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PD-1 Blockade inTumors withMismatch-RepairDeficiency Dung T. LeJennifer N. UramHao Wang2015 год

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
статья из журнала

Полный текстСтраница публикацииПубликация в OpenAlex
Аннотация: 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.).
Год издания: 2015
Авторы: Dung T. Le, Jennifer N. Uram, Hao Wang, Bjarne R. Bartlett, Holly Kemberling, Aleksandra Eyring, Andrew D. Skora, Brandon Luber, Nilofer S. Azad, Dan Laheru, Barbara Biedrzycki, Ross C. Donehower, Atif Zaheer, George A. Fisher, Todd S. Crocenzi, James J. Lee, Steven M. Duffy, Richard M. Goldberg, Albert de la Chapelle, Minori Koshiji, Feriyl Bhaijee, Thomas Huebner, Ralph H. Hruban, Laura D. Wood, Nathan Cuka, Drew M. Pardoll, Nickolas Papadopoulos, Kenneth W. Kinzler, Shibin Zhou, Toby C. Cornish, Janis M. Taube, Robert A. Anders, James R. Eshleman, Bert Vogelstein, Luis A. Díaz
Издательство: Massachusetts Medical Society
Источник: New England Journal of Medicine
Ключевые слова: Genetic factors in colorectal cancer, Cancer Immunotherapy and Biomarkers, Cancer Genomics and Diagnostics
Другие ссылки: New England Journal of Medicine (PDF)
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Europe PMC (PubMed Central) (PDF)
Europe PMC (PubMed Central) (HTML)
PubMed Central (HTML)
PubMed (HTML)