完成。
2015年12月3日至2017年5月31日，589名患者入选，248例间皮素过表达患者被随机分配到两个治疗组（166名患者被随机分配接受阿尼单抗ravtansine，82名患者被随机分配接受长春瑞滨）。166例接受anetumabravtansine治疗的患者中有105例（63％）（中位随访时间4·0个月[IQR1·4-5·5]）与接受长春瑞滨治疗的82例患者（3·9个月[1·4-5·4]）中有43例（52％）疾病进展或死亡（中位无进展生存期4·3个月[95％CI4·1·5最常见的3级或更严重的不良事件是中性粒细胞减少症（163例患者中的1例[1％]使用阿尼单抗ravtansine，72例患者中的28例[39％]使用长春瑞滨），肺炎（七[4%]对五[7%]），中性粒细胞计数减少（2[1%]vs12[17%]），和呼吸困难（9[6%]vs3[4%]）。12例（7％）使用Anetumabravtansine治疗的患者和11例（15％）使用长春瑞滨治疗的患者发生了严重的药物相关治疗引起的不良事件。使用anetumabravtansine发生了10例（6％）治疗紧急死亡：肺炎（3[2％]），呼吸困难（两个[1%]），败血症（两个[1%]），心房颤动（1[1%]），物理退化（1[1%]），肝功能衰竭（1[1%]），间皮瘤（1[1%]），和肾功能衰竭（1例[1%]；1例患者有3例事件）。长春瑞滨组（肺炎）发生了1例（1％）因治疗引起的死亡。
Anetumabravtansine显示出可控的安全性，并不优于长春瑞滨。需要进一步的研究来确定复发性表达间皮素的恶性胸膜间皮瘤的积极治疗。
拜耳医疗制药。
