中国原创新药登上《柳叶刀肿瘤学分册》
前情提要
2017年2月10日，英国《柳叶刀肿瘤学分册》在线发表中国原创新药优替德隆＋卡培他滨对比卡培他滨单药用于蒽环类和紫杉类难治性转移性乳腺癌的多中心非盲优效性Ⅲ期随机对照（BG01-1323L）研究报告，卡司阵容如下：
中国医学科学院肿瘤医院暨国家癌症中心：张频、徐兵河（通信作者）
中国医科大学附属肿瘤医院暨辽宁省肿瘤医院：孙涛
哈尔滨医科大学附属第三医院暨黑龙江省肿瘤医院：张清媛
中山大学肿瘤防治中心暨中山大学附属肿瘤医院：袁中玉、彭柔君
军事医学科学院附属医院暨307医院：江泽飞、张少华
浙江中医药大学附属浙江省肿瘤医院暨肿瘤医院：王晓稼、黄健
郑州大学附属肿瘤医院暨河南省肿瘤医院：崔树德、闫敏
中国医科大学附属第一医院：滕月娥
复旦大学附属肿瘤医院：胡夕春
解放军总医院暨301医院：杨俊兰
浙江大学医学院附属邵逸夫医院：潘宏铭
天津医科大学附属肿瘤医院暨天津市肿瘤医院：佟仲生
北京大学肿瘤医院：李惠平
南开大学人民医院暨天津市人民医院：姚嫱
山东大学附属山东省肿瘤医院：王永胜
南京医科大学第一附属医院暨江苏省人民医院：殷咏梅
青岛大学烟台毓璜顶医院：孙萍
四川大学华西医院：郑鸿
华中科技大学同济医学院附属协和医院：程晶
上海交通大学医学院附属仁济医院：陆劲松
南通大学附属肿瘤医院暨南通市肿瘤医院：张葆春
河北医科大学第四医院暨河北省肿瘤医院：耿翠芝
福建医科大学附属福建省肿瘤医院：刘健
北京华昊中天生物技术有限公司：唐莉、邱荣国
2016年6月，徐兵河教授曾经应邀在美国临床肿瘤学会（ASCO）年会对该研究进行口头报告（摘要号：1004）。
优替德隆（UTD1）是一种基因工程埃博霉素类似物，在Ⅰ期和Ⅱ期临床研究中，显示出有希望作为乳腺癌的潜在治疗方法。该Ⅲ期研究比较了优替德隆＋卡培他滨和卡培他滨单药用于转移性乳腺癌患者的有效性和安全性。
该多中心非盲优效性Ⅲ期随机对照研究于2014年8月8日～2015年12月14日在中国26家医院入组蒽环类和紫杉类化疗方案治疗失败的转移性乳腺癌女性患者405位，采用计算机按2∶1进行随机分组，其中联合组270位接受每周期21天的优替德隆（第1～5天静脉注射30mg/m²）＋卡培他滨（第1～14天每天两次口服1000mg/m²），对照组135位接受卡培他滨单药（第1～14天每天两次口1250mg/m²），直至疾病进展或发生不可接受的毒性反应。患者、医生、评定者（除了评定效果的独立影像学复核委员会）均知晓治疗分组。主要研究终点为独立影像学复核委员会集中评定的无进展生存，并在意向治疗群体中使用生存曲线乘积极限法进行分析。次要研究终点为总生存、客观有效（完全有效＋部分有效）率、临床获益（完全有效＋部分有效＋疾病稳定）率、起效时间、有效维持时间、安全性。随访仍在进行。该研究在美国政府临床试验网站（ClinicalTrials.gov）注册编号：NCT02253459。
结果发现，截至2016年9月1日，联合组、对照组的无进展生存中位随访时间分别为6.77、4.55个月（四分位距：3.81～10.32、2.55～9.39），独立影像学复核委员会评定的中位无进展生存分别为8.44、4.27个月（95%置信区间：7.95～9.92、3.22～5.68；风险比：0.46，95%置信区间：0.36～0.59，P＜0.0001）。
此外，在次要研究终点中，联合组与单药组相比，独立影像学复核委员会评定的客观有效率分别为40.4%、21.5%（P=0.0002），临床获益率分别为53.9%、26.0%（P＜0.0001）。总生存事件数尚未达到预设值，但是初步分析结果显示，总生存分别为16.13、12.78个月（95%置信区间：13.54～17.05、11.14～14.32；风险比：0.63，95%置信区间：0.45～0.88，对数秩检验P=0.0059）。
外周神经病变为联合组最常见的3级不良事件（267位患者出现58例，占22%），而单药组的130位患者仅出现1例（＜1%）。手足综合征为单药组最常见的3级不良事件（130位患者出现10例，占8%），为联合组次常见的3级不良事件（267位患者出现18例，占7%）。
联合组报告16例严重不良事件（最常见为腹泻，出现于3位患者，占1%），单药组报告14例严重不良事件（最常见为腹泻、血胆红素升高、贫血，出现于2位患者，占2%）。患者死亡155位（联合组99位，单药组56位）。所有死亡均与疾病进展相关，除了联合组心包积液、单药组呼吸困难各一例考虑可能或很有可能与治疗相关。
因此，虽然先前化疗后疾病进展，优替德隆＋卡培他滨与卡培他滨单药相比，对于无进展生存、总生存、客观有效率、临床获益率等结局显然更为有效，而且毒性轻微，除了外周感觉神经病变之外，不过容易处理。该研究结果支持使用优替德隆＋卡培他滨作为转移性乳腺癌患者的有效选择方案。
作者解说
转移性乳腺癌的治疗通常包括蒽环类和紫杉类，但是这些药物的治疗效果通常是短暂或无法获得，并且耐药性经常发生。埃博霉素与紫杉类相似，是一种细胞有丝分裂微管稳定抗癌药，并已显示出高效抗多药耐药肿瘤活性。伊沙匹隆是半合成的埃博霉素类似物，在该类药物中，唯一已被美国食品药品管理局（FDA）批准单药或与卡培他滨联合用于蒽环类和紫杉类治疗失败后的转移性乳腺癌患者。根据对PubMed、会议网站（美国临床肿瘤学会和圣安东尼奥乳腺癌会议）和中国数据库临床研究参考文献进行检索，关于埃博霉素、卡培他滨、艾日布林和其他微管动力抑制剂的临床研究，尤其是关于转移性乳腺癌药物审批的Ⅱ或Ⅲ期研究，结果发现优替德隆是中国唯一完成Ⅰ、Ⅱ、Ⅲ期研究的埃博霉素药物，其中Ⅰ、Ⅱ期研究结果已经发表。
既往研究结果表明，优替德隆单药或联合卡培他滨对于已经大量治疗、耐药、晚期转移性乳腺癌患者具有较高活性，副作用也容易处理。此外，在非盲非对照Ⅱ期研究中，优替德隆联合卡培他滨治疗对蒽环类或紫杉类治疗失败的晚期转移性乳腺癌患者显示出良好的有效性、耐受性和安全性。
此次Ⅲ期研究结果显示，优替德隆＋卡培他滨与卡培他滨单药相比，对于已经大量治疗的转移性乳腺癌患者，显著改善了无进展生存、总生存、客观有效率、临床获益率。安全性结局无显著组间差异，除了优替德隆＋卡培他滨与卡培他滨单药相比的周围神经病变显著更多。值得注意的是，与伊沙匹隆相比，优替德隆仅仅引起非常轻微的骨髓抑制且无肝脏毒性。
总之，该研究为第一项在中国启动并进行的埃博霉素类似物随机多中心Ⅲ期研究。此外，联合方案具有容易处理的安全性，与伊沙匹隆相比，无显著的骨髓抑制或肝脏毒性。这些结果支持该方案良好的利弊特征，并为已经大量治疗的转移性乳腺癌患者提供了有潜力的新选择，尤其用于治疗对蒽环类和紫杉类耐药的转移性乳腺癌。
同期评论
对此，法国贝桑松弗朗什孔泰大学让·明热斯医院的泽维尔·匹维特发表同期评论《经典的细胞毒药物：监管审批的狭窄道路》。他认为，优替德隆＋卡培他滨与卡培他滨单药相比的无进展生存令人鼓舞。虽然数据尚不成熟，但是在同一时间点，也显示优替德隆＋卡培他滨与卡培他滨单药相比的总生存更长。不过，在监管部门做出任何批准优替德隆的决策之前，仍然需要成熟的总生存数据。新的治疗药物（例如具有新作用机制和非交叉毒性特征的优替德隆）是有必要的，尤其对于难治性疾病患者。将来，转移性乳腺癌的大型随机研究应该包括能够提供有关总生存结论的统计学计划，研究人群应该限于一组无疑仅需化疗的患者。
Lancet Oncol. 2017 Feb 10. [Epub ahead of print]
Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial.
Pin Zhang, Tao Sun, Qingyuan Zhang, Zhongyu Yuan, Zefei Jiang, Xiao Jia Wang, Shude Cui, Yuee Teng, Xi-Chun Hu, Junlan Yang, Hongming Pan, Zhongsheng Tong, Huiping Li, Qiang Yao, Yongsheng Wang, Yongmei Yin, Ping Sun, Hong Zheng, Jing Cheng, Jinsong Lu, Baochun Zhang, Cuizhi Geng, Jian Liu, Roujun Peng, Min Yan, Shaohua Zhang, Jian Huang, Li Tang, Rongguo Qiu, Binghe Xu, BG01-1323L study group.
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Liaoning Cancer Hospital and Institute, Shenyang, China; Harbin Medical University Cancer Hospital, Harbin, China; Sun Yat-sen University Cancer Center, Guangzhou, China; The 307th Hospital of Chinese PLA, Beijing, China; Zhejiang Cancer Hospital, Hangzhou, China; Breast Cancer Center, Henan Cancer Hospital, Zhengzhou, China; The First Hospital of China Medical University, Shenyang, China; Fudan University Cancer Center, Shanghai, China; The 301st Hospital of Chinese PLA, Beijing, China; Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Tianjin Medical University Cancer Hospital, Tianjin, China; Peking University Cancer Hospital, Beijing, China; Nankai University Tianjin People's Hospital, Tianjin, China; Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China; The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Qingdao University Yantai Yuhuangding Hospital, Yantai, China; Sichuan University West China Hospital, Chengdu, China; Tongji Medical College Wuhan Union Hospital, Wuhan, China; Shanghai Jiaotong University Renji Hospital, Shanghai, China; Nantong Tumor Hospital, Nantong, China; Hebei Medical University Tumor Hospital, Shijiazhuang, China; Fujian Medical University Cancer Hospital, Fuzhou, China; Beijing Biostar Technologies, Beijing, China.
BACKGROUND: Utidelone, a genetically engineered epothilone analogue, has shown promise as a potential treatment for breast cancer in phase 1 and 2 trials. The aim of this phase 3 trial was to compare the efficacy and safety of utidelone plus capecitabine versus capecitabine alone in patients with metastatic breast cancer.
METHODS: We did a multicentre, open-label, superiority, phase 3, randomised controlled trial in 26 hospitals in China. Eligible participants were female patients with metastatic breast cancer refractory to anthracycline and taxane chemotherapy regimens. We randomly assigned participants (2:1) using computer based randomisation and block sizes of 6 to a 21-day cycle of either utidelone (30 mg/m² intravenously once per day on days 1-5) plus capecitabine (1000 mg/m² orally twice per day on days 1-14), or capecitabine alone (1250 mg/m² orally twice per day on days 1-14), until disease progression or unacceptable toxicity occurred. Patients, physicians, and assessors were not masked to treatment allocation; however, an independent radiology review committee used to additionally assess response was masked to allocation. The primary endpoint was centrally assessed (by an independent radiology review committee) progression-free survival, and analysed using the Kaplan-Meier product-limit method in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. Follow-up is ongoing. This study is registered at ClinicalTrials.gov, number NCT02253459.
FINDINGS: Between Aug 8, 2014, and Dec 14, 2015, we enrolled and randomly assigned 270 patients to treatment with utidelone plus capecitabine, and 135 to capecitabine alone. Median follow-up for progression-free survival was 6.77 months (IQR 3.81-10.32) for the utidelone plus capecitabine group and 4.55 months (2.55-9.39) for the capecitabine alone group. Median progression-free survival by central review in the utidelone plus capecitabine group was 8.44 months (95% CI 7.95-9.92) compared with 4.27 months (3.22-5.68) in the capecitabine alone group; hazard ratio 0.46, 95% CI 0.36-0.59; p<0.0001. Peripheral neuropathy was the most common grade 3 adverse event in the utidelone plus capecitabine group (58 [22%] of 267 patients vs 1 [<1%] of 130 patients in the capecitabine alone group). Palmar-plantar erythrodysaesthesia was the most prominent grade 3 adverse event in the capacitabine alone group (in 10 [8%] of 130 patients) and was the next most frequent grade 3 event in the utidelone plus capecitabine group (in 18 [7%] of 267 patients). 16 serious adverse events were reported in the combination therapy group (diarrhoea was the most common, in three [1%] patients) and 14 serious adverse events were reported in the monotherapy group (the most common were diarrhoea, increased blood bilirubin, and anaemia, in two [2%] patients for each event). 155 patients died (99 in the combination therapy arm, 56 in the monotherapy arm). All deaths were related to disease progression except for one in each group (attributed to pericardial effusion in the combination therapy group and dyspnoea in the monotherapy group) that were considered possibly or probably treatment-related.
INTERPRETATION: Despite disease progression with previous chemotherapies, utidelone plus capecitabine was more efficacious compared with capecitabine alone for the outcome of progression-free survival, with mild toxicity except for peripheral sensory neuropathy, which was manageable. The findings from this study support the use of utidelone plus capecitabine as an effective option for patients with metastatic breast cancer.
FUNDING: Beijing Biostar Technologies, Beijing, China.
EVIDENCE BEFORE THIS STUDY
Treatment of metastatic breast cancer often includes anthracyclines and taxanes, but therapeutic response to these drugs is frequently short lived or not achieved, and drug resistance develops frequently. Similar to taxanes, epothilones are a class of microtubule-stabilising anticancer drugs, and have shown promising activity against multidrug-resistant tumours. Ixabepilone, a semi-synthetic epothilone analogue, is the only drug in this class that has been approved by the US Food and Drug Administration in patients with metastatic breast cancer after failure of an anthracycline and a taxane treatment either as monotherapy or in combination with capecitabine. We searched PubMed and congress websites (American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium) with no date limitations for English-language articles with the search terms "breast cancer" OR "recurrent" OR "refractory" OR "drug resistance" OR "pretreated" OR "metastatic". We also used the following search terms to find reports about breast cancer molecular subtypes: "triple negative" OR "HER2 negative" AND "estrogen-receptor negative" OR "ER negative" AND "progesterone-receptor negative" OR "PR negative"; reports of epothilones and microtubule inhibitors: "epothilone" OR "epothilones" OR "epothilone analog" OR "epothilone analogs" OR "epothilone B" OR "ixabepilone" OR "microtubule inhibitor" OR "microtubule inhibitors" OR "eribulin"; and capecitabine: "capecitabine". We also used various combination terms to search for combination studies, with emphasis placed on clinical studies of epothilones, capecitabine, eribulin, and other microtubule dynamic inhibitors, especially phase 2 or phase 3 trials, particularly those supporting drug approvals in the metastatic breast cancer setting.
We also searched the Chinese database for references on clinical trials of epothilones and identified no other publications. Utidelone is the only epothilone drug in China that has completed phase 1, phase 2, and phase 3 studies; with the phase 1 and phase 2 results having been published.
The findings from our previous studies have suggested promising activity in patients with heavily pretreated, drug-resistant, and advanced metastatic breast cancer and manageable adverse effects with utidelone alone or in combination with capecitabine. Additionally, in an open-label, non-comparative phase 2 trial, utidelone in combination with capecitabine showed good efficacy and tolerability, and advantageous safety profiles in the treatment of patients with advanced metastatic breast cancer that was refractory to anthracyclines or taxanes.
ADDED VALUE OF THIS STUDY
The results of our phase 3 study showed that utidelone plus capecitabine significantly improved progression-free survival, the proportion of patients with an objective response, and overall survival compared with capecitabine alone in heavily pretreated patients with metastatic breast cancer. No significant between-group differences were noted for safety outcomes, except for peripheral neuropathy which was significantly higher with utidelone plus capecitabine compared with capecitabine alone. Notably, utidelone caused only very mild myelosuppression and no liver toxicities.
IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE
To our knowledge, ours is the first randomised, multicentre, phase 3 trial of an epothilone analogue initiated and undertaken in China. Furthermore, the combination regimen had a manageable safety profile, with no significant myelosuppression or liver toxicities. These results support the favourable benefit-risk profile of this regimen and offer a new potential option for patients with heavily pretreated metastatic breast cancer, especially for the treatment of metastatic breast cancer that is resistant to anthracyclines and taxanes.
DOI: 10.1016/S1470-2045(17)30088-8
Lancet Oncol. 2017 Feb 10. [Epub ahead of print]
Classic cytotoxic drugs: a narrow path for regulatory approval.
Xavier Pivota.
Université de Franche-Comté Hôpital Jean-Minjoz, Besançon Cedex, France.
New treatments such as utidelone, with new mechanisms of action and non-overlapping toxicity profiles are needed, particularly for patients with refractory disease. In the future, large randomised studies in metastatic breast cancer should include a statistical plan that is able to provide conclusions about overall survival and the population should be restricted to a group of patients that unquestionably require chemotherapy alone.
DOI: 10.1016/S1470-2045(17)30089-X