依维莫司联合紫杉醇和卡铂作为转移性大细胞神经内分泌肺癌的一线治疗：一项多中心 II 期试验。

Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial.

机构信息

Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Member of the German Center for Lung Research (DZL).

Department of Pneumology, Lung Hospital Cologne Merheim, City of Cologne Municipal Hospitals, Cologne.

出版信息

Ann Oncol. 2017 Aug 1;28(8):1898-1902. doi: 10.1093/annonc/mdx268.

DOI:10.1093/annonc/mdx268

PMID:28535181

Abstract

BACKGROUND

Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC.

PATIENTS AND METHODS

In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment.

RESULTS

Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2.

CONCLUSION

Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC.

REGISTERED CLINICAL TRIAL NUMBERS

EudraCT number 2010-022273-34, NCT01317615.

摘要

背景

肺大细胞神经内分泌癌（LCNEC）是一种预后不良且治疗选择有限的罕见疾病。神经内分泌肿瘤常表现出 mTOR 通路的过度激活。基于 mTOR 抑制剂依维莫司在不同类型神经内分泌肿瘤中的良好活性，以及之前的 I 期试验结果，我们评估了依维莫司联合卡铂和紫杉醇作为晚期 LCNEC 患者一线治疗的疗效和安全性。

患者和方法

在这项前瞻性、多中心的 II 期试验中，化疗初治的 IV 期 LCNEC 患者接受依维莫司 5mg 每日一次联合紫杉醇 175mg/m2 和卡铂 AUC 5，每 3 周一次，最多 4 个周期，随后依维莫司 5mg 每日一次维持治疗，直至疾病进展。根据中心放射学评估确定疗效参数。

结果

在 10 个德国中心，共有 49 名平均年龄为 62±9 岁且以男性（71%）为主的吸烟者（98%）入组。总缓解率为 45%（95%置信区间 [CI] 31%-60%），疾病控制率为 74%（CI 59%-85%），中位无进展生存期为 4.4 个月（CI 3.2-6），中位总生存期为 9.9 个月（CI 6.9-11.7）。根据 Kaplan-Meier 分析，3 个月时的无进展生存率为 76%（CI 64%-88%）（主要终点）。51%的患者发生 3/4 级毒性，主要包括一般健康状况恶化（8%）、血细胞减少症（24%）、感染（10%）和胃肠道问题（8%）。依维莫司相关的典型不良反应，如口炎、皮疹和眼部问题，仅少数患者（<15%）发生，且均为 1-2 级。