乌鸦传媒

CHICAGO -- Tumors with a specific type of DNA repair defect had a high likelihood of responding to treatment with the immune checkpoint inhibitor pembrolizumab (Keytruda), according to a small study reported here.

More than 60% of colorectal cancers associated with mismatch repair (MMR) deficiency responded to the immune-system inducer. In contrast, no patient without the repair deficiency responded to pembrolizumab.

A group of patients with other types of MMR-deficient tumors also responded to the PD-1 inhibitor 60% of the time, suggesting the defect is a generalized marker for susceptibility to PD-1/PD-L1 inhibition, as reported at the American Society of Clinical Oncology meeting.

"This is the first study to use [tumor] genetics in a prospective manner to guide immunotherapy," , of Johns Hopkins, said during an ASCO press briefing. "Mismatch repair-deficient tumors are highly responsive to checkpoint blockade with anti-PD1 therapy."

"Mismatch repair deficiency is represented in approximately 4% to 5% of many tumor types, so it has broad applicability, and we saw responses in colorectal cancer, endometrial cancer, stomach cancer, small-bowel cancer, and bile-duct cancer.

MMR deficiency is "easily determined using an existing, commercially available test," she added. "This study suggests genomics are more influential than histology for mismatch repair-deficient tumors treated with anti-PD-1 therapy."

Determining an efficient and cost-effective strategy for testing patients for the tumor deficiency constitutes a major challenge for applying the findings to clinical practice, she and other cancer specialists acknowledged at the briefing. Le said testing would probably add "hundreds, not thousands" of dollars to the cost of care for an individual patient.

The MMR pathway is a principal mechanism by which cells repair errors in DNA replication. Cellular MMR deficiency leads to accumulation of mutations. A typical tumor has dozens of mutations. MMR-deficient tumors may have thousands, which increases the odds that the immune system will recognize and destroy a tumor, said Le.

Drugs that target PD-1/PD-L1 block tumors' ability to keep the immune system in check. The inhibitory effect enhances the immune system's ability to destroy tumor cells.

Le and colleagues hypothesized that PD-1 blockade with pembrolizumab would be particularly effective against tumors with MMR deficiency. To test the hypothesis, they enrolled and treated three groups of patients: 28 with MMR-deficient colorectal cancer, 26 with MMR-proficient (normal) colorectal cancer, and 21 with noncolorectal cancers with MMR deficiency.

Le reported data for 48 of the patients: 25 with MMR-deficient colorectal cancer, 13 with MMR-proficient colorectal cancer, and 10 with other MMR-deficient tumors. The data showed a 62% response rate and 92% disease control rate (response plus stable disease) in MMR-deficient colorectal cancer versus no objective responses and a disease control rate of 16% in patients with MMR-proficient colorectal cancer.

Objective responses occurred in six of the 10 patients with other MMR-deficient tumors, and another patient had stable disease, resulting in a disease control rate of 70%.

"The responses were durable, and many are ongoing for more than a year," said Le.

Preliminary overall survival data are encouraging, she added, as the median has yet to be reached in patients with MMR-deficient tumors (colorectal cancer and all tumors) as compared with a median of less than 10 months in patients with MMR-proficient colorectal cancer.

Consistent with previous studies, mutation analysis showed that MMR-deficient tumors harbored an average of about 1,700 mutations versus about 70 in MMR-proficient tumors (P=0.007).

The large number of mutations in MMR-deficient tumors "is like putting a red flag on cancer cells and saying to the immune system, 'Here I am,' and allows the immune system to recognize these cancer cells as foreign," said press briefing moderator , of the University of Pennsylvania in Philadelphia.

The study provides a different perspective about immunotherapeutic approaches to treating cancer.

"It's not all about the immune characteristics of the tumors. It's not all about PD-L1 expression," Schuchter added. "Is there something about the genetic makeup of the tumor? Is it about how many red flags are on a cancer cells that really predicts response? It's a different way of thinking about which patients are going to respond to immunotherapy."

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