中国原创新药重归国际乳腺癌学术舞台
前情提要
中国原创新药优替德隆（优替帝）是通过基因工程合成的埃博霉素类细胞微管抑制剂，作用机制与紫杉类相似，可阻止肿瘤细胞分裂增殖、促进肿瘤细胞凋亡、抑制肿瘤血管生成，但结合位点不完全一致、亲和力更强，三期临床研究初步分析结果表明可显著改善化疗耐药型晚期乳腺癌患者的无进展生存和客观缓解率，故先后登上过2016年和2018年美国临床肿瘤年会、2017年英国《柳叶刀》肿瘤学分册。随后，优替德隆就如泥牛入海再无消息，而2017年才登上国际学术舞台的中国原创新药吡咯替尼，已于2018年以二期临床研究提前上市，如今已是如日中天。不过，今年双十一，优替德隆回到了国际乳腺癌学术舞台。
2020年11月11日，欧洲肿瘤内科学会《肿瘤学报》在线发表中国医学科学院肿瘤医院徐兵河和张频、中国医科大学辽宁省肿瘤医院孙涛、哈尔滨医科大学黑龙江省肿瘤医院张清媛、中山大学肿瘤医院袁中玉、解放军总医院第五医学中心江泽飞、中国科学院大学浙江省肿瘤医院王晓稼、郑州大学河南省肿瘤医院崔树德、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、天津医科大学肿瘤医院佟仲生、北京大学肿瘤医院李惠平、南开大学天津市人民医院姚嫱、山东大学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、福建医科大学福建省肿瘤医院刘健、上海交通大学医学院附属瑞金医院沈坤炜、华中科技大学同济医学院附属同济医院于世英、电子科技大学医学院四川省肿瘤医院李卉、北京华昊中天生物技术有限公司唐莉和邱荣国等学者的BG01-1323L研究报告，对优替德隆＋卡培他滨治疗蒽环类和紫杉类耐药型晚期乳腺癌患者的总生存以及其他指标进行了最终分析。
BG01-1323L (NCT02253459): Phase III Clinical Trials of UTD1 Injection Plus Capecitabine Versus Capecitabine Alone in Patients With Advanced and Metastatic Breast Cancer
该多中心非盲优效随机对照三期临床研究于2014年8月8日～2015年12月14日从全国26家医院入组蒽环类和紫杉类化疗方案治疗失败的晚期乳腺癌女性患者405例，按2∶1的比例随机分为两组：
联合治疗组270例（完成至少2轮治疗243例）每21天第1～14天每天2次口服卡培他滨1000mg/m²、第1～5天每天1次静脉注射优替德隆30mg/m²超过90分钟
单药治疗组135例（完成至少2轮治疗116例）每21天第1～14天每天2次口服卡培他滨1250mg/m²
治疗直至疾病进展或毒性反应无法耐受。主要终点为无进展生存，次要终点包括总生存结局、客观缓解率、药物安全性。预设死亡事件超过310例时，通过生存曲线分析总生存结局。
结果，截至2018年12月15日，死亡事件共计313例。
对于全部入组患者，优替德隆＋卡培他滨与卡培他滨单药相比：
总死亡比例：75.2%比81.5%
中位总生存：19.8个月比16.0个月
总死亡风险：减少25%（风险比：0.75，95%置信区间：0.59～0.94，P=0.0142）
进展死亡比例：79.3%比85.2%
中位无进展生存：8.4个月比4.1个月
进展死亡风险：减少53%（风险比：0.47，95%置信区间：0.37～0.59，P<0.0001）
客观缓解率：45.6%比23.7%（P<0.0001）
对于完成至少2轮治疗患者，优替德隆＋卡培他滨与卡培他滨单药相比：
总死亡比例：74.9%比85.3%
中位总生存：20.9个月比15.7个月
总死亡风险：减少31%（风险比：0.69，95%置信区间：0.54～0.89，P=0.0032）
进展死亡比例：81.1%比81.5%
中位无进展生存：8.6个月比4.1个月
进展死亡风险：减少54%（风险比：0.46，95%置信区间：0.36～0.58，P<0.0001）
客观缓解率：49.8%比26.7%（P<0.001）
毒性反应发生率、严重性和特异性等安全性结果与初步报道相似，未见新出现的毒性反应或新的安全问题。优替德隆仅引起轻度骨髓抑制，而无明显肝脏毒性。虽然周围神经病变发生率较高，但是对剂量进行调整后，通常可控可逆。
因此，该研究结果表明，对于蒽环类和紫杉类耐药的难治型晚期乳腺癌患者，卡培他滨±优替德隆相比，总生存、无进展生存、客观缓解率显著较好。这些结果支持优替德隆＋卡培他滨作为治疗晚期乳腺癌患者的新方案。
Ann Oncol. 2020 Nov 11. Online ahead of print.
Efficacy of utidelone plus capecitabine versus capecitabine for heavily pretreated, anthracycline- and taxane-refractory metastatic breast cancer: final analysis of overall survival in a phase 3 randomised controlled trial.
Xu B, Sun T, Zhang Q, Zhang P, Yuan Z, Jiang Z, Wang X, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Shen K, Yu S, Li H, Tang L, Qiu R; Study group of BG01-1323L.
National Cancer Centre/National Clinical Research Centre for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China; Harbin Medical University Cancer Hospital, Harbin, China; Sun Yat-sen University Cancer Centre, Guangzhou, China; The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China; Zhejiang Cancer Hospital, Hangzhou, China; Henan Cancer Hospital, Zhengzhou, China; The First Hospital of China Medical University, Shenyang, China; Fudan University Cancer Center, Shanghai, China; The PLA General Hospital, Beijing, China; Sir 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 Tianjing People's Hospital, Tianjing, 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; Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China; Sichuan Cancer Hospital, Chengdu, China; Beijing Biostar Technologies, Beijing, China.
HIGHLIGHTS
The phase 3 study evaluated utidelone plus CAP versus CAP alone in patients with anthracycline- and taxane-refractory MBC.
In this final analysis of OS, utidelone plus CAP significantly improved OS compared with CAP alone.
No significant differences were observed in the safety profiles of the treatment groups.
Of note, utidelone caused only mild myelosuppression and no significant hepatic toxicity.
Although peripheral neuropathy was common, it was generally manageable and reversible with dose modifications.
BACKGROUND: Primary analysis of the phase 3 trial BG01-1323L demonstrated that utidelone plus capecitabine significantly improved progression-free survival (PFS) and overall response rate (ORR) vs capecitabine alone in heavily pretreated patients with metastatic breast cancer (MBC). Here, we report the final overall survival (OS) analysis and updates of other endpoints.
PATIENTS AND METHODS: In total, 405 patients were randomised 2:1 to receive utidelone (30 mg/m 2 IV daily, days 1-5, over 90 minutes) plus capecitabine (1000 mg/m 2 orally bid, days 1-14) or capecitabine alone (1250 mg/m 2 orally bid, days 1-14) every 21 days. The secondary endpoint, OS, was estimated using the Kaplan-Meier product-limit approach at a two-sided alpha level of 0.05 after the pre-specified 310 death events had been reached. Exploratory analyses of the primary endpoint, PFS, and the secondary endpoint, ORR, were also done. Safety was analysed in patients who had at least one dose of study drug.
RESULTS: At the final OS analysis, the median duration of follow up was 19.6 months in the utidelone plus capecitabine group and 15.4 months in the capecitabine alone group. In the intention-to-treat population, 313 deaths had occurred at data cut-off, 203 of 270 patients in the combination group and 110 of 135 in the monotherapy group. Median OS in the combination group was 19.8 months compared with 16.0 months in the monotherapy group (hazard ratio [HR]=0.75, 95% CI 0.59-0.94, P=0.0142). The updated analysis of PFS and ORR showed that the combination therapy remained superior to monotherapy. Safety results were similar to those previously reported with respect to incidence, severity and specificity. No late-emerging toxicities or new safety concerns occurred.
CONCLUSIONS: For heavily pretreated, anthracycline- and taxane-resistant MBC patients, utidelone plus capecitabine significantly improved OS vs capecitabine alone. These results support the use of utidelone plus capecitabine as a novel therapeutic regimen for patients with MBC.
KEYWORDS: utidelone; capecitabine; metastatic breast cancer; overall survival; anthracycline- and taxane-refractory
DOI: 10.1016/j.annonc.2020.10.600