Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases.
Pilot Clinical Trial of Perioperative Durvalumab and Tremelimumab in the Treatment of Resectable Colorectal Cancer Liver Metastases.
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围手术期Durvalumab和Tremelimumab的试验临床试验在可切除的结直肠癌肝转移治疗中。
DOI：
10.1158/1078-0432.ccr-21-0163
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发表时间：
2021-06-01
期刊：
影响因子：
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通讯作者：
Overman MJ
中科院分区：
文献类型：
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作者：
Kanikarla Marie P;Haymaker C;Parra ER;Kim YU;Lazcano R;Gite S;Lorenzini D;Wistuba II;Tidwell RSS;Song X;Foo WC;Maru DM;Chun YS;Futreal A;Kee B;Menter D;Solis L;Tzeng CW;Parseghian C;Raghav K;Morris V;Chang CC;Jenq R;Tam A;Bernatchez C;Kopetz S;Vauthey JN;Overman MJ
尽管免疫浸润对结直肠癌（CRC）的预后具有重要意义，但免疫疗法在难治性转移性精通错配修复（pMMR） CRC中的临床活性有限。本研究探讨了联合抗ctla -4和抗pdl -1治疗可切除的结直肠癌肝转移的术前管理，目的是改善这种疾病的免疫反应。可切除的结直肠癌仅肝转移患者术前接受1剂量的tremelimumab和durvalumab，术后接受单药durvalumab。主要目标是确定可行性和安全性。在2016年11月至2019年11月期间，共有24名患者入组。23例患者接受治疗[21例pMMR和2例缺陷错配修复（dMMR）]，随后17例（74%;95%CI: 53-88%）接受手术切除。3/4级治疗相关免疫毒性和术后3/4级毒性分别见于5/23 （22%;95%CI: 10-44%）和2/17 （12%;95%CI: 2-38%）患者。中位RFS为9.7 （95%CI: 8.1-17.8）个月，OS为24.5 （95%CI: 16.5-28.4）个月。4例患者表现出完全的病理反应，2例dMMR患者和2例POLE突变患者。通过流式细胞术、免疫荧光和RNA测序对肿瘤前后组织进行分析，发现T细胞浸润水平相似，但治疗后确实显示CD8+和CD4+活化的证据。延长RFS患者的治疗后样本中存在B细胞转录组特征和B细胞密度的增加。该研究证明了在结直肠癌肝切除术前新辅助联合tremelimumab和durvalumab的安全性。在pMMR mCRC中发现了这种治疗后T细胞和B细胞活化的证据。
Despite the prognostic importance of immune infiltrate in colorectal cancer (CRC), immunotherapy has demonstrated limited clinical activity in refractory metastatic proficient mismatch repair (pMMR) CRC. This study explores combining anti-CTLA-4 and an anti-PDL-1 therapy in the preoperative management of resectable CRC liver metastases with the intent to improve immune responses in this disease setting. Patients with resectable CRC liver-only metastases received 1 dose of tremelimumab and durvalumab preoperatively followed by single-agent durvalumab postoperatively. Primary objectives were to determine feasibility and safety. A total of 24 patients were enrolled between 11/2016-11/2019. 23 patients received treatment [21 pMMR and 2 deficient mismatch repair (dMMR)] and subsequently 17 (74%; 95%CI: 53-88%) underwent surgical resection. Grade 3/4 treatment-related immune toxicity and postoperative grade 3/4 toxicity were seen in 5/23 (22%; 95%CI: 10-44%) and 2/17 (12%; 95%CI: 2-38%) patients. The median RFS was 9.7 (95%CI: 8.1-17.8) months and OS was 24.5 (95%CI: 16.5-28.4) months. Four patients demonstrated complete pathological response, two dMMR patients and two POLE mutation patients. Pre- and post-tumor tissue analysis by flow cytometry, immunofluorescence, and RNA sequencing revealed similar levels of T cell infiltration, but did demonstrate evidence of CD8+ and CD4+ activation post treatment. An increase in B-cell transcriptome signature and B cell density was present in post-treatment samples from patients with prolonged RFS. This study demonstrates the safety of neoadjuvant combination tremelimumab and durvalumab prior to CRC liver resection. Evidence for T and B cell activation following this therapy was seen in pMMR mCRC.