Roxanne Nelson

May 29, 2015

Chicago — A mismatch repair (MMR) deficiency has been identified as the first genomic marker to predict response to the immunotherapy pembrolizumab (Keytruda, Merck).

"This is the first study to use genetics to guide immunotherapy," said lead study author Dung T. Le, MD, assistant professor of oncology at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

Speaking during a press briefing here at the annual meeting of the American Society of Clinical Oncology, she noted that these data suggest that genomics may be more influential than histology for predicting which patients will respond to immunotherapy with drugs acting on the program death pathway.

MMR deficiency is found in 15% to 20% of sporadic colorectal cancer and in nearly all colorectal cancers that are associated with Lynch syndrome, which constitute up to 5% of all cases. MMR deficiency is also found in other tumor types including stomach, small bowel, endometrial, prostate, and ovarian cancers.

Right now, testing is standard of care in patients with colorectal cancer to check for the presence of Lynch syndrome. "It is in the NCCN [National Comprehensive Cancer Network] guidelines to check for that," she said, "and also in endometrial cancer."

As far as cost, Dr Le explained that testing can be done using different methods, but typically is not that expensive and runs "in the hundreds of dollars" and not thousands.

"We are beginning to pinpoint and predict which patients will benefit and [it is] important to precisely define who is going to benefit from immunotherapy and who isn't," commented Lynn Schuchter, MD, moderator of the briefing and chief of the hematology/oncology division at the University of Pennsylvania, Philadelphia.

"It is important to know who shouldn't be exposed to these treatments as they have a potential for side effects," she said.

MMR Deficiency Predicts Response

Pembrolizumab is currently approved by the US Food and Drug Administration to treat patients with advanced melanoma that has not responded to other standard therapies.

The study looking at MMR deficiency as a predictor of response was a phase II study conducted in a cohort that was divided into three groups: MMR-proficient metastatic colorectal cancer (n = 25), MMR-deficient metastatic colorectal cancer (n = 13), and other MMR-deficient cancers (n = 10).

Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to all patients, and the coprimary endpoints were immune-related objective response rate and immune-related progression-free survival at 20 weeks.

Among 48 patients with previously treated, progressive metastatic disease with and without MMR deficiency, 62% of those with MMR-deficient colorectal cancer had an objective response, and disease control was 92%.

The response and disease control rates were 60% and 70%, respectively, in patients with other types of MMR-deficient tumors.

However, for patients with MMR-proficient tumors, the response rate was 0% and the disease control rate was 16%.

The researchers found that the study met both primary endpoints for both MMR-deficient cohorts. The immune-related objective response rate and the immune-related progression-free survival at 20 weeks in MMR-deficient colorectal cancer were 40% and 78%, respectively, and for MMR-deficient other cancers the rates were 71% and 67%, respectively.

In contrast, for MMR-proficient colorectal cancer, the immune-related objective response rate and the immune-related progression-free survival at 20 weeks were 0% and 11%, respectively.

Among patients with MMR-deficient colorectal cancer, eight achieved a partial response to pembrolizumab, while four had prolonged, stable disease.

All 25 colorectal patients that were MMR-proficient failed to respond to the drug.

In the third group, where all patients were MMR-deficient (four with pancreatic/bile duct cancers, two with uterine cancers, two with small bowel cancers, one with stomach cancer, and one with prostate cancer), one uterine cancer patient achieved a complete response, five had partial responses, one had stable disease, and the remaining three patients had disease progression.

Median overall and progression-free survival in MMR-deficient colorectal cancer patients have not yet been reached, as several patients have continued to respond for more than 12 months, the authors note, and median follow-up is 36 weeks.

MMR-proficient colorectal cancer patients had a median overall survival of 7.6 months, and progression-free survival was 2.3 months, with a follow-up of 42 weeks.

In the third cohort, median overall survival has also not been reached, and median progression-free survival was 5.4 months after being followed-up for up to 42 weeks.

High Somatic Mutation Loads Predictive

Whole exome sequencing revealed an average of 1782 somatic mutations per tumor in MMR-deficient tumors compared with only 73 in MMR-proficient tumors (P = .0015). The high somatic mutation loads were associated with progression-free survival (P = .02).

"The 1700 mutations is like putting a red flag on a cancer cell and saying to the immune system 'here I am, and now allows the immune system to view these cancer cells as foreign," commented Dr Schuchter.

The next step is to reproduce the findings of this prospective study in a larger group of patients, according to Dr Le. She noted that the durability of response with little toxicity could eventually lead to testing this approach in initial treatment for these patients.

"This study helped identify a whole new population of patients who might benefit from PD-1 immunotherapy. MMR deficiency appears to be a predictor of response to pembrolizumab, and it's very encouraging that the responses in MMR-deficient tumors thus far have been long-lasting," said Smitha S. Krishnamurthi, MD, associate professor of medicine at Case Western Reserve University, Cleveland, Ohio, in a statement.

This study received funding from Swim Across America, The Commonwealth Fund, The Ludwig Center at Johns Hopkins, and the National Institutes of Health. Several of the authors report relationships with industry, as noted in the abstract.

American Society of Clinical Oncology (ASCO) 2015 Annual Meeting: Abstract LBA 100. Presented May 30, 2015.

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