In cohort C (patients with mismatch repairCdeficient noncolorectal cancer), the median progression-free survival was 5

In cohort C (patients with mismatch repairCdeficient noncolorectal cancer), the median progression-free survival was 5.4 months (95% CI, 3 to not Mouse monoclonal to EphB3 estimable), and the median overall survival was not reached. 18 patients) and 11% (2 of 18 patients) for mismatch repairCproficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort Floxuridine with mismatch repairCdeficient colorectal malignancy but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repairCproficient 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 repairCdeficient noncolorectal malignancy had responses much like those of patients with mismatch repairCdeficient colorectal malignancy (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 repairCdeficient tumors, as compared with 73 in mismatch repairCproficient 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, “type”:”clinical-trial”,”attrs”:”text”:”NCT01876511″,”term_id”:”NCT01876511″NCT01876511.) The Programmed Death 1 (PD-1) PATHway is a negative feedback system that represses Th1 cytotoxic immune responses and that, if unregulated, can damage the host.1C3 It is up-regulated in many tumors and in their surrounding microenvironment. Blockade of this pathway with antibodies to PD-1 or its ligands has Floxuridine led to remarkable clinical responses in patients with many different types of cancer, including melanomas, nonCsmall-cell lung cancer, renal-cell carcinoma, bladder cancer, and Hodgkins lymphoma.4C10 The expression of PD-1 ligands (PD-L1 or PD-L2) on the surface of tumor cells or immune cells is an important but not a definitive predictive biomarker of response to PD-1 blockade.4,6C8,11 In reports of the effects of PD-1 blockade in human tumors, only 1 1 of 33 patients with colorectal cancer had a response to this treatment, in contrast to substantial fractions of patients with melanomas, renal-cell cancers, and lung tumors who have a response.10,12 What was different about this single patient? We hypothesized that this patient had mismatch-repair deficiency, because mismatch-repair deficiency occurs in a small fraction of advanced colorectal cancers,13,14 somatic mutations found in tumors can be recognized by the patients own immune system,15 and mismatch repairCdeficient colorectal cancers have 10 to 100 times as many somatic mutations as mismatch Floxuridine repairCproficient colorectal cancers.16C18 Moreover, mismatch repairCdeficient cancers contain prominent lymphocyte infiltrates, a finding consistent with an immune response.19C22 In addition, two of the tumor types that were most responsive to PD-1 blockade in a study by Topalian et al.10 had high numbers of somatic mutations as a result of exposure to cigarette smoke (lung cancers) or ultraviolet radiation (melanomas).23,24 Our hypothesis was correct: the tumor of the single patient with colorectal cancer who had a response to PD-1 blockade was mismatch repairCdeficient.25 Therefore, we hypothesized that mismatch repairCdeficient tumors are more responsive to PD-1 blockade than are mismatch repairCproficient tumors. To test this hypothesis, we initiated a phase 2 clinical trial to evaluate immune checkpoint blockade in patients whose tumors had or did not have mismatch-repair deficiency. Because mismatch-repair deficiency in tumors arises through two routes,26C28 we recruited patients with hereditary nonpolyposis colorectal cancer (also known as the Lynch syndrome), which results from an inherited germline defect in one of four mismatch-repair genes followed by a second inactivating somatic change in the remaining wild-type allele. We also recruited patients with sporadic mismatch repairCdeficient tumors, in which both alleles of a mismatch-repair gene are inactivated by somatic mutations or by epigenetic silencing.29 In either case, the neoplasms that arise harbor hundreds or thousands of mutations.16,18 METHODS PATIENTS Patients with treatment-refractory progressive metastatic cancer were recruited from three centers for this phase 2 study (Table 1). Three cohorts were evaluated: cohort A included patients with mismatch repairCdeficient colorectal adenocarcinomas, cohort B included patients with mismatch repairCproficient colorectal adenocarcinomas, and cohort C included patients with mismatch repairCdeficient cancers of types other than colorectal. Table 1 Demographic and Baseline Characteristics of the Patients.* wild type no. (%)0.64?Yes8 (73)11 (52)4 (44)?No01 (5)0?Unknown3 (27)9 (43)5 (56)wild type no. (%)0.72?Yes6 (55)13 (62)4 (44)?No5 (45)8 (38)1 (11)?Unknown004 (44) Open in a separate window *NA denotes not.