2. Academic Validation
  3. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

  • N Engl J Med. 2015 Jun 25;372(26):2509-20. doi: 10.1056/NEJMoa1500596.
Dung T Le 1,  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 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 Diaz Jr
Affiliations

Affiliation

  • 1 From the Swim Across America Laboratory (D.T.L., J.N.U., B.R.B., L.A.D.), Sidney Kimmel Comprehensive Cancer Center (D.T.L., J.N.U., H.W., H.K., A.D.E., A.D.S., B.S.L., N.S.A., D.L., B.B., R.C.D., D.M.P., N.P., K.W.K., S.Z., B.V., L.A.D.), Ludwig Center and Howard Hughes Medical Institute (B.R.B., A.D.S., N.P., K.W.K., S.Z., B.V., L.A.D.), and the Departments of Radiology (A.Z.) and Pathology (F.B., T.H., R.H.H., L.D.W., N.C., T.C.C., J.M.T., R.A.A., J.R.E.), Johns Hopkins University School of Medicine, Baltimore; Department of Medicine, Stanford University School of Medicine, Stanford, CA (G.A.F.); Providence Cancer Center at Providence Health and Services, Portland, OR (T.S.C.); Department of Medicine, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh (J.J.L.); Bon Secours Cancer Institute, Richmond, VA (S.M.D.); Division of Medical Oncology, Ohio State University Comprehensive Cancer Center-James Cancer Center and Solove Research Institute, and Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, Columbus (R.M.G., A.C.); and Merck, Kenilworth, NJ, and North Wales, PA (M.K.).
PMID: 26028255 DOI: 10.1056/NEJMoa1500596
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. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.).

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