Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients. Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling. Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20–81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9–11.6] and 1.4 months [95%CI:1.2–2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses. This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy. EudraCT N°: 2015–005464-42; Clinicaltrial.gov number: NCT02992912.

中文翻译：

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SBRT 和 atezolizumab 在晚期预处理结直肠癌中的国际 II 期试验和免疫分析

尽管优化的组合方式仍不清楚，但免疫放射治疗可能会改善晚期实体瘤患者的预后。在这里，我们报告了 SABR-PDL1 试验的结直肠 (CRC) 队列分析，该试验评估了 PD-L1 抑制剂 atezolizumab 与立体定向全身放射治疗 (SBRT) 联合治疗晚期癌症患者的情况。符合条件的患者每 3 周接受 atezolizumab 1200 mg，直至出现进展或无法控制的毒性，并与第 2 个周期同时进行消融性 SBRT（推荐剂量为 45 Gy，分 3 次，根据正常组织耐受限制进行调整）。 SBRT 被递送到至少一个肿瘤部位，同时至少一个额外的可测量病灶远离放射野。主要疗效终点是从阿替利珠单抗开始使用后的一年无进展生存率 (PFS)。收集连续的肿瘤活检样本以进行深入的多特征免疫分析。 5 个中心招募了 60 名接受过治疗的晚期 CRC 患者（前 2 行的中位数）（38 名男性 [63%]；中位年龄 59 岁[范围，20-81 岁]；77% 患有肝转移）（法国：n = 4、西班牙：n = 1) 从 11/2016 到 04/2019。除一名患者 (98%) 外，所有患者均接受了阿替利珠单抗治疗，54/60 (90%) 的患者接受了 SBRT。最常受照射的部位是肺（n = 30/54；56.3%）。在 3 名 (5%) 患者中观察到与治疗相关的 G3（无 G4-5）毒性。中位 OS 和 PFS 分别为 8.4 [95%CI:5.9–11.6] 和 1.4 个月 [95%CI:1.2–2.6]，其中 5 名 (9%) 患者 PFS > 1 年（中位进展时间：19.2 个月，包括 2/5 MMR 熟练）。最佳总体缓解包括疾病稳定（n = 38；64%）、部分缓解（n = 3；5%）和完全缓解（n = 1；2%）。以免疫为中心的多重 IHC 和 RNAseq 表明，即使在放射诱导的淋巴细胞减少症的情况下，SBRT 也能将免疫细胞重新导向肿瘤病变。在有反应的患者中，基线肿瘤 PD-L1 和 IRF1 核表达（在 CD3 + T 细胞和 CD68 + 细胞中）较高。编码已知可增加 T 和 B 细胞向肿瘤运输（CCL19、CXCL9）、迁移（MACF1）和肿瘤细胞杀伤（GZMB）的蛋白质的基因上调与反应相关。这项研究提供了关于肿瘤的可行性、疗效和免疫背景的新数据，可能有助于识别最有可能对免疫放射治疗产生反应的晚期结直肠癌患者。 EudraCT 编号：2015–005464-42； ClinicalTrial.gov 编号：NCT02992912。