Mismatch repair defects predict response to new class of cancer drugs

Reuters Health Information: Mismatch repair defects predict response to new class of cancer drugs

Mismatch repair defects predict response to new class of cancer drugs

Last Updated: 2015-06-01

By Julie Steenhuysen

CHICAGO (Reuters) - Patients whose colorectal and other tumors have mismatch repair defects are far more likely to respond to a new class of drugs called PD-1 inhibitors, a new study has shown.

The small study of Merck & Co's Keytruda (pembrolizumab), financed not by Big Pharma but by swimmers who raised charitable donations, involved patients with advanced colon and rectal cancers and other types of tumors.

At 20 weeks, 92% of patients whose colorectal tumors had mismatch repair deficiencies had their disease controlled, compared to 16% of patients with MMR-proficient colorectal tumors. In patients with MMR-deficient cancers of other sites, the disease control rate was 70 percent.

The findings, announced on Friday at the American Society of Clinical Oncology (ASCO) meeting in Chicago and presented by the researchers on Saturday morning, point to a new way to predict who will respond to PD-1 inhibitors, which can cost $150,000 a year.

"Conservatively speaking, we think this would help 2 to 3% of all cancer patients," said Dr. Luis Diaz of the Ludwig Center at Johns Hopkins Kimmel Cancer Center in Baltimore.

"These are patients with metastatic disease that wouldn't have any other alternatives."

Since the immune system is trained to recognize foreign invaders, Hopkins researchers hypothesized that patients with tumors loaded with mutations due to mismatch repair deficiencies might have a more robust response to cancer drugs that rev up the immune system, such as Merck's Keytruda or Bristol-Myers Squibb's Opdivo (nivolumab).

Diaz said he and Hopkins colleague Dr. Dung Le proposed the trial to several drugmakers who refused to pay for it. Merck donated the study drug but the researchers had to raise money for the trial on their own. They turned to Swim Across America, which raises funds for cancer research. Some 500 Baltimore swimmers raised money for the study by taking a chilly dip last fall into a river leading to the Chesapeake Bay.

The scientists tested Keytruda in 48 patients: 13 with MMR-deficient colorectal cancer, 25 with MMR-proficient colorectal cancer, and 10 with other MMR-deficient cancers.

In the 13 with MMR-deficient colorectal cancer, the immune-related objective response rate was 62 percent and the disease control rate was 92 percent.

In the colorectal cancer patients with MMR-proficient tumors, there were no complete or partial responses, and the disease control rate was 16 percent.

In the group with MMR-deficient other cancers, the objective response rate was 60 percent and the disease control rate was 70 percent.

The median progression-free survival (PFS) and overall survival (OS) were not reached in the MMR-deficient colorectal cancer group, whereas PFS was 2.3 months and OS was 7.6 months in the MMR-proficient colorectal cancer group.

Many of the responses lasted over a year, which is impressive considering the study was done in patients whose "life expectancy was measured in weeks to months," Le said.

Dr. Lynn Schuchter, an ASCO spokeswoman and a University of Pennsylvania oncologist who was not involved in the trial, said the findings need to be confirmed in a larger study but provide an important explanation of why some patients have remarkable responses to these treatments and others do not.

For Adrienne Skinner of Larchmont, New York, the study was a last-ditch option after she failed to respond to two types of chemotherapy to treat her rare gastrointestinal cancer.

When she started treatment with Keytruda, her cancer had spread to her liver, making it inoperable. She has now been on the therapy for 13 months.

"There is no tumor. I don't have to have surgery. It's phenomenal."

The study was published online May 30 in the New England Journal of Medicine, but updated data were presented at the meeting.

SOURCE: http://bit.ly/1LVB42O

N Engl J Med 2015.

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