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High Expectations for Immunotherapy in GI Cancers

Published on 27 March 2018  | Download | back to previous

 (click to view the video)Rhonda Ball was all too familiar with the ups and downs of cancer treatment when, in 2016, she entered a clinical trial for Keytruda (pembrolizumab), a drug that boosts the immune system. By then, she had endured surgery and chemotherapy to treat breast cancer that was diagnosed in 2009 and uterine cancer that occurred three years later. Finally, after an unrelated cancerous blockage appeared in her bowel in 2016, she was offered immunotherapy — a treatment that was possible because of a particular genetic characteristic of her tumors.

Two years earlier, three small tumors had emerged on the back of Ball’s skull, hip and stomach, two of which were removed and studied. DNA sequencing revealed an abnormal biomarker called microsatellite instabilityhigh (MSI-high), also known as mismatch repair-deficient. It meant that her cancer cells had a diminished ability to repair their own DNA. This deficiency could make them vulnerable to drugs like Keytruda, which are designed to free up the immune system to recognize and attack cancer.

From day one, Ball could tell Keytruda was working on the stomach tumor, which had started to break through her skin. “The very first day I had the treatment, the tumor was just burning, and visually I could tell it was shrinking,” says Ball, who, starting in August 2016, received infusions at the Ohio State University Comprehensive Cancer Center’s Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, in Columbus. “That made me think it was working.” Ball’s most recent scans in January 2018 showed no signs of cancer.

The Food and Drug Administration (FDA) approved Keytruda in May 2017 to treat any metastatic or nonresectable type of cancer that’s MSI-high. The first FDA approval based on a genetic characteristic of cancer rather than its location in the body, it was hailed as a breakthrough by oncologists — particularly those who treat gastrointestinal cancers. Keytruda is known as a checkpoint inhibitor because it interferes with the protein PD-1, which would otherwise keep the immune system in check, preventing it from going into overdrive to attack cancer.

“Anti–PD-1 therapy for MSI-high colorectal cancer was the first immunotherapy approved for gastrointestinal cancers, in part because this therapy works extremely well for the majority of patients who are MSI-high,” says Michael Overman, M.D., associate professor in the department of gastrointestinal medical oncology at MD Anderson Cancer Center in Houston. “And when it works, it often seems to keep working.”

An estimated 15 percent of colorectal cancers are MSIhigh, as are up to 39 percent of gastric tumors, although the mutational status is less common in advanced disease. About 3 percent of colorectal cancers with the abnormality occur in patients who have Lynch syndrome — an inherited collection of gene mutations that are associated with cancer risk — but other MSI-high tumors, like Ball’s, appear to form spontaneously. MSI-high status is sometimes also seen in glioblastoma brain tumors; lymphomas; and cancers of the urinary tract, ovaries or endometrium, according to a 2017 study published by Harvard researchers in the journal Nature Communications. This mutational status can also appear in biliary, bladder, breast, pancreatic, prostate, renal cell, sarcoma, small cell lung, small intestinal, thyroid and peritoneal cancers, according to Merck & Co., the maker of Keytruda.

Because MSI-high tumors cannot repair their DNA, they have about 1,700 mutations, on average, compared with 70 found in normal cancer cells. Scientists who helped develop the drug for MSI-high tumors believe it works because of the sheer quantity of mutations the irregularity causes. “The more mutations a tumor has, the more foreign it looks to the immune system,” explains Dung Thi Le, M.D., an associate professor of oncology at Johns Hopkins University School of Medicine in Baltimore and a clinical trial investigator who tested Keytruda in MSI-high cancers. Once the mutations flag MSI-high tumors as foreign invaders, the drug unveils the cancer to the immune system, which sets out to eliminate the disease.

Keytruda had previously been indicated for the treatment of several specific tumor types, including melanoma and non-small cell lung cancer. A few months after Keytruda was approved for all MSI-high cancers, another PD-1 inhibitor, Opdivo (nivolumab), won FDA approval in MSI-high, metastatic colorectal cancer that had progressed despite chemotherapy. Both drugs produced impressive results in late-stage clinical studies, with objective response rates of about one-third in patients with colorectal cancer. Side effects included fatigue, fever, diarrhea and itchy skin.

Ball, who expects to stay in the Keytruda trial until mid-2018, says she has experienced no side effects from the drug, which she gets by infusion every two weeks.

She doesn’t require any other treatments to control her cancer. When she renewed her wedding vows with her husband on Aug. 10, as she does every year, she fit into her wedding dress, thanks to the shrunken tumor on her stomach. “I feel so blessed to have been given this opportunity,” says Ball, who lives near Ohio State and works as an insurance salesperson.

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