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Title: Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM).
Author: Hurwitz HI, Tan BR, Reeves JA, Xiong H, Somer B, Lenz HJ, Hochster HS, Scappaticci F, Palma JF, Price R, Lee JJ, Nicholas A, Sommer N, Bendell J.
Journal: Oncologist; 2019 Jul; 24(7):921-932. PubMed ID: 30552157.
Abstract:
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. 摘要 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)，以及 5‐氟尿嘧啶/亚叶酸钙/奥沙利铂 (FOLFOX) 或 5‐氟尿嘧啶/亚叶酸钙/伊立替康 (FOLFIRI)。STEAM (NCT01765582) 评估了BEV 和 FOLFOX/FOLFIRI (FOLFOXIRI) 在同步用药 (cFOLFOXIRI‐BEV) 或序贯用药(sFOLFOXIRI‐BEV，FOLFOX‐BEV 与 FOLFIRI‐BEV 交替使用)的情况下对比 FOLFOX‐BEV 治疗 mCRC 的有效性。 患者和方法。既往未经治疗的 mCRC 患者 (n = 280) 按照 1:1:1 的比例被随机分配使用 cFOLFOXIRI‐BEV、sFOLFOXIRI‐BEV 或 FOLFOX‐BEV，并在进行 4~6 个月的诱导治疗之后接受维持治疗。共同的主要终点为总缓解率(ORR；一线 cFOLFOXIRI‐BEV vs. FOLFOX‐BEV)以及无进展生存期(PFS；联合一线 cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV vs. FOLFOX‐BEV)。次要/探索性终点包括总生存期 (OS)、肝脏切除率、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 个月、11.4 个月和 9.5 个月。组间的 OS 很相似。cFOLFOXIRI‐BEV 和 FOLFOX‐BEV 之间的 ORR 没有显著差异 (p = 0.132)；因此，未达到主要 ORR 终点。无论 RAS 状态如何，cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV 均在数字方面改进了 ORR 和 PFS。联合同步和序贯 FOLFOXIRI‐BEV 对比 FOLFOX‐BEV 的中位 PFS 更高(11.7 个月vs. 9.5 个月；风险比，0.7；90% 置信区间，0.5–0.9；p < 0.01)。肝脏切除率为 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) 的患者中观察到治疗相关的 ≥ 3 级不良反应 (TEAE)，与严重化疗相关的 TEAE 没有增加。 结论。 与 FOLFOX‐BEV 对比而言，cFOLFOXIRI‐BEV 和 sFOLFOXIRI‐BEV 具有良好的耐受性，在数字方面改进了 ORR、PFS 和肝脏切除率，因而支持将三联化疗加 BEV 作为 mCRC 的一线治疗方案。 实践意义:相对于 FOLFIRI‐BEV 或 FOLFOX‐BEV，一线 FOLFIRI 与 FOLFOX 和贝伐单抗(同步 FOLFOXIRI‐BEV)的组合可以为转移性结直肠癌 (mCRC) 患者改进临床结果，但是，该组合方案被认为与毒性增加有关。FOLFOX 和 FOLFIRI(序贯 FOLFOXIRI‐BEV)交替治疗可以提高耐受性。在 II 期 STEAM 试验(即美国患者中最大型的 FOLFOXIRI‐BEV 研究)中，我们发现同步和序贯 FOLFOXIRI‐BEV 对既往未经治疗的 mCRC 患者具有活性和良好的耐受性，因而支持使用此类疗法作为针对此类人群的潜在一线治疗方案。

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