CMAB009联合伊立替康或伊立替康单药二线治疗氟嘧啶和奥沙利铂治疗失败的KRAS野生型转移性结直肠癌患者的研究:一项前瞻性、开放、随机、Ⅲ期试验

背景与目的5-氟尿嘧啶/左亚叶酸钙联合奥沙利铂(5-fluorouracil/leucovorin plus oxaliplatin,FOLFOX)方案是转移性结直肠癌(metastatic colorectal cancer,mCRC)的标准一线治疗方案,但KRAS野生型mCRC患者的最佳二线治疗方案仍在研究中。在本研究中,我们旨在探索CMAB009联合伊立替康二线治疗KRAS野生型mCRC患者的临床疗效和安全性。方法将FOLFOX治疗失败的KRAS野生型mCRC患者按照2∶1比例随机分组,接受CMAB009联合伊立替康或伊立替康单药治疗。伊立替康单药治疗的患者在疾病进展时可转为CMAB009治疗,分为CMAB009序贯治疗组。主要终点为总缓解率(overall response rate,ORR)和中位无进展生存期(progression-free survival,PFS)。次要终点为中位总生存期(overall survival,OS)、疾病控制率(disease control rate,DCR)、临床获益率(clinical benefit rate,CBR)和缓解持续时间(duration of response,DOR)。结果CMAB009联合伊立替康治疗组与伊立替康单药治疗组相比,ORR显著提高(33.2%vs.12.8%;P<0.001),中位PFS延长(169 d vs.95 d;P<0.001),DCR(80.1%vs.65.2%,P<0.001)、CBR(30.0%vs.14.6%,P<0.001)和DOR(210 d vs.109 d;P<0.001)均有所改善。然而,接受CMAB009治疗的患者出现皮疹(66.9%vs.5.5%,P<0.001)和甲沟炎(9.8%vs.0.0%,P<0.001)的风险增加。3.6%的患者检测出抗药抗体(antidrug antibodies,ADA),接受CMAB009治疗的患者中仅有0.9%出现过敏反应。伊立替康治疗失败后CMAB009序贯治疗患者的中位PFS为84 d(95%CI:65–113 d)。CMAB009联合伊立替康治疗患者的中位OS为425 d,而CMAB009序贯治疗组患者的中位OS为401 d(P=0.940)。结论对于KRAS野生型mCRC患者,CMAB009联合伊立替康的二线治疗方案优于伊立替康单药治疗方案。此外,伊立替康单药二线治疗失败改用CMAB009序贯治疗可作为一种有效的三线治疗方案。临床实验注册号:NCT01550055,回顾性注册于2012年3月9日。

CMAB009 plus irinotecan versus irinotecan-only as second-line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild-type metastatic colorectal cancer patients:promising findings from a prospective,open-label,randomized,phase III trial

Background:The 5-fluorouracil/leucovorin plus oxaliplatin(FOLFOX)regimen is the standard first-line treatment for metastatic colorectal cancer(mCRC),however,the optimal second-line regimen for KRAS wild-type mCRC patients is still investigational.In this study,we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan-only as a second-line regimen for treating KRAS wild-type mCRC patients.Methods:Patients with KRAS wild-type mCRC who had previously failed to respond to FOLFOX treatment were ran-domly assigned in a 2:1 ratio,to receive CMAB009 plus irinotecan or irinotecan-only.Patients receiving irinotecan-only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential-CMAB009 arm.The primary endpoints were overall response rate(ORR)and median progression-free survival(PFS).The second-ary endpoints were median overall survival(OS),disease control rate(DCR),clinical benefit rate(CBR),and duration of response(DOR).Results:The CMAB009 plus irinotecan arm demonstrated significantly improved ORR(33.2%vs.12.8%;P<0.001)and longer median PFS(169 days vs.95 days;P<0.001)as compared to the irinotecan-only arm.Patients receiv-ing CMAB009 plus irinotecan also demonstrated improved DCR(80.1%vs.65.2%,P<0.001),CBR(30.0%vs.14.6%,P<0.001),and DOR(210 days vs.109 days;P<0.001)as compared to irinotecan-only.However,patients treated with CMAB009 had an increased risk of skin rash(66.9%vs.5.5%,P<0.001)and paronychia(9.8%vs.0.0%,P<0.001).Anti-drug antibodies(ADA)were detected in 3.6%of patients,and only 0.9%of patients who received CMAB009 experienced hypersensitivity reactions.In patients receiving sequential-CMAB009 therapy after failure with irinotecan,their median PFS was 84 days (95% CI 65 to 113 days). The median OS was 425 days for patients receiving CMAB009 plus irinotecan and 401 days for those with sequential-CMAB009 (P = 0.940). Conclusions: Treatment with CMAB009 plus irinotecan was found to be a superior second-line regimen in com-parison to irinotecan-only in KRAS wild-type mCRC patients. Further, switching to CMAB009 can be considered as an efficient third-line of treatment after treatment failure with second-line irinotecan-only. Trial registration ClinicalTrials.gov: NCT01550055, retrospectively registered on March 9, 2012.

多糖基化位点抗体药物质控中基于单四级杆的多属性分析方法开发与验证

抗体药物已经成为生物制品的重要组成部分,此类产品具有复杂的质量属性,尤其是具有多糖基化位点的抗体药物,其质量控制面临更高挑战。虽然基于高分辨质谱的多属性分析方法(Multi-attribute method,MAM)已在抗体药物的质控中获得应用,但针对多糖基化位点抗体药物的快速且简便的检测技术仍较为少见。开发一种基于单四级杆的多属性分析方法,对于提升这类药物的质控效率具有重要意义。本研究以双糖基化位点的治疗类单抗CMAB009为模型。通过基于高分辨质谱的MAM对其进行了深入的预表征分析,成功获取了其主要质量属性。随后将预表征信息用于基于单四级杆的MAM开发。该方法在单次分析中有效监测了多种产品质量属性,其准确性通过基于高分辨质谱的方法进行了确认。随后我们对该方法进行了严格的方法学验证。验证结果显示,该方法具有良好的专属性、线性、准确度以及精密度等。基于单四级杆的MAM不仅有效地解决了多糖基化位点单抗药物的多属性检测难题,还展示了一定的方法普适性,为不同糖基化位点抗体药物的质量控制提供了一种新的、简便的技术方案。本研究结果预计将推动相关技术平台的改进和理念的更新,从而增强产品开发和质控的整体能力。