PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. | Read by QxMD (original) (raw)

Clinical Trial, Phase II

Journal Article

Research Support, N.I.H., Extramural

Research Support, Non-U.S. Gov't

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 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

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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