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MMR Deficiency Ties to Checkpoint Blockade Response Explored in Prospective Study

NEW YORK (GenomeWeb) – Researchers are continuing to accumulate data suggesting that cancer cases marked by certain DNA repair problems are more likely to respond to immune checkpoint blockade drugs in a manner that's independent of the tumor's tissue of origin.

In a study appearing online today in Science, investigators from Johns Hopkins University and elsewhere took a prospective look at the possibility of using tumor mismatch repair (MMR) deficiency as a pan-cancer marker for immune checkpoint inhibitor response. They focused on 86 already-treated individuals affected by a dozen cancer types.

In those cases, which were all marked by MMR-deficiency, the team saw objective response rates exceeding 50 percent following treatment with the anti-PD-1 immunotherapy drug pembrolizumab (marketed as Keytruda by Merck). A little more than 20 percent of the patients had complete response to the drug, based on radiographic tumor imaging, the group reported.

Data from the study "support the hypothesis that the large proportion of mutant neoantigens in MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin," corresponding author Luis Diaz Jr. and his colleagues wrote. Diaz was affiliated with the Bloomberg-Kimmel Institute for Cancer Immunotherapy and the Sidney Kimmel Comprehensive Cancer Center when the research was performed. As of mid-April, he heads Memorial Sloan Kettering Cancer Center's solid tumor oncology division.

At last year's American Society of Clinical Oncology annual meeting, Diaz reported on pembrolizumab response patterns in dozens of advanced colorectal cancer (CRC) patients with MMR-deficient or MMR-proficient tumors.

At 2015's ASCO conference, Diaz presented data from a phase II study of around 50 individuals with previously-treated cancer who were treated with pembrolizumab, comparing response to the checkpoint blockade in MMR-deficient CRC, MMR-intact CRC, or MMR-deficient cancer of another type.

In 2015, he and his colleagues also reported on apparent MMR ties to pembrolizumab response in 41 individuals with metastatic CRC or other progressive metastatic cancer types in the New England Journal of Medicine.

In their new Science study, Diaz and his co-authors wrote, "The genomes of mismatch repair-deficient tumors all harbor hundreds to thousands of somatic mutations, regardless of their cell of origin. We therefore sought to investigate the effects of PD-1 blockade (using the anti-PD-1 antibody pembrolizumab) in mismatch repair-deficient tumors independent of the tissue of origin."

For the latest published study, the team prospectively followed 86 cancer patients with one or more past treatment who were enrolled consecutively between September 2013 and September 2016. Using PCR or immunohistochemistry profiles, the researchers saw signs of MMR problems in each of the cases progressive cancer cases — patterns explored in more detail in a subset of the cases using targeted germline sequencing on MMR-related genes such as MSH2, MSH6, PMS2, and MLH1.

In 32 of the individuals with MSH2-mutated tumors, for example, the researchers uncovered germline alterations associated with Lynch syndrome. And another seven individuals who were not assessed by germline sequencing had family histories that appeared to be consistent with Lynch syndrome-related mutation carriage in their families.

Eighteen of the individuals had a complete response to the PD-1-targeting antibody drug pembrolizumab, and dozens more had a partial response or stable disease, translating into an objective response rate of 42 percent to 64 percent and a disease control rate of 66 percent to 85 percent.

Another 14 percent of individuals had disease progression, while 9 percent could not be evaluated at the scheduled 12-week scan, the researchers reported. Comparing exome sequences for matched tumor and normal samples from three non-responders and 15 individuals who did respond to pembrolizumab, they did not see discernable differences in non-synonymous mutation rates.

The team also used exome sequencing to identify new mutations that turned up in brain metastases from two of the five patients who experienced acquired resistance to pembrolizumab and were subsequently treated with additional radiation- and/or surgery-based treatments. And in a handful of pembrolizumab responders, deep T-cell receptor sequencing offered a peek at T-cell representation during this drug response.

To get a broader look at the frequency of MMR-deficiency across even more tumor types, the researchers used targeted sequencing to evaluate MMR status in more than 12,000 tumors from 32 cancer subtypes, uncovering MMR deficiency in less than 1 percent to roughly 17 percent of tumors depending on the cancer subtype considered.

"Because genetic and immunohistochemical tests for MMR-deficiency are already widely available," the authors concluded, "these results tie immunity, cancer genetics, and therapeutics together in a manner that will likely establish a new standard-of-care and in the future, testing for MMR-deficiency in patients' refractory to other treatments might be considered in order to identify those who may benefit from PD-1 pathway blockade, regardless of tumor type."

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