PD-1 blockade in tumors with mismatch-repair deficiency

Dung Le, Jennifer Uram, Hao Wang, Bjarne R. Bartlett, Holly Kemberling, Aleksandra D. Eyring, Andrew D. Skora, Brandon S. Luber, Nilofer Azad, Daniel 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 Delong Wood, Nathan Cuka, Andrew Mark Pardoll, Nickolas Papadopoulos, Kenneth W Kinzler, Shibin Zhou, Toby C. Cornish, Janis M Taube, Robert A Anders, James 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

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

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DNA Mismatch Repair
Colorectal Neoplasms
Neoplasms
Disease-Free Survival
Survival Rate
Mutation
Turcot syndrome
Disease Progression
Body Weight
Carcinoma
Antigens
Survival

ASJC Scopus subject areas

  • Medicine(all)

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PD-1 blockade in tumors with mismatch-repair deficiency. / Le, Dung; Uram, Jennifer; Wang, Hao; Bartlett, Bjarne R.; Kemberling, Holly; Eyring, Aleksandra D.; Skora, Andrew D.; Luber, Brandon S.; Azad, Nilofer; Laheru, Daniel; Biedrzycki, Barbara; Donehower, Ross C; Zaheer, Atif; Fisher, George A.; Crocenzi, Todd S.; Lee, James J.; Duffy, Steven M.; Goldberg, Richard M.; De La Chapelle, Albert; Koshiji, Minori; Bhaijee, Feriyl; Huebner, Thomas; Hruban, Ralph H; Wood, Laura Delong; Cuka, Nathan; Pardoll, Andrew Mark; Papadopoulos, Nickolas; Kinzler, Kenneth W; Zhou, Shibin; Cornish, Toby C.; Taube, Janis M; Anders, Robert A; Eshleman, James; Vogelstein, Bert; Diaz, Luis A.

In: New England Journal of Medicine, Vol. 372, No. 26, 25.06.2015, p. 2509-2520.

Research output: Contribution to journalArticle

Le, D, Uram, J, Wang, H, Bartlett, BR, Kemberling, H, Eyring, AD, Skora, AD, Luber, BS, Azad, N, Laheru, D, Biedrzycki, B, Donehower, RC, Zaheer, A, Fisher, GA, Crocenzi, TS, Lee, JJ, Duffy, SM, Goldberg, RM, De La Chapelle, A, Koshiji, M, Bhaijee, F, Huebner, T, Hruban, RH, Wood, LD, Cuka, N, Pardoll, AM, Papadopoulos, N, Kinzler, KW, Zhou, S, Cornish, TC, Taube, JM, Anders, RA, Eshleman, J, Vogelstein, B & Diaz, LA 2015, 'PD-1 blockade in tumors with mismatch-repair deficiency', New England Journal of Medicine, vol. 372, no. 26, pp. 2509-2520. https://doi.org/10.1056/NEJMoa1500596
Le, Dung ; Uram, Jennifer ; Wang, Hao ; Bartlett, Bjarne R. ; Kemberling, Holly ; Eyring, Aleksandra D. ; Skora, Andrew D. ; Luber, Brandon S. ; Azad, Nilofer ; Laheru, Daniel ; Biedrzycki, Barbara ; Donehower, Ross C ; Zaheer, Atif ; Fisher, George A. ; Crocenzi, Todd S. ; Lee, James J. ; Duffy, Steven M. ; Goldberg, Richard M. ; De La Chapelle, Albert ; Koshiji, Minori ; Bhaijee, Feriyl ; Huebner, Thomas ; Hruban, Ralph H ; Wood, Laura Delong ; Cuka, Nathan ; Pardoll, Andrew Mark ; Papadopoulos, Nickolas ; Kinzler, Kenneth W ; Zhou, Shibin ; Cornish, Toby C. ; Taube, Janis M ; Anders, Robert A ; Eshleman, James ; Vogelstein, Bert ; Diaz, Luis A. / PD-1 blockade in tumors with mismatch-repair deficiency. In: New England Journal of Medicine. 2015 ; Vol. 372, No. 26. pp. 2509-2520.
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T1 - PD-1 blockade in tumors with mismatch-repair deficiency

AU - Le, Dung

AU - Uram, Jennifer

AU - Wang, Hao

AU - Bartlett, Bjarne R.

AU - Kemberling, Holly

AU - Eyring, Aleksandra D.

AU - Skora, Andrew D.

AU - Luber, Brandon S.

AU - Azad, Nilofer

AU - Laheru, Daniel

AU - Biedrzycki, Barbara

AU - Donehower, Ross C

AU - Zaheer, Atif

AU - Fisher, George A.

AU - Crocenzi, Todd S.

AU - Lee, James J.

AU - Duffy, Steven M.

AU - Goldberg, Richard M.

AU - De La Chapelle, Albert

AU - Koshiji, Minori

AU - Bhaijee, Feriyl

AU - Huebner, Thomas

AU - Hruban, Ralph H

AU - Wood, Laura Delong

AU - Cuka, Nathan

AU - Pardoll, Andrew Mark

AU - Papadopoulos, Nickolas

AU - Kinzler, Kenneth W

AU - Zhou, Shibin

AU - Cornish, Toby C.

AU - Taube, Janis M

AU - Anders, Robert A

AU - Eshleman, James

AU - Vogelstein, Bert

AU - Diaz, Luis A.

PY - 2015/6/25

Y1 - 2015/6/25

N2 - 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

AB - 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

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