Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program.
Sunitinib added to FOLFIRI versus FOLFIRI in patients with chemorefractory advanced adenocarcinoma of the stomach or lower esophagus: a randomized, placebo-controlled phase II AIO trial with serum biomarker program.
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DOI：
10.1186/s12885-016-2736-9
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发表时间：
2016-08-31
期刊：
影响因子：
3.8
通讯作者：
Galle PR
中科院分区：
文献类型：
--
作者：
Moehler M;Gepfner-Tuma I;Maderer A;Thuss-Patience PC;Ruessel J;Hegewisch-Becker S;Wilke H;Al-Batran SE;Rafiyan MR;Weißinger F;Schmoll HJ;Kullmann F;von Weikersthal LF;Siveke JT;Weusmann J;Kanzler S;Schimanski CC;Otte M;Schollenberger L;Koenig J;Galle PR
舒尼替尼（sunitinib， SUN）作为一种多靶点抗血管生成受体酪氨酸激酶（RTK）抑制剂，已被证实用于治疗肾癌和胃肠道间质瘤。在晚期难治性食管胃癌患者中，SUN单药治疗具有良好的耐受性，但肿瘤反应有限。这项双盲、安慰剂对照、多中心、II期临床试验旨在评估SUN作为二线和三线FOLFIRI （NCT01020630）辅助治疗的有效性、安全性和耐受性。患者随机接受6周周期的治疗，包括每两周一次的FOLFIRI加亚叶酸钠（Na-FOLFIRI）和连续4周的SUN或安慰剂（PL），随后是2周的休息期。主要研究终点为无进展生存期（PFS）。回顾性分析预先计划的血清VEGF-A、VEGF-D、VEGFR2和SDF-1α。总共91例患者被随机分组，每组45例（1例患者退出）。≥3级ae主要为中性粒细胞减少症和白细胞减少症，FOLFIRI + SUN/FOLFIRI + PL分别为56% / 20%和27% / 16%。FOLFIRI + SUN和FOLFIRI + PL的中位PFS相似，分别为3.5个月和3.3个月（风险比（HR） 1.11, 95% CI 0.70-1.74, P = 0.66）。对于FOLFIRI + SUN，与安慰剂相比，观察到中位总生存期（OS）更长（10.4个月vs 8.9个月，HR 0.82, 95% CI 0.50-1.34，单侧P = 0.21）。在亚组血清分析中，观察到VEGF-A （P = 0.017）、VEGFR2 （P = 0.012）和VEGF-D （P < 0.001）血清水平的显著变化。虽然舒尼替尼联合FOLFIRI没有改善化疗耐药胃癌的PFS和反应，但观察到更好的OS趋势。进一步的生物标志物驱动的研究与其他抗血管生成RTK抑制剂是必要的。该研究在美因茨莱茵兰-普法尔茨医学协会主要伦理委员会于2009年9月16日与参与的伦理委员会（见附加文件2）协调批准后，于2009年11月23日在NCT临床试验登记处（ClinicalTrials.gov）注册，编号NCT01020630。本文的在线版本（doi:10.1186/s12885-016-2736-9）包含补充材料，授权用户可以使用。
As a multi-targeted anti-angiogenic receptor tyrosine kinase (RTK) inhibitor sunitinib (SUN) has been established for renal cancer and gastrointestinal stromal tumors. In advanced refractory esophagogastric cancer patients, monotherapy with SUN was associated with good tolerability but limited tumor response. This double-blind, placebo-controlled, multicenter, phase II clinical trial was conducted to evaluate the efficacy, safety and tolerability of SUN as an adjunct to second and third-line FOLFIRI (NCT01020630). Patients were randomized to receive 6-week cycles including FOLFIRI plus sodium folinate (Na-FOLFIRI) once every two weeks and SUN or placebo (PL) continuously for four weeks followed by a 2-week rest period. The primary study endpoint was progression-free survival (PFS). Preplanned serum analyses of VEGF-A, VEGF-D, VEGFR2 and SDF-1α were performed retrospectively. Overall, 91 patients were randomized, 45 in each group (one patient withdrew). The main grade ≥3 AEs were neutropenia and leucopenia, observed in 56 %/20 % and 27 %/16 % for FOLFIRI + SUN/FOLFIRI + PL, respectively. Median PFS was similar, 3.5 vs. 3.3 months (hazard ratio (HR) 1.11, 95 % CI 0.70–1.74, P = 0.66) for FOLFIRI + SUN vs. FOLFIRI + PL, respectively. For FOLFIRI + SUN, a trend towards longer median overall survival (OS) compared with placebo was observed (10.4 vs. 8.9 months, HR 0.82, 95 % CI 0.50–1.34, one-sided P = 0.21). In subgroup serum analyses, significant changes in VEGF-A (P = 0.017), VEGFR2 (P = 0.012) and VEGF-D (P < 0.001) serum levels were observed. Although sunitinib combined with FOLFIRI did not improve PFS and response in chemotherapy-resistant gastric cancer, a trend towards better OS was observed. Further biomarker-driven studies with other anti-angiogenic RTK inhibitors are warranted. This study was registered prospectively in the NCT Clinical Trials Registry (ClinicalTrials.gov) under NCT01020630 on November 23, 2009 after approval by the leading ethics committee of the Medical Association of Rhineland-Palatinate, Mainz, in coordination with the participating ethics committees (see Additional file 2) on September 16, 2009. The online version of this article (doi:10.1186/s12885-016-2736-9) contains supplementary material, which is available to authorized users.
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