Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
Department of Oncology, University of Turin, Orbassano, Turin, Italy.
Lancet Oncol. 2022 Apr;23(4):540-552. doi: 10.1016/S1470-2045(22)00061-4.
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/m 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.
恶性胸膜间皮瘤二线治疗的选择有限。我们旨在评估抗体药物偶联物 anetumab ravtansine 与长春瑞滨在间皮素过表达的不可切除局部晚期或转移性疾病患者中的疗效，这些患者在接受含铂培美曲塞化疗加或不加贝伐珠单抗的一线治疗后进展。
这是一项在 14 个国家的 76 家医院进行的、针对不可切除局部晚期或转移性恶性胸膜间皮瘤、东部肿瘤协作组体力状态 0-1 且在接受含铂培美曲塞化疗加或不加贝伐珠单抗的一线治疗后进展的成人（年龄≥18 岁）患者进行的 2 期、随机、开放标签研究。患者前瞻性筛选间皮素过表达（定义为免疫组化检测至少 30%的存活肿瘤细胞上膜染色强度为 2+或 3+），并使用赞助商提供的交互式语音和网络应答系统按 2:1 的比例随机分配，接受静脉注射 anetumab ravtansine（每 21 天周期的第 1 天 6.5mg/kg）或静脉注射长春瑞滨（每周 30mg/m），直至疾病进展、毒性或死亡。主要终点为盲法中心影像学评估的无进展生存期，在意向治疗人群中进行评估，所有接受任何研究治疗的患者均进行安全性评估。该研究在 ClinicalTrials.gov 上注册，编号为 NCT02610140，现已完成。
2015 年 12 月 3 日至 2017 年 5 月 31 日期间，共纳入 589 例患者，248 例间皮素过表达患者随机分配至两组治疗（166 例患者随机分配接受 anetumab ravtansine 治疗，82 例患者随机分配接受长春瑞滨治疗）。接受 anetumab ravtansine 治疗的 166 例患者中，105 例（63%）发生疾病进展或死亡（中位随访 4.0 个月[IQR 1.4-5.5]），而接受长春瑞滨治疗的 82 例患者中，43 例（52%）发生疾病进展或死亡（中位无进展生存期 4.3 个月[95%CI 4.1-5.2]；危险比 1.22[0.85-1.74]；对数秩检验 p=0.86）。最常见的 3 级或更高级别的不良事件是中性粒细胞减少症（anetumab ravtansine 治疗的 163 例患者中有 1 例[1%]，长春瑞滨治疗的 72 例患者中有 28 例[39%]）、肺炎（anetumab ravtansine 治疗的 7 例[4%]，长春瑞滨治疗的 5 例[7%]）、中性粒细胞计数减少（anetumab ravtansine 治疗的 2 例[1%]，长春瑞滨治疗的 12 例[17%]）和呼吸困难（anetumab ravtansine 治疗的 9 例[6%]，长春瑞滨治疗的 3 例[4%]）。anetumab ravtansine 治疗的 12 例（7%）和长春瑞滨治疗的 11 例（15%）患者发生严重药物相关治疗突发不良事件。anetumab ravtansine 治疗的 10 例（6%）治疗突发死亡：肺炎（3 例[2%]）、呼吸困难（2 例[1%]）、脓毒症（2 例[1%]）、心房颤动（1 例[1%]）、身体恶化（1 例[1%]）、肝衰竭（1 例[1%]）、间皮瘤（1 例[1%]）和肾衰竭（1 例[1%]；1 例患者发生 3 项事件）。长春瑞滨治疗的 1 例（1%）患者发生治疗突发死亡（肺炎）。
anetumab ravtansine 显示出可管理的安全性，且不比长春瑞滨更有效。需要进一步研究以确定间皮素过表达的复发性恶性胸膜间皮瘤的有效治疗方法。
拜耳医疗保健制药公司。
