PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.
复制标题
肿瘤中的PD-1封锁不匹配缺陷。
DOI：
10.1056/nejmoa1500596
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发表时间：
2015-06-25
期刊：
影响因子：
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通讯作者：
Diaz LA Jr
中科院分区：
文献类型：
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作者：
Le DT;Uram JN;Wang H;Bartlett BR;Kemberling H;Eyring AD;Skora AD;Luber BS;Azad NS;Laheru D;Biedrzycki B;Donehower RC;Zaheer A;Fisher GA;Crocenzi TS;Lee JJ;Duffy SM;Goldberg RM;de la Chapelle A;Koshiji M;Bhaijee F;Huebner T;Hruban RH;Wood LD;Cuka N;Pardoll DM;Papadopoulos N;Kinzler KW;Zhou S;Cornish TC;Taube JM;Anders RA;Eshleman JR;Vogelstein B;Diaz LA Jr
体细胞突变具有编码“非自身”免疫原性抗原的潜力。我们假设由于错配修复缺陷而具有大量体细胞突变的肿瘤可能对免疫检查点阻断敏感。我们进行了一项2期研究，以评估pembrolizumab（一种抗程序性死亡1免疫检查点抑制剂）在41例伴有或不伴有错配修复缺陷的进行性转移癌患者中的临床活性。Pembrolizumab以每14天10 mg/kg体重的剂量静脉注射给药于错配修复缺陷型结直肠癌患者、错配修复熟练型结直肠癌患者和非结直肠错配修复缺陷型癌症患者。共同主要终点为免疫相关客观缓解率和20周免疫相关无进展生存率。错配修复缺陷型结直肠癌的免疫相关客观缓解率和免疫相关无进展生存率分别为40%（10例患者中的4例）和78%（9例患者中的7例），而错配修复熟练型结直肠癌的免疫相关客观缓解率和免疫相关无进展生存率分别为0%（18例患者中的0例）和11%（18例患者中的2例）。错配修复缺陷型结直肠癌队列未达到中位无进展生存期和总生存期，而错配修复功能正常型结直肠癌队列分别为2.2和5.0个月（疾病进展或死亡风险比为0.10 [P<0.001]，死亡风险比为0.22 [P = 0.05]）。错配修复缺陷型非结直肠癌患者的缓解率与错配修复缺陷型结直肠癌患者相似（免疫相关客观缓解率为71% [5/7例患者];免疫相关无进展生存率为67% [4/6例患者]）。全外显子组测序显示，在错配修复缺陷型肿瘤中，平均每个肿瘤有1782个体细胞突变，而在错配修复功能型肿瘤中，平均每个肿瘤有73个体细胞突变（P = 0.007），高体细胞突变负荷与延长的无进展生存期相关（P = 0.02）。这项研究表明，错配修复状态可预测pembrolizumab免疫检查点阻断的临床获益。（由约翰霍普金斯大学和其他人资助; ClinicalTrials.gov编号，NCT 01876511。
Somatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P = 0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair–deficient tumors, as compared with 73 in mismatch repair–proficient tumors (P = 0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P = 0.02). This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.)