PD-1 Blockade in Tumors with Mismatch-Repair Deficiency.
Le, Dung T. M.D.; Uram, Jennifer N. Ph.D.; Wang, Hao Ph.D.; Bartlett, Bjarne R. B.S.; Kemberling, Holly R.N.; Eyring, Aleksandra D. M.Pharm.; Skora, Andrew D. Ph.D.; Luber, Brandon S. Sc.M.; Azad, Nilofer S. M.D.; Laheru, Dan M.D.; Biedrzycki, Barbara Ph.D., C.N.R.P.; Donehower, Ross C. M.D.; Zaheer, Atif M.D.; Fisher, George A. M.D., Ph.D.; Crocenzi, Todd S. M.D.; Lee, James J. M.D., Ph.D.; Duffy, Steven M. M.D.; Goldberg, Richard M. M.D.; de la Chapelle, Albert M.D., Ph.D.; Koshiji, Minori M.D., Ph.D.; Bhaijee, Feriyl M.D.; Huebner, Thomas M.D.; Hruban, Ralph H. M.D.; Wood, Laura D. M.D., Ph.D.; Cuka, Nathan M.D.; Pardoll, Drew M. M.D., Ph.D.; Papadopoulos, Nickolas Ph.D.; Kinzler, Kenneth W. Ph.D.; Zhou, Shibin M.D., Ph.D.; Cornish, Toby C. M.D., Ph.D.; Taube, Janis M. M.D.; Anders, Robert A. M.D., Ph.D.; Eshleman, James R. M.D., Ph.D.; Vogelstein, Bert M.D.; Diaz, Luis A. Jr. M.D.
[Article]
New England Journal of Medicine.
372(26):2509-2520, June 25, 2015.
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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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