Early Phase Trials Unit, Institut Bergonié, Bordeaux, France.
Clinical and Epidemiological Research Unit, INSERM CIC1401, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France.
Clin Cancer Res. 2021 Apr 15;27(8):2139-2147. doi: 10.1158/1078-0432.CCR-20-3416. Epub 2021 Jan 25.
Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models.
This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1.
Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8-5.4] and 10.8 months (95% CI, 5.9-NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome ( = 14, 30%), hypertension ( = 11, 23%), and diarrhea ( = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; = 0.002) and OS (3.7 months vs. not reached; = 0.002). Increased tumor infiltration by CD8 T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome.
The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.
在结直肠癌的临床前模型中，regorafenib 与免疫检查点抑制具有协同作用。
这是一项单臂、多中心的 2 期临床试验。regorafenib 每 3 周给药 1 次，然后停药 1 周，每天 160mg；avelumab 每 2 周静脉输注 10mg/kg，从第 1 周期第 15 天开始，直到疾病进展或出现不可接受的毒性。主要终点是根据 RECIST 1.1 标准，治疗后的确认客观缓解率。次要终点包括 1 年无进展率、无进展生存期（PFS）和总生存期（OS）、安全性和在基线和第 2 周期第 1 天连续获得的肿瘤样本上进行的生物标志物研究。
四个中心共纳入 48 例患者。在中央放射学审查后，43 例可评估疗效。最佳缓解为 23 例患者的疾病稳定（53.5%）和 17 例患者的疾病进展（39.5%）。中位 PFS 和 OS 分别为 3.6 个月（95%CI，1.8-5.4）和 10.8 个月（95%CI，5.9-未达到）。最常见的 3 级或 4 级不良事件为掌跖红斑感觉迟钝综合征（14 例，30%）、高血压（11 例，23%）和腹泻（6 例，13%）。高基线肿瘤相关巨噬细胞浸润与不良 PFS（1.8 个月 vs. 3.7 个月； = 0.002）和 OS（3.7 个月 vs. 未达到； = 0.002）显著相关。与基线相比，第 2 周期第 1 天肿瘤中 CD8 T 细胞浸润增加与更好的结果显著相关。
regorafenib + avelumab 的联合应用在微卫星稳定结直肠癌的患者亚群中调动了抗肿瘤免疫。通过定量免疫细胞浸润的计算病理学可能会改善患者选择，以进一步研究这种方法。
