CHICAGO – Tumors that carry a genetic signature known as mismatch repair deficiency are highly responsive to immune checkpoint blockade with pembrolizumab, according to results from a small proof-of-concept study.
“This is the first study to use genetics in a prospective manner to guide immunotherapy,” study author Dr. Dung T. Le said in a press conference at the annual meeting of the American Society of Clinical Oncology.
The phase II study, also published online May 30 in the New England Journal of Medicine, enrolled three cohorts, all of which had previously treated metastatic cancer. Pembrolizumab (Keytruda) 10 mg/kg was given intravenously every two weeks.
An objective response was observed in 62% of 25 patients with mismatch repair-deficient colorectal cancer versus none of the 25 patients with mismatch repair-proficient colorectal cancer, she said.
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Disease control rates, which also included stable disease for at least 12 weeks, were 92% vs. 16%, respectively.
In a third cohort of 21 patients with a variety of mismatch repair-deficient cancers including pancreatic/bile duct, uterine, small bowel, stomach, and prostate, the response rate was 60% and disease control rate 70%.
Median overall survival has not been reached in the mismatch repair-deficient cohorts, with some patients continuing to respond to the immunotherapy drug for more than a year Dr. Le, with the Johns Hopkins Kimmel Cancer Center in Baltimore, said. Median overall survival was about 7.6 months in the mismatch repair-proficient colorectal cohort.
“These data suggest that genomics is more influential than histology for mismatch repair-deficient tumors when treated with anti-PD-1,” she said.
Defects in mismatch repair genes disable cells’ ability to repair errors in the DNA replication process. As a result, tumors deficient in mismatch repair proteins produce hundreds to thousands of mutations. Immunotherapy may work best in patients with more mutations in their tumors because multiple mutations trigger production of more abnormal proteins in cancer cells, and in turn prompt the immune system to mount a bigger response.
Indeed, higher somatic mutation loads were associated with better response and prolonged progression free-survival. On average, mismatch repair-deficient tumors had about 1,700 mutations vs. about 70 mutations in mismatch repair-proficient tumors (P = .007), Dr. Le said.
“Seventeen-hundred mutations: that’s like you put a red flag on the cancer cell and say to the immune system, ‘Here I am,’ ” press conference moderator Dr. Lynn Schuchter, chief of hematology-oncology at University of Pennsylvania in Philadelphia, remarked to reporters.
The study was funded by Swim Across America, The Commonwealth Fund, The Ludwig Center at Johns Hopkins, and the National Institutes of Health. Merck provided the study drug. Personal Genome Diagnostics performed the sequencing analysis. Dr. Le reported having no financial disclosures. Dr. Schuchter reported institutional research funding from Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Merck, and Roche.