The Next Frontier: The Promise of Immunotherapy in Gastrointestinal Cancers

In the oncology world, gastrointestinal cancers may be the next in line to realize the promise of immunotherapy.
MARY ANN MACHOL, diagnosed with stage 4 colorectal cancer, has responded well to immunotherapy.
MARY ANN MACHOL, diagnosed with stage 4 colorectal cancer, has responded well to immunotherapy.
Mary Ann Machol was 44 in 2013 when she learned she had inoperable stage 4 colorectal cancer — a difficult diagnosis that left her with no choice but to undergo the harsh three-drug chemotherapy regimen known as FOLFOX. The cocktail (consisting of leucovorin, fluorouracil and oxaliplatin) helped shrink her tumors, but then she was diagnosed with uterine cancer, and had to stop all treatments. After undergoing surgery to remove her uterus, Machol, who lives in the San Francisco Bay area, was put on a different chemotherapy regimen for the colorectal cancer.

By the end of 2014, Machol had run out of options. Then she learned about a trial at Stanford University involving a drug that stimulates the immune system to fight off cancer. The drug, Keytruda (pembrolizumab), from Merck, was already on the market and being used successfully in melanoma and certain lung cancer patients. In March 2015, Machol was accepted into the trial and began receiving infusions of Keytruda every two weeks.

“After the second dose, I started feeling better,” Machol says. “I had been in severe pain — on high doses of morphine around the clock, bedridden and sleeping 16 to 20 hours a day. Then, all of a sudden, I was cutting back on the morphine. I was down to about 100 pounds because I couldn’t eat, but by summer I had gained all my weight back.” Machol’s tumors are shrinking, classifying her as a partial responder to the drug so far. She will remain in the trial through 2017.

Keytruda is among an emerging class of drugs that block “checkpoints” in the body that prevent the immune system from being able to recognize and eradicate cancer cells. Keytruda specifically targets the checkpoint PD-1, which has emerged as an important target in several types of gastrointestinal (GI) cancers, including colorectal, gastric and esophageal cancers.

“GI malignancies are the next frontier for immunotherapy,” says Yelena Janjigian, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York who has been an investigator for several immunotherapy trials. “Several patients of mine with metastatic stomach cancer have failed every standard treatment and have had dramatic and durable responses to immunotherapy. It really has changed lives.”

Inhibiting PD-1 in Colorectal Cancer

Colorectal cancer is the third most commonly diagnosed cancer in both men and women, according to the American Cancer Society. About 90 percent of cases of the disease and 93 percent of deaths occur in people over age 50. While 20 percent of patients have some family history of the disease, a few lifestyle factors are also believed to raise the risk of colorectal cancer, including smoking, certain diets and heavy alcohol use. Obesity is another risk factor.

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