DNA Repair Deficiencies Predictive of Immunotherapy Response

June 13, 2017
DNA Repair Deficiencies Predictive of Immunotherapy Response
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Research from a team of scientists at the Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy, and other institutions, is shedding new light on the role of the DNA mismatch repair (MMR) pathway in the development of a variety of cancers and response to therapy.

In a three-year clinical trial of 86 patients with colorectal and 11 other kinds of cancer that have MMR genetic defects, the investigators found that half of the patients responded to the immunotherapy pembrolizumab, marketed under the brand name Keytruda, and that patient immune responses closely aligned with mutations found in their cancers. Findings from the study were published recently in Science in an article entitled “Mismatch-Repair Deficiency Predicts Response of Solid Tumors to PD-1 Blockade.”

"Our study results may lead to a new standard-of-care that includes MMR deficiency testing to help identify a wider group of patients who have failed other therapies but may benefit from immunotherapy drugs." explained lead study investigator Dung Le, M.D., associate professor of oncology at the Johns Hopkins Bloomberg–Kimmel Institute.

In the current study, 86 adult men and women with 12 cancer types were recruited to the clinical trial at six U.S. hospitals. All the patients 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, imaging scans showed that tumors shrunk by at least 30% in 46 of the 86 patients (53%). Amazingly, the tumors completely disappeared in 18 of the 46 patients.

Twenty-one of the 40 patients with colorectal cancer (52%) and 25 of 46 patients with cancers (54%) in other organs, such as the pancreas, ampullary, cholangiocarcinoma, gastric, endometrial, neuroendocrine, prostate, small intestine, and unknown primary, responded to the drug.

In all, 66 of 86 (77%) had at least some degree of disease control, including those who had partial responses (meaning their cancers shrunk by at least 30% in diameter) and complete responses  (meaning no radiologic evidence of the tumor). This also included 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.

At the time the report was generated, 18 patients were taken off therapy after two years of treatment. Eleven patients have been off immunotherapy for a median of 8.3 months, and none have shown evidence of a cancer recurrence. The remaining patients had some residual disease, were taken off therapy at two years (some because of side effects), and after an average of 7.6 months, none of these patients has had 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.

"We still do not understand why only half of the patients in the study responded, and half did not," noted study co-author Drew Pardoll, M.D., Ph.D., director of the Johns Hopkins Bloomberg–Kimmel Institute. "But in testing for MMR deficiency, we essentially married genetic biomarkers with an immunotherapy drug to find patients we thought would be more likely to respond to this increasingly used drug, and we believe it's a terrific example of the future of precision immunotherapy. The hope is that other immunotherapy drugs can be aligned with genetic factors to further increase success."