Merck Drug Helps Colon Cancer Patients With DNA Repair Defect

A small study found that Merck & Co.’s immune system-triggering drug Keytruda shrank tumors in colon cancer patients with a specific gene flaw, showing that genetic tests may help identify those likely to benefit from immune therapy treatments.

The genetic defect, called mismatch repair deficiency, affects about 15 percent of colon cancer patients as well as a minority of patients with endometrial, bile duct and various other tumors. It leads to cancers with huge numbers of mutations because patients’ cells can’t fix “mismatches,” or genetic spelling errors, that sometimes occur as genetic material is synthesized in the body.

In the study being presented at the American Society of Clinical Oncology meeting in Chicago, doctors from Johns Hopkins University’s Sidney Kimmel Comprehensive Cancer Center found that Keytruda helped shrink tumors in eight of 13 patients with colon and rectal cancer mismatch repair problems.

The results provide the first clear indication that immune therapy drugs may work in some colon cancer patients, said Leonard Saltz, a gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center in New York, who wasn’t involved with the study. “Clearly, this is a scientifically defined subset of tumors in whom this class of compounds works.”

In addition to colon and rectal cancer, six of 10 patients with other types of mismatch repair deficient tumors responded to the drug, the study found. By comparison, of 25 colon cancer patients without mismatch repair problems, none experienced tumor shrinkage after taking the drug, according to the results.

Profound Difference

“It is very profound the difference between the two groups,” said Dung Le, a Johns Hopkins oncologist and lead author on the study. “It is always surprising to see something work so well” in such advanced cases.

Only one of the patients who responded to the treatment has relapsed, Le said. The mismatch repair finding is also being published in the New England Journal of Medicine. Side effects of the drug included thyroid disorders and rashes.

Keytruda, currently approved by regulators for the treatment of advanced melanoma, is among the first in a new class of drugs that aim to trigger the body’s immune system to attack a wide variety of tumors. Merck is competing with Bristol-Myers Squibb Co., whose drug Opdivo is approved for melanoma and lung cancer, as well as numerous other companies to identify new types of cancer that immune therapy may work in.

Merck is planning a larger study of Keytruda in colon cancer patients with mismatch repair deficiency, spokeswoman Pamela Eisele said in an e-mail.

Hyper-Mutated Tumors

A variety of gene and protein tests can detect mismatch repair deficiency. Some people are born with the problem as a result of an inherited gene mutation -- called Lynch syndrome -- that vastly increases the risk of colon cancer. Others develop mutations or defects inside their tumors that turn off DNA repair enzymes.

Immune therapy drugs may work well in mismatch repair cases precisely because the tumors are “hyper-mutated,” Saltz said. “You are going to have a whole lot of mutations that nature never intended, and that is what the immune system can recognize.”

The tougher problem is figuring out why the immune therapy drugs have not worked in colon cancer patients without mismatch repair problems, Saltz said. In this much larger group of colon cancer patients, “they have been very disappointing,” he said.

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