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

共 54 条

[11] Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity [J].

Chen, LP .

NATURE REVIEWS IMMUNOLOGY, 2004, 4 (05) :336-347

[12] Circulating mutant DNA to assess tumor dynamics [J].

Diehl, Frank ;

Schmidt, Kerstin ;

Choti, Michael A. ;

Romans, Katharine ;

Goodman, Steven ;

Li, Meng ;

Thornton, Katherine ;

Agrawal, Nishant ;

Sokoll, Lori ;

Szabo, Steve A. ;

Kinzler, Kenneth W. ;

Vogelstein, Bert ;

Diaz, Luis A., Jr. .

NATURE MEDICINE, 2008, 14 (09) :985-990

[13] High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability [J].

Dolcetti, R ;

Viel, A ;

Doglioni, C ;

Russo, A ;

Guidoboni, M ;

Capozzi, E ;

Vecchiato, N ;

Macrì, E ;

Fornasarig, M ;

Boiocchi, M .

AMERICAN JOURNAL OF PATHOLOGY, 1999, 154 (06) :1805-1813

[14]

ESHLEMAN JR, 1995, ONCOGENE, V10, P33

[15] Selection of Endometrial Carcinomas for DNA Mismatch Repair Protein Immunohistochemistry Using Patient Age and Tumor Morphology Enhances Detection of Mismatch Repair Abnormalities [J].

Garg, Karuna ;

Leitao, Mario M., Jr. ;

Kauff, Noah D. ;

Hansen, Jessica ;

Kosarin, Kristi ;

Shia, Jinru ;

Soslow, Robert A. .

AMERICAN JOURNAL OF SURGICAL PATHOLOGY, 2009, 33 (06) :925-933

[16] Integrated genomic characterization of endometrial carcinoma [J].

Getz, Gad ;

Gabriel, Stacey B. ;

Cibulskis, Kristian ;

Lander, Eric ;

Sivachenko, Andrey ;

Sougnez, Carrie ;

Lawrence, Mike ;

Kandoth, Cyriac ;

Dooling, David ;

Fulton, Robert ;

Fulton, Lucinda ;

Kalicki-Veizer, Joelle ;

McLellan, Michael D. ;

O'Laughlin, Michelle ;

Schmidt, Heather ;

Wilson, Richard K. ;

Ye, Kai ;

Ding, Li ;

Mardis, Elaine R. ;

Ally, Adrian ;

Balasundaram, Miruna ;

Birol, Inanc ;

Butterfield, Yaron S. N. ;

Carlsen, Rebecca ;

Carter, Candace ;

Chu, Andy ;

Chuah, Eric ;

Chun, Hye-Jung E. ;

Dhalla, Noreen ;

Guin, Ranabir ;

Hirst, Carrie ;

Holt, Robert A. ;

Jones, Steven J. M. ;

Lee, Darlene ;

Li, Haiyan I. ;

Marra, Marco A. ;

Mayo, Michael ;

Moore, Richard A. ;

Mungall, Andrew J. ;

Plettner, Patrick ;

Schein, Jacqueline E. ;

Sipahimalani, Payal ;

Tam, Angela ;

Varhol, Richard J. ;

Robertson, A. Gordon ;

Pashtan, Itai ;

Saksena, Gordon ;

Onofrio, Robert C. ;

Schumacher, Steven E. ;

Tabak, Barbara .

NATURE, 2013, 497 (7447) :67-73

[17] Multicenter retrospective analysis of metastatic colorectal cancer (CRC) with high-level microsatellite instability (MSI-H) [J].

Goldstein, J. ;

Tran, B. ;

Ensor, J. ;

Gibbs, P. ;

Wong, H. L. ;

Wong, S. F. ;

Vilar, E. ;

Tie, J. ;

Broaddus, R. ;

Kopetz, S. ;

Desai, J. ;

Overman, M. J. .

ANNALS OF ONCOLOGY, 2014, 25 (05) :1032-1038

[18] Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens [J].

Gubin, Matthew M. ;

Zhang, Xiuli ;

Schuster, Heiko ;

Caron, Etienne ;

Ward, Jeffrey P. ;

Noguchi, Takuro ;

Ivanova, Yulia ;

Hundal, Jasreet ;

Arthur, Cora D. ;

Krebber, Willem-Jan ;

Mulder, Gwenn E. ;

Toebes, Mireille ;

Vesely, Matthew D. ;

Lam, Samuel S. K. ;

Korman, Alan J. ;

Allison, James P. ;

Freeman, Gordon J. ;

Sharpe, Arlene H. ;

Pearce, Erika L. ;

Schumacher, Ton N. ;

Aebersold, Ruedi ;

Rammensee, Hans-Georg ;

Melief, Cornelis J. M. ;

Mardis, Elaine R. ;

Gillanders, William E. ;

Artyomov, Maxim N. ;

Schreiber, Robert D. .

NATURE, 2014, 515 (7528) :577-+

[19] Safety and Tumor Responses with Lambrolizumab (Anti-PD-1) in Melanoma [J].

Hamid, Omid ;

Robert, Caroline ;

Daud, Adil ;

Hodi, F. Stephen ;

Hwu, Wen-Jen ;

Kefford, Richard ;

Wolchok, Jedd D. ;

Hersey, Peter ;

Joseph, Richard W. ;

Weber, Jeffrey S. ;

Dronca, Roxana ;

Gangadhar, Tara C. ;

Patnaik, Amita ;

Zarour, Hassane ;

Joshua, Anthony M. ;

Gergich, Kevin ;

Elassaiss-Schaap, Jeroen ;

Algazi, Alain ;

Mateus, Christine ;

Boasberg, Peter ;

Tumeh, Paul C. ;

Chmielowski, Bartosz ;

Ebbinghaus, Scot W. ;

Li, Xiaoyun Nicole ;

Kang, S. Peter ;

Ribas, Antoni .

NEW ENGLAND JOURNAL OF MEDICINE, 2013, 369 (02) :134-144

[20] Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients [J].

Herbst, Roy S. ;

Soria, Jean-Charles ;

Kowanetz, Marcin ;

Fine, Gregg D. ;

Hamid, Omid ;

Gordon, Michael S. ;

Sosman, Jeffery A. ;

McDermott, David F. ;

Powderly, John D. ;

Gettinger, Scott N. ;

Kohrt, Holbrook E. K. ;

Horn, Leora ;

Lawrence, Donald P. ;

Rost, Sandra ;

Leabman, Maya ;

Xiao, Yuanyuan ;

Mokatrin, Ahmad ;

Koeppen, Hartmut ;

Hegde, Priti S. ;

Mellman, Ira ;

Chen, Daniel S. ;

Hodi, F. Stephen .

NATURE, 2014, 515 (7528) :563-+

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