Pembrolizumab in Solid Tumors With Mismatch-Repair Deficiency
As reported by Le et al in Science, pembrolizumab (Keytruda) was found to be active across a range of solid tumors with mismatch-repair (MMR) deficiency. Pembrolizumab was recently approved for treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch-repair deficient (dMMR) solid tumors progressing following prior treatment or with MSI-H or dMMR colorectal progressing after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
Study Details
In the study, 86 consecutive patients with 12 cancer types who had evidence of MMR deficiency on polymerase chain reaction or immunohistochemistry began treatment with pembrolizumab between September 2013 and September 2016. All patients had received at least one prior therapy and had evidence of progressive disease.
Colorectal cancer was the most common tumor type, followed by osteosarcoma; other tumor types included cholangiocarcinoma and ampullary, endometrial, gastroesophageal, pancreatic, prostate, neuroendocrine, small intestinal, and thyroid cancers. Germline-sequence changes diagnostic of Lynch syndrome were found in 32 patients (48%), with the most common alteration being MSH2 mutation.
Response Rates
Objective responses were observed in 46 patients (53%), with a complete response occurring in 18 patients (21%). An additional 20 patients had stable disease, yielding a disease control rate of 77%. Objective response was observed in 52% of patients with colorectal cancer and in 54% of those with other tumors; response was observed in 46% of patients with Lynch syndrome–associated tumors and in 59% of those without such tumors (P = .27). In 11 patients with a complete response who were taken off pembrolizumab after 2 years, no evidence of recurrence has been detected after a median time off therapy of 8.3 months.
Median progression-free survival was not reached (95% confidence interval [CI] = 14.8 months to not estimable); 2-year progression-free survival was 53%. Median overall survival was not reached (95% CI = not estimable to not estimable); 2-year overall survival was 64%.
Adverse Events
Adverse events were similar to those reported in other pembrolizumab trials. Adverse events of any grade occurred in 74% of patients, with endocrine disorders, mainly hypothyroidism, occurring in 21%.
The investigators concluded: “These data support the hypothesis that the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.”
They noted: “Because genetic and immunohistochemical tests for MMR-deficiency are already widely available, these results tie immunity, cancer genetics, and therapeutics together in a manner that will likely establish a new standard of care and in the future, testing for MMR deficiency in patients’ refractory to other treatments might be considered in order to identify those who may benefit from [programmed cell death protein 1] pathway blockade, regardless of tumor type.”
The study was funded by The Swim Across America Laboratory at Johns Hopkins, Ludwig Center for Cancer Genetics and Therapeutics, Howard Hughes Medical Institutes, Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, National Institutes of Health, Merck & Co, and others.
Luis A. Diaz Jr, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of the Science article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
