Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis.
Upfront, randomized, phase 2 trial of sorafenib versus sorafenib and low-dose interferon alfa in patients with advanced renal cell carcinoma: clinical and biomarker analysis.
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DOI：
10.1002/cncr.24685
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发表时间：
2010-01-01
期刊：
影响因子：
6.2
通讯作者：
Tannir NM
中科院分区：
文献类型：
--
作者：
Jonasch E;Corn P;Pagliaro LC;Warneke CL;Johnson MM;Tamboli P;Ng C;Aparicio A;Ashe RG;Wright JJ;Tannir NM
本研究的目的是独立评估索拉非尼和索拉非尼加低剂量干扰素-α 2b (IFN) 作为一线治疗转移性肾细胞癌 (mRCC) 患者的客观缓解率。未经治疗的透明细胞 mRCC 患者随机接受索拉非尼 400 mg 口服，每日两次，或索拉非尼 400 mg 口服，每日两次加皮下注射 IFN 0.5 百万 U (MU) 每日两次。主要终点包括客观缓解率（ORR）和安全性。次要终点包括无进展生存期（PFS）和总生存期（OS）。探索性终点包括肿瘤组织生物标志物的预测价值。八十名患者被招募。中位随访时间为 19.7 个月（范围：0-34.2 个月）。索拉非尼组的 ORR 为 30%（95% 置信区间 [CI]，16.6%–46.5%），联合治疗组的 ORR 为 25%（95% CI，12.7%–41.2%）。索拉非尼单独治疗组的中位 PFS 为 7.39 个月（95% CI，5.52-9.20 个月），索拉非尼加 IFN 治疗组的中位 PFS 为 7.56 个月（95% CI，5.19-11.07 个月）。联合组的中位 OS 为 27.04 个月（95% CI，从 22.31 至未达到），索拉非尼组未达到。两组的毒性相当。在多变量模型中，磷酸化蛋白激酶 B (pAKT) 水平升高与较差的 PFS（风险比，1.04；95% CI，1.00–1.08；P = 0.0411）和 OS（风险比，1.15；95% CI，1.02–1.29；P = 0.0173）相关。在索拉非尼中添加低剂量干扰素所产生的疗效结果与索拉非尼单一疗法所达到的效果相当。目前的结果表明 pAKT 水平可以预测临床结果，但需要进一步的机制研究。
The objective of this study was to independently evaluate the objective response rate of sorafenib and sorafenib plus low-dose interferon-alfa 2b (IFN) as frontline therapy in patients with metastatic renal cell carcinoma (mRCC). Untreated patients with clear cell mRCC were randomized to receive sorafenib 400 mg orally twice daily or sorafenib 400 mg orally twice daily plus subcutaneous IFN 0.5 million U (MU) twice daily. Primary endpoints included the objective response rate (ORR) and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the predictive value of tumor tissue biomarkers. Eighty patients were enrolled. The median follow-up was 19.7 months (range, 0–34.2 months). The ORR was 30% (95% confidence interval [CI], 16.6%–46.5%) in the sorafenib arm and 25% (95% CI, 12.7%–41.2%) in the combination arm. The median PFS was 7.39 months in the sorafenib-alone arm (95% CI, 5.52–9.20 months) and 7.56 months in the sorafenib plus IFN arm (95% CI, 5.19–11.07 months). The median OS was 27.04 months in the combination arm (95% CI, from 22.31 to not attained) and was not reached in the sorafenib arm. Toxicities were comparable in both arms. In a multivariate model, increased phosphorylated protein kinase B (pAKT) levels were associated with poorer PFS (hazard ratio, 1.04; 95% CI, 1.00–1.08; P = .0411) and OS (hazard ratio, 1.15; 95% CI, 1.02–1.29; P = .0173). The addition of low-dose IFN to sorafenib resulted in efficacy outcomes that were comparable to those achieved with sorafenib monotherapy. The current results indicated that pAKT levels may predict for clinical outcome, but further mechanistic study is required.