Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM)
Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM)
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DOI：
10.1634/theoncologist.2018-0344
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发表时间：
2019-07-01
期刊：
影响因子：
5.8
通讯作者：
Bendell, Johanna
中科院分区：
文献类型：
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作者：
Hurwitz, Herbert, I;Tan, Benjamin R.;Bendell, Johanna
背景转移性结直肠癌（mCRC）的一线治疗通常需要生物制剂，如贝伐单抗（BEV）联合5-氟尿嘧啶/亚叶酸/奥沙利铂（FOLFOX）或5-氟尿嘧啶/亚叶酸/伊立替康（FOLFIRI）。STEAM（NCT 01765582）评估了BEV + FOLFOX/FOLFIRI（FOLFOXIRI）联合给药（cFOLFOXIRI-BEV）或序贯给药（sFOLFOXIRI-BEV，FOLFOX-BEV与FOLFIRI-BEV交替）与FOLFOX-BEV治疗mCRC的疗效。患者和方法既往未经治疗的mCRC患者（n = 280）以1：1：1的比例随机分配至cFOLFOXIRI-BEV、sFOLFOXIRI-BEV或FOLFOX-BEV组，并接受4-6个月的诱导治疗，随后维持治疗。共同主要目的是总缓解率（ORR;一线cFOLFOXIRI-BEV vs. FOLFOX-BEV）和无进展生存期（PFS;合并一线cFOLFOXIRI-BEV和sFOLFOXIRI-BEV vs. FOLFOX-BEV）。次要/探索性目的包括总生存期（OS）、肝切除率、生物标志物分析和安全性。结果cFOLFOXIRI-BEV、sFOLFOXIRI-BEV和FOLFOX-BEV的ORR分别为72.0%、72.8%和62.1%，中位PFS分别为11.9、11.4和9.5个月。两组的OS相似。cFOLFOXIRI-BEV和FOLFOX-BEV之间的ORR无显著差异（p = 0.132）;因此，未达到主要ORR终点。cFOLFOXIRI-BEV和sFOLFOXIRI-BEV在数值上改善了ORR和PFS，无论RAS状态如何。合并并行和序贯FOLFOXIRI-BEV的中位PFS高于FOLFOX-BEV（11.7 vs 9.5个月;风险比，0.7; 90%置信区间，0.5-0.9; p <0.01）。肝切除率分别为17.2%（cFOLFOXIRI-BEV）、9.8%（sFOLFOXIRI-BEV）和8.4%（FOLFOX-BEV）。在91.2%（cFOLFOXIRI-BEV）、86.7%（sFOLFOXIRI-BEV）和85.6%（FOLFOX-BEV）的患者中观察到≥ 3级治疗后出现的不良事件（TEAE），严重化疗相关TEAE未增加。结论cFOLFOXIRI-BEV和sFOLFOXIRI-BEV耐受性良好，与FOLFOX-BEV相比，ORR、PFS和肝切除率在数值上有所改善，支持三联化疗加BEV作为mCRC的一线治疗选择。与FOLFIRI-BEV或FOLFOX-BEV相比，一线FOLFIRI联合FOLFOX和贝伐单抗（同时FOLFOXIR-BEV）可改善转移性结直肠癌（mCRC）患者的临床结局，但被认为与毒性增加相关。FOLFOX和FOLFIRI交替治疗（序贯FOLFOXIRI-BEV）可改善耐受性。在II期STEAM试验中，这是美国最大的FOLFOXIRI-BEV患者研究，研究发现，在既往未经治疗的mCRC患者中，同时和序贯FOLFOXIRI-BEV均具有活性且耐受性良好，支持将这些方案用作该人群的潜在一线治疗选择。
Background First-line treatment for metastatic colorectal cancer (mCRC) typically entails a biologic such as bevacizumab (BEV) with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI). STEAM (NCT01765582) assessed the efficacy of BEV plus FOLFOX/FOLFIRI (FOLFOXIRI), administered concurrently (cFOLFOXIRI-BEV) or sequentially (sFOLFOXIRI-BEV, FOLFOX-BEV alternating with FOLFIRI-BEV), versus FOLFOX-BEV for mCRC. Patients and Methods Patients with previously untreated mCRC (n = 280) were randomized 1:1:1 to cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, or FOLFOX-BEV and treated with 4-6-month induction followed by maintenance. Coprimary objectives were overall response rate (ORR; first-line cFOLFOXIRI-BEV vs. FOLFOX-BEV) and progression-free survival (PFS; pooled first-line cFOLFOXIRI-BEV and sFOLFOXIRI-BEV vs. FOLFOX-BEV). Secondary/exploratory objectives included overall survival (OS), liver resection rates, biomarker analyses, and safety. Results ORR was 72.0%, 72.8%, and 62.1% and median PFS was 11.9, 11.4, and 9.5 months with cFOLFOXIRI-BEV, sFOLFOXIRI-BEV, and FOLFOX-BEV, respectively. OS was similar between arms. ORR between cFOLFOXIRI-BEV and FOLFOX-BEV did not significantly differ (p = .132); thus, the primary ORR endpoint was not met. cFOLFOXIRI-BEV and sFOLFOXIRI-BEV numerically improved ORR and PFS, regardless of RAS status. Median PFS was higher with pooled concurrent and sequential FOLFOXIRI-BEV versus FOLFOX-BEV (11.7 vs. 9.5 months; hazard ratio, 0.7; 90% confidence interval, 0.5-0.9; p < .01). Liver resection rates were 17.2% (cFOLFOXIRI-BEV), 9.8% (sFOLFOXIRI-BEV), and 8.4% (FOLFOX-BEV). Grade >= 3 treatment-emergent adverse events (TEAEs) were observed in 91.2% (cFOLFOXIRI-BEV), 86.7% (sFOLFOXIRI-BEV), and 85.6% (FOLFOX-BEV) of patients, with no increase in serious chemotherapy-associated TEAEs. Conclusion cFOLFOXIRI-BEV and sFOLFOXIRI-BEV were well tolerated with numerically improved ORR, PFS, and liver resection rates versus FOLFOX-BEV, supporting triplet chemotherapy plus BEV as a first-line treatment option for mCRC. Implications for Practice The combination of first-line FOLFIRI with FOLFOX and bevacizumab (concurrent FOLFOXIRI-BEV) improves clinical outcomes in patients with metastatic colorectal cancer (mCRC) relative to FOLFIRI-BEV or FOLFOX-BEV, but it is thought to be associated with increased toxicity. Alternating treatment of FOLFOX and FOLFIRI (sequential FOLFOXIRI-BEV) could improve tolerability. In the phase II STEAM trial, which is the largest study of FOLFOXIRI-BEV in patients in the U.S., it was found that both concurrent and sequential FOLFOXIRI-BEV are active and well tolerated in patients with previously untreated mCRC, supporting the use of these regimens as potential first-line treatment options for this population.