Maqola

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Dung T. LeSidney Kimmel Comprehensive Cancer CenterJennifer N. UramFrom the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,Hao WangSidney Kimmel Comprehensive Cancer CenterBjarne R. BartlettAnna Needs Neuroblastoma AnswersHolly KemberlingFrom the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,Aleksandra EyringSidney Kimmel Comprehensive Cancer CenterAndrew D. SkoraSidney Kimmel Comprehensive Cancer CenterBrandon LuberSidney Kimmel Comprehensive Cancer CenterNilofer S. AzadSidney Kimmel Comprehensive Cancer CenterDan LaheruSidney Kimmel Comprehensive Cancer CenterBarbara BiedrzyckiSidney Kimmel Comprehensive Cancer CenterRoss C. DonehowerSidney Kimmel Comprehensive Cancer CenterAtif ZaheerDepartments of Radiology, Johns Hopkins University School of Medicine, BaltimoreGeorge A. FisherDepartment of Medicine, Stanford University School of Medicine, Stanford, CATodd S. CrocenziProvidence Health & ServicesJames J. LeeUPMC Hillman Cancer CenterSteven M. DuffyFrom the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,Richard M. GoldbergDivision of Medical Oncology, Ohio State University Comprehensive Cancer Center–James Cancer Center and Solove Research Institute, and Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, ColumbusAlbert de la ChapelleFrom the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,Minori KoshijiMerck, Kenilworth, NJ, and North Wales, PAFeriyl BhaijeeAnna Needs Neuroblastoma AnswersThomas HuebnerFrom the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,Ralph H. HrubanPathology, Johns Hopkins University School of Medicine, BaltimoreLaura D. WoodAnna Needs Neuroblastoma AnswersNathan CukaAnna Needs Neuroblastoma AnswersDrew M. PardollFrom the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,Nickolas PapadopoulosSidney Kimmel Comprehensive Cancer CenterKenneth W. KinzlerSidney Kimmel Comprehensive Cancer CenterShibin ZhouSidney Kimmel Comprehensive Cancer CenterToby C. CornishAnna Needs Neuroblastoma AnswersJanis M. TaubeAnna Needs Neuroblastoma AnswersRobert A. AndersPathology, Johns Hopkins University School of Medicine, BaltimoreJames R. EshlemanPathology, Johns Hopkins University School of Medicine, BaltimoreBert VogelsteinSidney Kimmel Comprehensive Cancer CenterLuis A. DíazFrom the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine,

2015en

ABI

Annotatsiya

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. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

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DOI: 10.1056/nejmoa1500596

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