FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial
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DOI：
10.1016/s1470-2045(16)30269-8
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发表时间：
2016-10-01
期刊：
影响因子：
51.1
通讯作者：
Heinemann, Volker
中科院分区：
文献类型：
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作者：
Stintzing, Sebastian;Modest, Dominik P.;Heinemann, Volker
FIRE-3比较了一线5-氟尿嘧啶、亚叶酸钙和伊立替康（FOLFIRI）联合西妥昔单抗与FOLFIRI联合贝伐单抗治疗KRAS外显子2野生型转移性结直肠癌患者的疗效。同一研究还报告了对其他RAS基因（KRAS和NRAS外显子2 - 4）为野生型的肿瘤患者亚组的探索性分析。我们在此报告FIRE-3最终RAS（KRAS/NRAS，外显子2 - 4）野生型亚组的疗效结果。此外，委员会认为，在一项集中放射学回顾中探讨了肿瘤动力学的新指标，以研究FOLFIRI联合西妥昔单抗如何在没有化疗评估的客观缓解和无进展生存率差异的情况下提供总生存率获益。转移性结直肠癌FIRE-3研究的主要终点是意向治疗人群中根据实体瘤疗效评价标准（RECIST）1.0达到客观缓解的患者比例。在事后分析中对CT扫描进行了集中放射学审查，以根据RECIST1.1评估最终RAS野生型亚组的客观缓解、早期肿瘤缩小、缓解深度、缓解持续时间和至缓解时间。使用Fisher精确检验（双侧）比较治疗组之间的客观缓解率和早期肿瘤缩小，而使用双侧Wilcoxon检验研究缓解深度的差异。本试验在ClinicalTrials注册。结果在最终的RAS野生型人群（n = 400）中，FOLFIRI联合西妥昔单抗组的中位总生存期优于FOLFIRI联合贝伐单抗组（33.1个月[95% CI 24.5 - 39.4] vs 25.0个月[23.0 - 28.1];风险比0.70 [0.54 - 0.90]; p = 0.0059），尽管治疗组之间的评估者评估的客观缓解和无进展生存期相当。CT可评估患者（n = 330）的集中放射学审查显示，达到客观缓解的患者比例（113/157，72.0%[95% CI 64.3 - 78.8] vs 97/173，56.1%[48.3 - 63.6]; p = 0.0029），早期肿瘤缩小的频率（157例中的107例，68.2%[60.3 - 75.4] vs 173例中的85例，49.1%[41.5 - 56.8]; p = 0.0005）和中位反应深度（-48.9%[-54.3至-42.0] vs-32.3%[-38.2至-29.2]; p
Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes (KRAS and NRAS exons 2-4). We report here efficacy results for the FIRE-3 final RAS (KRAS/NRAS, exons 2-4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival.Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials. gov, number NCT00433927.Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33.1 months [95% CI 24.5-39.4] vs 25.0 months [23.0-28.1]; hazard ratio 0.70 [0.54-0.90]; p=0.0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72.0% [95% CI 64.3-78.8] vs 97 of 173, 56.1% [48.3-63.6]; p= 0.0029), frequency of early tumour shrinkage (107 of 157, 68.2% [60.3-75.4] vs 85 of 173, 49.1% [41.5-56.8]; p= 0.0005), and median depth of response (-48.9% [-54.3 to -42.0] vs-32.3% [-38.2 to -29.2]; p