PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

被引：7328

作者：

Le, D. T. ^{[1
,2
]}

Uram, J. N. ^{[1
,2
]}

Wang, H. ^{[2
]}

Bartlett, B. R. ^{[1
,3
,4
]}

Kemberling, H. ^{[2
]}

Eyring, A. D. ^{[2
]}

Skora, A. D. ^{[2
,3
,4
]}

Luber, B. S. ^{[2
]}

Azad, N. S. ^{[2
]}

Laheru, D. ^{[2
]}

Biedrzycki, B. ^{[2
]}

Donehower, R. C. ^{[2
]}

Zaheer, A. ^{[5
]}

Fisher, G. A. ^{[7
]}

Crocenzi, T. S. ^{[8
]}

Lee, J. J. ^{[9
]}

Duffy, S. M. ^{[10
]}

Goldberg, R. M. ^{[11
,12
,13
]}

de la Chapelle, A. ^{[11
,12
,13
]}

Koshiji, M. ^{[14
,15
]}

Bhaijee, F. ^{[6
]}

Huebner, T. ^{[6
]}

Hruban, R. H. ^{[6
]}

Wood, L. D. ^{[6
]}

Cuka, N. ^{[6
]}

Pardoll, D. M. ^{[2
]}

Papadopoulos, N. ^{[2
,3
,4
]}

Kinzler, K. W. ^{[2
,3
,4
]}

Zhou, S. ^{[2
,3
,4
]}

Cornish, T. C. ^{[6
]}

Taube, J. M. ^{[6
]}

Anders, R. A. ^{[6
]}

Eshleman, J. R. ^{[6
]}

Vogelstein, B. ^{[2
,3
,4
]}

Diaz, L. A., Jr. ^{[1
,2
,3
,4
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Swim Across America Lab, Baltimore, MD USA

[2] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA

[3] Johns Hopkins Univ, Sch Med, Ludwig Ctr, Baltimore, MD USA

[4] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA

[5] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[7] Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA

[8] Providence Hlth & Serv, Providence Canc Ctr, Portland, OR USA

[9] Univ Pittsburgh, Sch Med, Dept Med, Univ Pittsburgh Canc Inst, Pittsburgh, PA USA

[10] Bon Secours Canc Inst, Richmond, VA USA

[11] Ohio State Univ, Comprehens Canc Ctr, Div Med Oncol, James Canc Ctr, Columbus, OH 43210 USA

[12] Ohio State Univ, Comprehens Canc Ctr, Solove Res Inst, Columbus, OH 43210 USA

[13] Ohio State Univ, Comprehens Canc Ctr, Human Canc Genet Program, Columbus, OH 43210 USA

[14] Merck, Kenilworth, NJ USA

[15] Merck, N Wales, PA USA

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2015年 / 372卷 / 26期

关键词：

MICROSATELLITE INSTABILITY; COLORECTAL CARCINOMAS; ANTI-PD-L1; ANTIBODY; GERMLINE MUTATIONS; CLINICAL ACTIVITY; CANCER; SAFETY; DNA; LYMPHOCYTES; PREDISPOSE;

D O I：

10.1056/NEJMoa1500596

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab.

引用

页码：2509 / 2520

页数：12

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