Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer.
Phase II Single-arm Study of Durvalumab and Tremelimumab with Concurrent Radiotherapy in Patients with Mismatch Repair-proficient Metastatic Colorectal Cancer.
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Durvalumab和Tremelimumab联合放疗在失配修复熟练转移性结直肠癌患者中的II期单臂研究。
DOI：
10.1158/1078-0432.ccr-20-2474
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发表时间：
2021-04-15
期刊：
影响因子：
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通讯作者：
Saltz LB
中科院分区：
文献类型：
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作者：
Segal NH;Cercek A;Ku G;Wu AJ;Rimner A;Khalil DN;Reidy-Lagunes D;Cuaron J;Yang TJ;Weiser MR;Romesser PB;Stadler ZK;Varghese AM;Ganesh K;Yaeger R;Connell LC;Faleck D;Abou-Alfa GK;Mcauliffe KC;Vaiskauskas P;Solter ML;Ogle M;Adamow MJ;Holland A;Vedantam P;Wong P;Merghoub T;Vakiani E;Hollmann TJ;Juluru K;Chou JF;Capanu M;Erinjeri J;Solomon S;Yamada Y;Kemeny N;Crane CH;Saltz LB
单独的免疫检查点抑制（ICI）在错配修复（MMR-P）转移性结直肠癌（mCRC）中没有活性，单独的放疗（RT）也不会产生客观的全身获益。然而，在临床前和临床模型中，联合RT加ICI可以诱导全身抗肿瘤免疫。在这项单中心、II期研究中，化疗难治性MMR-P mCRC患者接受durvalumab 1500 mg + tremelimumab 75 mg每4周一次+RT治疗。主要终点是非放射性病变的客观缓解率（ORR）。治疗和疗效与外周免疫细胞谱相关。我们招募了24名患者，并在中位随访21.8（范围：15.9至26.3）个月后报告结局。ORR为8.3%（2例患者）（95%置信区间[CI]，1.0%-27.0%）。中位无进展生存期为1.8（95%CI，1.7 - 1.9）个月，中位总生存期为11.4（95%CI，10.1 - 17.4）个月。25%的患者（n=6）发生了治疗相关的3-4级不良事件。我们观察到客观缓解患者的循环CD 8 + T淋巴细胞活化、分化和增殖增加。RT + ICI联合研究不符合预先规定的终点标准，认为值得进一步研究。然而，在非辐照病变中观察到罕见的全身免疫增强和消退（远位反应）。联合durvalumab和tremelimumab加RT在MMR-P mCRC中是可行的，安全性特征可控。新的免疫治疗组合的进一步研究，并确定生物标志物的预测远位反应是必要的。
Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy (RT) alone result in objective systemic benefit. However, combined RT plus ICI can induce systemic anti-tumor immunity in pre-clinical and clinical models. In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks plus RT. The primary endpoint was objective response rate (ORR) in non-irradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. We enrolled 24 patients, and report outcomes after a median follow up of 21.8 (range: 15.9 to 26.3) months. The ORR was 8.3% (2 patients) (95% confidence interval [CI], 1.0% to 27.0%). The median progression-free survival was 1.8 (95% CI, 1.7 to 1.9) months, median overall survival was 11.4 (95% CI, 10.1 to 17.4) months. Twenty five percent of patients (n=6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. This combination of RT plus ICI study did not meet the prespecified end point criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in non-irradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus RT is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.