Dept. of Urology, Rechts der Isar Medical Center, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany; AUO Study Group, Germany.
Dept. of Urology, Eberhard Karls University Tübingen, Hoppe-Seyler-Str.3, 72076 Tübingen, Germany.
Eur J Cancer. 2019 Jan;107:37-45. doi: 10.1016/j.ejca.2018.11.001. Epub 2018 Dec 7.
This trial compared the sequential therapy with the multikinase inhibitor sorafenib (So) followed by pazopanib (Pa) or vice versa in advanced/metastatic renal cell carcinoma (mRCC) patients.
This multicenter, randomized phase 3 study assessed the sequential use of So-Pa versus Pa-So in patients with mRCC without prior systemic therapy. Pts were randomized to So 2 × 400 mg/day followed by Pa 1 × 800 mg/day in case of progression or intolerable toxicity or vice versa. Primary endpoint was total PFS (tPFS), defined as time from randomization to progression, or death during second-line therapy. Key secondary endpoints included overall survival (OS), first-line PFS, disease control rate (DCR) and safety.
A total of 377 pts were randomized (So-Pa, n = 189; Pa-So, n = 188). Recruitment of a total 544 pts was calculated, but actual accrual rate turned out to be lower than expected. The primary endpoint median tPFS was 8.6 mo (95% CI 7.7-10.2) for So-Pa and 12.9 mo (95% CI 10.8-15.2) for Pa-So with a hazard ratio (HR) of 1.36 (upper limit of one-sided 95% CI 1.68), which exceeded a predefined HR <1.225 as a one-sided 95% confidence interval. Non-inferiority of So-Pa regarding tPFS was not met. Secondary endpoints displayed marked statistical differences in favor of Pa-So in first-line PFS and DCR but not for OS and 2nd-line PFS. Side effect profiles were consistent with known toxicities of the respective multikinase-inhibitor including diarrhea, fatigue, hand-foot skin reaction and hypertension.
Non-inferiority of the primary endpoint tPFS could not be demonstrated for So-Pa. The results for first-line PFS and DCR favored the Pa-So sequence.
NCT01613846, www.clinicaltrials.gov.
本试验比较了多激酶抑制剂索拉非尼（So）序贯治疗与帕唑帕尼（Pa）序贯治疗在晚期/转移性肾细胞癌（mRCC）患者中的疗效。
这是一项多中心、随机 3 期研究，评估了 So-Pa 序贯治疗与 Pa-So 序贯治疗在未经系统治疗的 mRCC 患者中的应用。患者随机分为 So 2×400mg/天，随后在进展或不耐受毒性时换用 Pa 1×800mg/天，反之亦然。主要终点是总无进展生存期（tPFS），定义为从随机分组到进展或二线治疗期间死亡的时间。主要次要终点包括总生存期（OS）、一线 PFS、疾病控制率（DCR）和安全性。
共 377 例患者随机分组（So-Pa 组 189 例，Pa-So 组 188 例）。预计招募 544 例患者，但实际入组率低于预期。So-Pa 组和 Pa-So 组的中位 tPFS 分别为 8.6 个月（95%CI 7.7-10.2）和 12.9 个月（95%CI 10.8-15.2），风险比（HR）为 1.36（单侧 95%CI 上限为 1.68），超过了预设的 HR<1.225（单侧 95%CI）。So-Pa 组的 tPFS 未能达到非劣效性。次要终点在一线 PFS 和 DCR 方面显示出 Pa-So 组的显著统计学差异，但在 OS 和二线 PFS 方面没有差异。副作用谱与各自的多激酶抑制剂已知毒性一致，包括腹泻、疲劳、手足皮肤反应和高血压。
So-Pa 组的主要终点 tPFS 未能达到非劣效性。一线 PFS 和 DCR 的结果有利于 Pa-So 序贯治疗。
NCT01613846，www.clinicaltrials.gov。
