CHICAGO (EGMN) —Maintenance therapy with bevacizumab fell short of statistical non-inferiority to maintenance with standard XELOX chemotherapy plus bevacizumab for metastatic colorectal cancer, but that may not matter when quality of life is considered, according to investigators from the MACRO trial of the Spanish Cooperative Group for the Treatment of Digestive Tumors.
“This study suggests that maintenance therapy with single-agent bevacizumab may be an appropriate treatment option following induction XELOX-bevacizumab in patients with [metastatic] colorectal cancer,” they concluded.
There were no significant differences in overall response rates, progression-free survival, or overall survival between XELOX (capecitabine and oxaliplatin) plus bevacizumab (XELOX-BEV) vs. bevacizumab-alone as maintenance in the randomized trial, Dr. Josep Tabernero explained at the annual meeting of the American Society of Clinical Oncology.
Bevacizumab’s hazard ratio for non-inferiority in progression-free survival was 1.11, which did not meet the trial’s standard of 1.32 after 70% of study events had occurred. “The data indicate that a priori specified non-inferiority cannot still be confirmed, but we can reliably exclude a detriment of larger than 3 weeks in median PFS,” said Dr. Tabernero of Vall d’Hebron University Hospital in Barcelona.
That projected 3-week detriment could actually be much larger, commented Dr. Alan Paul Venook, the invited discussant from the University of California at San Francisco. The upper limit of the confidence interval for the non-inferiority hypothesis was 1.37, which at a median of 10 months would translate into a progression-free survival difference of about 3.7 months favoring XELOX-BEV, he said.
“However, I do agree that given the overall survival results and the quality-of-life that PFS is not terribly relevant in the analysis, and that patients lived the same length of time at the end of the day,” said Dr. Venook.
He pointed out that grade 3 or 4 sensory neuropathy occurred in 24.8% of patients on XELOX-BEV maintenance, compared with 18% of patients on bevacizumab maintenance. The difference reflects the excessive neurotoxicity commonly seen with oxaliplatin, he noted.
The investigators reported that progression-free survival rates were a median of 10.4 months among patients on XELOX-BEV and 9.7 months for those maintained on bevacizumab alone. Median overall survival was 23.4 months for XELOX-BEV and 21.7 months, respectively, and the confirmed overall response rates 46% and 49%, respectively. None of the differences were significant.
The MACRO trial was designed to demonstrate that maintenance with single-agent bevacizumab after 6 cycles of induction XELOX chemotherapy plus bevacizumab could provide good therapeutic efficacy while reducing cumulative toxicities
A total of 480 patients were enrolled and randomized: 239 patients to XELOX-BEV induction plus XELOX-BEV maintenance and 241 patients to the same induction regimen followed by single-agent bevacizumab maintenance at 7.6 mg/kg every 3 weeks. XELOX-BEV consists of oxaliplatin 130 mg/2 IV on day 1; capecitabine 1,000 mg/m2 oral bid on days 1-14, and bevacizumab 7.5 mg IV on day 1 of a 21-day cycle. Patients continued on their assigned maintenance therapies until disease progression, severe toxicities, or consent withdrawal.
The primary end point was progression-free survival. Secondary endpoints included overall survival, objective tumor response by RECIST, time to response, response duration, number of treatment cycles, and safety.
Grade 3/4 adverse events occurred in 53.8% of patients on XELOX-BEV, and 47.9% on bevacizumab alone. More adverse events leading to death (1.7% vs. 3.4%), and deaths within 60 days (1.7% vs. 2.5%) occurred in the bevacizumab arm.
The median number of total cycles received per patient was 9 for XELOX-BEV, and 10 for bevacizumab only. Median cumulative oxaliplatin dose exposures were 800 mg/m2 and 770 mg/m2, respectively. Salvage surgery was performed in 11.7% on XELOX-BEV (8.8% R0 resections) and 9.5% on bevacizumab (5.8% R0).
Other studies evaluating bevacizumab maintenance after standard chemotherapy in metastatic colorectal cancer are either currently recruiting patients or are under evaluation, Dr. Tabernero noted. These trials include DREAM, CAIRO-3, and AIO-ML21768.
The MACRO study was supported by Roche and Sanofi-Aventis. Dr. Taberno is a consultant/advisor to the companies and to Amgen, Bayer, Biogen Idec, Bristol-Myers Squibb, Merck KGaA, Novartis, Onyx, and Pfizer. He has received honoraria from Amgen, Bayer, Merck KGaA, Roche and Sanofi-Aventis. Dr. Venook serves as a consultant/advisor to GlobeImmune and Light Sciences Oncology, and has received honoraria from Amgen, Bayer, Genentech, GlaxoSmithKline, ImClone Systems, Novartis, Onyx, and Pfizer.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
芝加哥(EGMN)——据西班牙消化道肿瘤治疗协作组的MACRO试验研究者称，在转移性直结肠癌的维持治疗方面，与标准的XELOX化疗加贝伐单抗相比，贝伐单抗单药治疗未达到统计学上的非劣效性，但是，当考虑到生活质量时，以上结果可能并不重要。
他们总结说：“该研究表明，贝伐单抗单药维持治疗可能是转移性直结肠癌患者XELOX加贝伐单抗诱导治疗后合理的治疗选择。”
Josep Tabernero博士在美国临床肿瘤学会年会上解释说，在这项随机试验中，XELOX(卡培他滨加奥沙利铂)联合贝伐单抗(XELOX-BEV)维持治疗与贝伐单抗单药维持治疗之间在总有效率、无进展生存期或总生存期方面无显著差异。
贝伐单抗的无进展生存非劣效性危险比(HR)为1.11，未达到该研究设定的70%的研究事件发生后HR=1.32的标准。巴塞罗那Vall d’Hebron 大学医院的Tabernero博士说：“数据表明，之前阐释的非劣效性仍无法得到证实，但我们确实能排除中位PFS减少3周以上的不利情况。”
旧金山加州大学的特邀评论员Alan Paul Venook评论道，所反映出的减少3周的不利情况可能实际上会更严重。非劣效性假设的可信区间上限为1.37，中位生存期为10个月时，可理解为无进展生存期差异大约为3.7个月，这支持采用XELOX-BEV治疗，他说。
Venook博士说：“然而，我确实同意，考虑到这项分析的总生存结果和生活质量，PFS并无多大意义，患者最终的生活时间是等长的。”
他指出，接受XELOX-BEV 维持治疗的患者中有24.8%发生了3级或4级感觉神经病变，而接受贝伐单抗维持治疗的患者中有18%。这种差异反映了过度的神经不良反应，后者常见于采用奥沙利铂治疗时。
研究者报告，接受XELOX-BEV维持治疗的患者中位无进展生存期为10.4个月，而接受贝伐单抗单药维持治疗者为9.7个月；前者中位总生存期为23.4个月，而后者为21.7个月，两者经证实的总有效率分别为46%和49%。上述差异均无统计学意义。
MACRO试验旨在证实在6个周期的XELOX化疗联合贝伐单抗诱导治疗后采用贝伐单抗单药维持治疗能够产生良好的治疗效益，同时又可减少蓄积毒性。
共有480例患者入选本研究并接受随机分组：239例患者被分配至XELOX-BEV诱导治疗加XELOX-BEV维持治疗，241例患者被分配接受相同的诱导治疗方案继以贝伐单抗单药维持治疗，剂量为7.6 mg/kg，每3周进行1次。XELOX-BEV由第1天静脉给予奥沙利铂130 mg/m2、第1~14天口服卡培他滨1,000 mg/m2，1天2次、第1天静脉给予7.5 mg贝伐单抗构成，21天为1个周期。患者在病情进展、出现严重不良反应或撤出知情同意书前保持所分配的维持治疗方案。
主要终点为无进展生存期。次要终点包括总生存期、根据RECIST判定的客观有效率、起效时间、疗效持续时间、疗程数及安全性。
XELOX-BEV 治疗组3~4级不良事件发生率为53.8%，而贝伐单抗单药治疗组为47.9%。60天内，贝伐单抗单药治疗组致死性不良事件发生率较高(1.7% 对3.4%)，死亡率亦较高(1.7% 对 2.5%)。
XELOX-BEV治疗组与贝伐单抗单药治疗组每例患者接受的中位总周期数分别为9和10，奥沙利铂中位累计用药剂量分别为800 mg/m2 和770 mg/m2，行抢救手术率分别为11.7% (8.8% R0切除术)和9.5%(5.8% R0切除术)。
评估转移性直结肠癌标准化疗后贝伐单抗维持治疗的其他研究目前正处于招募受试者阶段或处于评估之中，Tabernero博士指出，其中包括DREAM、CAIRO-3以及 AIO-ML21768研究。
MACRO研究得到罗氏和赛诺菲安万特公司的支持。Taberno博士是这些公司及安进、拜耳、Biogen Idec、百时美施贵宝、默克、诺华、Onyx以及辉瑞等公司的顾问。他本人收到安进、拜耳、默克、罗氏及赛诺菲安万特的酬金。Venook博士担任GlobeImmune公司及Light Sciences Oncology公司的顾问，并收到安进、拜耳、基因泰克、葛兰素史克、ImClone Systems、诺华、Onyx及辉瑞公司的酬金。
爱思唯尔 版权所有
