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Growing evidence that flaws in a tumor's genetic mending kit drives response to immunotherapy
In an expanded, three-year clinical trial of 86 patients with colorectal cancer and eleven other types of tumors with genetic defects in their DNA repair machinery, scientists at Ludwig Johns Hopkins and the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins have found that half of the patients respond to an immunotherapy drug called pembrolizumab (Keytruda). In their report, which led the U.S. Food and Drug Administration to approve expanded use of pembrolizumab, the researchers also share evidence that anti-cancer immune responses in these patients correspond closely to mutations in their cancer cells. Their findings, which enable better personalization of immunotherapy, were published online today in Science.
Mismatch repair (MMR) genes are part of a system that helps cells recognize and correct mistakes during DNA replication. Defective MMR genes have long been linked to inherited and non-inherited (or sporadic) forms of colon cancer and are used as biomarkers for diagnostic screening and chemotherapy treatment planning.
For the current study—designed and led by Luis Diaz, who recently moved to the Memorial Sloan Kettering Cancer Center from Ludwig Johns Hopkins, and Dung Le of the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins—86 adult men and women with 12 cancer types were recruited to the clinical trial at six U.S. hospitals. All tested positive for MMR defects and had failed to respond to at least one prior therapy. They received pembrolizumab intravenously every two weeks for up to two years.
After a median follow-up of 12.5 months, tumors shrank by at least 30% in 46 of the 86 patients (53%). They completely disappeared in 18 of the 46. In all, 66 of 86 (77%) had at least some degree of disease control. That includes those who had partial responses, meaning their tumors shrank by at least 30%, and complete responses, in which there is no radiologic evidence of tumors. It also includes those whose tumors did not grow, but remained stable. At one year after the start of therapy, 65 of the 86 patients (76%) were alive, and 55 of the 86 (64%) were alive at two years.
Five of 20 patients (two with colon cancer, two with pancreatic cancer and one with small bowel cancer) who were listed as having progressive disease initially responded to pembrolizumab. But their cancers often regrew in areas such as the brain or bone. Three were treated additionally with surgery or radiation and continued treatment with pembrolizumab. All five remained alive at the time of the data cutoff.
Twenty-one of 40 patients with colorectal cancer (52%) and 25 of 46 patients with other cancers (54%)—including pancreas, ampullary, cholangiocarcinoma, gastric, endometrial, neuroendocrine, prostate, small intestine and those of unknown origin—responded to the drug. Common side effects included fatigue, skin inflammation, joint pain and thyroid dysfunction.
At the time of the data cutoff, 18 patients were taken off therapy after two years of treatment. Eleven patients have been off of immunotherapy for a median of 8.3 months, and none have shown evidence of a cancer recurrence. The remaining patients had some residual disease and were taken off therapy at two years (some because of side effects). After an average of 7.6 months, none of these patients has shown evidence of disease progression.
The median point of survival without disease progression and overall survival has not yet been reached. However, the scientists estimate that disease-free survival at one and two years is 64% and 53%, respectively. Without immunotherapy, patients with advanced, treatment-refractory cancers can expect to live less than six months.
The researchers also performed biopsies on residual tumors in 20 patients. In 12, they found no cancer cells, only inflamed cells, fibrotic tissue and mucus. These patients were more likely to survive longer without progression of their cancer (25.9 months) compared with the other eight who had residual cancer cells in their biopsies (2.9 months). However, there was no difference in overall survival between these two groups.
The researchers tracked T-cells in the tumors and blood of patients that could recognize the biochemical signatures of mutations in their cancers. In three patients, they found these cells rapidly increased in the circulating blood after immunotherapy was administered, peaking one to two months later, often prior to tumor regression.
On the basis of a genomic analysis, the researchers estimate that mismatch repair defects occur in nearly 5% of patients with 11 types of cancer.
The full news release from which this summary is derived can be found here.