Abstract
According to a phase II study, mismatch repair deficiency is the first genomic marker to predict response to PD-1 blockade in colorectal and other cancers.
A phase II study has identified the first genomic marker, mismatch repair (MMR) deficiency, to predict response to PD-1 blockade in colorectal and other cancers. Researchers presented the findings at the American Society of Clinical Oncology Annual Meeting in Chicago, IL, on May 30. Initial data from the study were published concurrently in The New England Journal of Medicine (N Engl J Med 2015 May 30 [Epub ahead of print]).
Researchers hypothesized that because tumors with MMR deficiency have a faulty DNA repair system and generally harbor hundreds—even thousands—of mutations, they might be more susceptible to augmentation of the immune system with a PD-1 inhibitor, explained Dung T. Le, MD, an assistant professor of oncology at the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine in Baltimore, MD, who presented the findings. This is because each mutation has the potential to encode a mutant protein that might be recognized as an antigen by the immune system.
To test their theory, researchers turned to patients with colorectal cancer, whose tumors are often sequenced to check for defects in any of four mismatch-repair genes—MLH1, MSH2, MSH6, and PSM2—characteristic of hereditary Lynch syndrome. They recruited 25 patients with MMR-deficient and 25 patients with MMR-proficient colorectal cancers. In addition, they recruited 21 patients with other types of tumors that exhibited MMR deficiency.
Patients in all three cohorts had previously treated metastatic cancer, and all received the anti–PD-1 antibody pembrolizumab (Keytruda; Merck), given intravenously at a dose of 10 mg/kg every 2 weeks. In patients with colorectal cancer, the tumor marker carcinoembryonic antigen (CEA) was measured before and during the trial.
Le reported that 62% of the patients with MMR-deficient colorectal cancer experienced tumor shrinkage compared with 0% of those with MMR-proficient disease. The disease control rates, which account for both tumor shrinkage and stable disease, were 92% and 16% respectively.
In the group of other MMR-deficient cancers, the overall response rate (ORR) was 60% and the disease control rate was 70%. Patients with MMR-deficient non-colorectal cancers responded much like those with MMR-deficient colorectal tumors: The ORR was 60% and the disease control rate was 70%. This group included patients with advanced endometrial cancer and several types of advanced gastrointestinal cancers.
“The responses were durable in a treatment-refractory patient population, and many of these responses are ongoing for over a year,” said Le.
Reductions in CEA levels occurred quickly in the MMR-deficient group, usually within a few weeks of starting treatment. That's an indication that “the T cells were sitting there and that they were inhibited,” said Le. “They were waiting to be released.” In contrast, CEA levels increased in patients with MMR-proficient tumors.
Of note, MMR-deficient tumors had an average of 1,782 mutations; MMR-proficient tumors had just 73. Having a higher number of mutations was linked to a better response. However, some patients with MMR-deficient tumors didn't respond to pembrolizumab, which may mean that “those patients may not have a mutation that the immune system can recognize,” explained Le, adding that researchers plan to further assess the MMR-deficient non-responders.
Dung T. Le, MD, discusses the use of mismatch repair deficiency to predict response to PD-1 blockade in colorectal and other cancers.
Dung T. Le, MD, discusses the use of mismatch repair deficiency to predict response to PD-1 blockade in colorectal and other cancers.
Although MMR deficiency can occur in many cancer types, including those in the uterus, stomach, biliary tract, pancreas, ovaries, prostate, and small intestine, in addition to colorectal cancer, Le said it is too early to recommend that all patients with cancer be tested for it. Researchers first need to confirm their findings in a larger group of patients. “This was a small study,” she said.
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