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.
In addition to chemotherapy, some monoclonal antibody-based, or targeted, drugs have been approved to treat colorectal cancer, including Avastin (bevacizumab), an “anti-angiogenic” treatment that works by targeting vascular endothelial growth factor (VEGF) and thereby cutting off the blood supply to tumors. There are also Erbitux (cetuximab) and Vectibix (panitumumab), which target epidermal growth factor receptor (EGFR), a protein that is over-expressed in some colorectal cancers.

Still, the prognosis for patients, particularly those in the late stages of the disease, is not good. The five-year survival rate for metastatic colon and rectal cancer is 11 percent and 12 percent, respectively.

One challenge with PD-1 inhibitors is that they tend to work particularly well in tumors that have a lot of mutations. The more mutated a cancer, the more foreign the cells look to the immune system and the more likely it is to go after the cancer once the checkpoint is removed. But colorectal cancer mostly resembles normal colon cells, making it difficult for the immune system to recognize them as foreign invaders that need to be eradicated, even with help from an immunotherapy.

In an early trial of Keytruda in colorectal cancer, only one out of 33 patients responded well to the drug. Researchers at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discovered that the patient had a condition called “mismatch repair” (MMR) deficiency, which renders tumors incapable of repairing damage to their DNA. As a result, the tumors accumulate thousands of mutations.

So they designed a phase 2 study of Keytruda to prove that colorectal cancer patients with MMR would respond well to the drug. The results were dramatic: The cancer was brought under control in 90 percent of MMR-positive patients, versus just 11 percent of patients without the deficiency. In November 2015, the FDA granted breakthrough therapy status to Keytruda for colorectal cancer patients with MMR defects, and a phase 3 study has been initiated.

Half of the MMR-deficient patients in the phase 2 trial saw their tumors shrink more than 50 percent. “In several patients, the tumors are completely gone,” says Luis Alberto Diaz, Jr., associate professor of oncology at Johns Hopkins and one of the investigators for the trial. “It’s exciting to see these patients alive and thriving.”

About 3 percent of colorectal cancer patients have Lynch syndrome, an inherited genetic mutation that almost always causes mismatch repair. Machol is among those patients. Although it’s rare — about one in 30 of all cancers have MMR, Diaz estimates — he anticipates that results from the trial of Keytruda in colorectal cancer patients with the deficiency may be relevant for treating a range of solid tumors. “Over the next six to 12 months, there will be continued advances,” he predicts.

Another benefit of PD-1 inhibitors is that they are considerably less toxic than chemotherapy, typically causing mild effects like fatigue, rash, stomach upset and joint pain, and more rarely touching off other auto-immune disorders. Machol, a pediatric nurse who is married with two children, says the only major side effect she has suffered was a swollen thyroid, which was easily controlled with medication. “I have some fatigue, but otherwise I have my life back,” she says.

Boosting Standard Treatments With Immunotherapy

Keytruda is also being tested in esophageal cancer — another type of GI cancer where advances in treatment have been slow to arrive. Esophageal cancer strikes three to four times as many men as women, according to the American Cancer Society. Smoking is a major risk factor for the disease. Some people with Barrett’s esophagus, a condition caused by long-term acid reflux disease, also go on to develop this cancer.

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