PD-1 blockade in tumors with mismatch-repair deficiency

Dung T. Le, Jennifer N. Uram, Hao Wang, Bjarne R. Bartlett, Holly Kemberling, Aleksandra D. Eyring, Andrew D. Skora, Brandon S. 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 KoshijiFeriyl 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. Diaz

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2509-2520
Number of pages12
JournalNew England Journal of Medicine
Volume372
Issue number26
DOIs
StatePublished - Jun 25 2015

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'PD-1 blockade in tumors with mismatch-repair deficiency'. Together they form a unique fingerprint.

  • Cite this

    Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., Biedrzycki, B., Donehower, R. C., Zaheer, A., Fisher, G. A., Crocenzi, T. S., Lee, J. J., Duffy, S. M., Goldberg, R. M., De La Chapelle, A., ... Diaz, L. A. (2015). PD-1 blockade in tumors with mismatch-repair deficiency. New England Journal of Medicine, 372(26), 2509-2520. https://doi.org/10.1056/NEJMoa1500596