BACKGROUND Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib. PATIENTS AND METHODS This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours-based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743). RESULTS From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4-not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15-0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23-1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0). CONCLUSION The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.

中文翻译：

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一项双盲安慰剂对照的随机II期临床试验，评估了瑞格非尼在先前接受过化疗和帕唑帕尼治疗的非脂肪细胞肉瘤患者中的活性和安全性。

背景技术转移性软组织肉瘤（STS）管理仍然是未满足的医学需求。我们评估了瑞格非尼在曾接受过化疗和帕唑帕尼治疗的转移性非脂肪性STS患者中的活性和安全性。患者与方法这项双盲，安慰剂对照，多中心比较随机II期临床试验包括经组织学证实为晚期且无法手术的STS患者。接受安慰剂的患者可以选择进行交叉治疗，以集中确认疾病进展。主要终点是集中审查基于实性肿瘤的无进展生存期（PFS）的反应评估标准，并根据意向治疗数据集进行了分析。总共需要进行24次事件才能获得90％的力量，危险比（HR）= 0.33（中位PFS，3.6个月和1.2个月），且单侧α= 0。1（ClinicalTrials.gov，NCT01900743）。结果2015年12月至2017年10月，随机分配了37例患者。regorafenib为18，安慰剂为19。进展后，分配给安慰剂的13名患者改用雷戈非尼。中位随访时间为27.2个月（95％置信区间[CI]：未达到24.4）。与安慰剂相比，我们观察到瑞格非尼具有显着的PFS获益（校正后的HR = 0.33； 95％CI：0.15-0.74； p = 0.0007，中位PFS分别为2.1个月和1.1个月），并且总体生存率较高且接近尽管存在交叉影响（调整后的HR = 0.49; 95％CI：0.23-1.06; p = 0.007;中位OS = 17.8对8.2个月）。分频前，最常见的III级或更高级别不良事件是淋巴细胞减少症（分别为5比1），腹泻（4比0），呼吸困难（3比1），皮肤毒性（3比0），动脉高血压（2比0）和转氨酶升高（2比0）。结论本研究证明了瑞格非尼在经过大量预处理的非脂肪细胞性STS患者中具有有意义的临床抗肿瘤活性。