Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
Department of Nursing, City of Hope National Medical Center, Duarte, California, USA.
Oncologist. 2020 Aug;25(8):e1188-e1194. doi: 10.1634/theoncologist.2020-0161. Epub 2020 May 30.
BACKGROUND: Metastatic colorectal cancers (MCRCs) with microsatellite stability (MSS) are resistant to immunotherapy with programmed cell death protein 1 (PD-1) and programmed death-ligand 1 inhibitors. However, the addition of regorafenib to nivolumab was recently associated with a high response rate and a protracted progression-free survival in a small cohort of MSS Japanese patients with metastatic colorectal cancer. MATERIALS AND METHODS: We evaluated the outcome of patients with MSS metastatic colorectal cancer who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib in a single U.S. center. RESULTS: A total of 18 patients were treated with a combination of regorafenib and PD-1 inhibitors. No treatment-related grade 3 or above toxicities were noted. Thirteen patients (69%) had progressive disease, and five patients (31%) experienced stable disease as best response. Four out of five stable diseases occurred in patients without liver metastases, whereas only 1 of 14 patients with history of liver metastases had a short disease stabilization. A rise in circulating tumor DNA (ctDNA) at the 4-week time pointuniversally predicted tumor progression at 2 months, whereas a decline was associated with radiographic disease stabilization. CONCLUSIONS: Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant metastatic colorectal cancer. Selection for patients without history of liver metastases may identify a cohort of patients with MSS colorectal cancer with a higher likelihood of benefit from this combination. ctDNA may represent a powerful tool for predicting early therapeutic efficacy of immunotherapy in the MSS colorectal cancer population. IMPLICATIONS FOR PRACTICE: This study showed that the combination of regorafenib and nivolumab was associated with a modest clinical activity in patients with advanced microsatellite stability (MSS) metastatic colorectal cancer. This combination should be avoided in clinical practice, especially in patients with MSS colorectal cancer with liver metastases. Further investigation of regorafenib plus PD-1 inhibitors should be considered in MSS colorectal cancer without liver metastases.
背景：微卫星稳定（MSS）的转移性结直肠癌（MCRC）对程序性细胞死亡蛋白 1（PD-1）和程序性死亡配体 1 抑制剂的免疫治疗具有耐药性。然而，regorafenib 联合 nivolumab 最近在一小部分日本转移性结直肠癌 MSS 患者中显示出高反应率和延长的无进展生存期。
材料和方法：我们评估了在美国一家中心接受 PD-1 抑制剂联合 regorafenib 姑息治疗的 MSS 转移性结直肠癌患者的治疗结果。
结果：共有 18 名患者接受了 regorafenib 和 PD-1 抑制剂的联合治疗。未观察到与治疗相关的 3 级或以上毒性。13 名患者（69%）出现疾病进展，5 名患者（31%）最佳反应为稳定疾病。5 例稳定疾病中有 4 例发生在无肝转移的患者中，而有肝转移史的 14 例患者中只有 1 例疾病稳定时间较短。在 4 周时循环肿瘤 DNA（ctDNA）升高普遍预示着 2 个月时肿瘤进展，而下降与影像学疾病稳定相关。
结论：regorafenib 和 nivolumab 联合治疗在 MSS 化疗耐药转移性结直肠癌患者中具有一定的临床活性。选择无肝转移史的患者可能会识别出 MSS 结直肠癌患者的一个亚组，他们从这种联合治疗中获益的可能性更高。ctDNA 可能代表一种预测 MSS 结直肠癌人群免疫治疗早期疗效的有力工具。
对实践的影响：这项研究表明，在 MSS 转移性结直肠癌患者中，regorafenib 和 nivolumab 的联合治疗具有一定的临床活性。在 MSS 结直肠癌伴肝转移的患者中，应避免使用这种联合治疗。对于无肝转移的 MSS 结直肠癌，应进一步考虑regorafenib 联合 PD-1 抑制剂的研究。
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