The Next Frontier: The Promise of Immunotherapy in Gastrointestinal Cancers

MARY ANN MACHOL, diagnosed with stage 4 colorectal cancer, has responded well to immunotherapy.

[PHOTO BY JULIE CHESHIRE (JULIECHESHIRE.COM)]

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.

Inhibiting PD-1 in Colorectal Cancer

“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.”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. 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.

Boosting Standard Treatments With Immunotherapy

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.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. Along with surgery, chemotherapy combinations are commonly used to treat esophageal cancer; some of the drugs often involved are fluorouracil (FU), cisplatin or other platinumbased chemotherapies, taxanes, anthracyclines, capecitabine and sometimes irinotecan hydrochloride. Radiation may also be used. Still, the five-year survival rate, averaged across all stages of esophageal cancer, is only about 20 percent.

In January 2016, Merck announced that Keytruda produced a 30 percent response rate in an early trial in patients with previously treated esophageal tumors that overexpressed PD-L1, a protein related to PD-1 that’s believed to be a good predictor of response to Keytruda. All of the responses were partial, and the patients were only followed for seven months, but the results were deemed promising enough to warrant further study. So Merck recently launched a phase 3 study, called Keynote-181, and is currently recruiting 600 patients.

PD-L1 inhibitors are also being explored in esophageal cancers, including Medimmune’s durvalumab (MEDI4736). It is currently in phase 2 trials.

After treatment with durvalumab for his stage 4 esophageal cancer, MICHAEL KENNEY’s tumors disappeared.

[PHOTO BY LAUREN SHEINTAL]

Michael Kenney, who was diagnosed with stage 4 esophageal cancer in June 2013 and treated with FOLFOX, qualified for the durvalumab trial in October of that year and jumped at the chance to participate. “I was told it would supercharge my immune system so it would recognize the cancer,” recalls Kenney, 55. He received the treatment at MedStar Georgetown University Hospital every other week for a year, but it only took six months for his tumors to virtually disappear. In July of 2015, he underwent surgery to remove a small tumor that remained at the junction of his esophagus and stomach. He no longer requires any treatment.

“It’s an absolute miracle,” says Kenney, a married father of two who lives in Rockville, Maryland. Kenney got a minor rash from the immunotherapy but otherwise felt as if he was taking nothing at all, he says. “It was surreal. I felt totally fine.”

Using Biomarkers to Improve Gastric Cancer Outcomes

Michael Pishvaian, the oncologist at Georgetown who treated Kenney in the trial, says immunotherapy seems to be particularly beneficial in patients with cancers of the upper GI tract, though scientists have not quite figured out why yet. And more than 70 percent of patients report no side effects, he says. Although oncologists are still trying to figure out how to predict who will best respond to these therapies, Pishvaian says, “there’s a good chance they will be part of the armamentarium in esophageal cancer.” Immunotherapy is also being tried along with either chemotherapy or radiation, Pishvaian adds. “That’s based on the premise that giving chemotherapy or radiation, even if doesn’t completely kill the cancer, might kill enough of the cancer cells to cause an immune response,” Pishvaian says. “That would enhance the response to the immunotherapy.”In January 2016, data was released showing a 14 percent response rate to another anti-PD-1 drug, Opdivo (nivolumab), in patients with metastatic gastric, esophageal or gastroesophageal junction cancers — a relatively low success rate. However, 27 percent of patients whose tumors expressed PD-L1 did respond, raising hope among oncologists that PD-L1 may be an important prognosticator of treatment response.

The quest to understand PD-L1 and other biomarkers of tumor response to immunotherapy is particularly pressing in gastric cancer, where there have been few advances in recent years. The disease is most common in men over 65, and it is more prevalent in Hispanic Americans, African Americans and Asian/Pacific Islanders than it is in Caucasians. Infection with Helicobacter pylori (H. pylori), a type of bacteria that can lead to ulcer, seems to raise the risk of gastric cancer, as does smoking. Less than 3 percent of cases have an inherited component.

The five-year survival rate for gastric cancer at the earliest stages is 71 percent, according to the American Cancer Society, but because its symptoms often aren’t noticeable until it has spread, the disease is rarely diagnosed until it is in stage 4, at which point the survival rate drops to 4 percent. As many as nine different chemotherapy drugs can be tried in various combinations, along with radiation and targeted antibodybased treatments such as Herceptin (trastuzumab), which is approved to treat metastatic or gastroesophageal junction tumors that test positive for the HER2 oncogene. About 20 percent of gastric tumors exhibit HER2 overexpression or gene amplication.

Other antibodies have shown modest survival benefits in gastric cancer, including the approved drug Cyramza (ramucirumab) and an experimental molecule called apatanib, both of which target the angiogenic factor VEGFR2. Still, “the landscape in gastric cancer in the second- and third-line setting is so bare. We can’t enrich treatments based on biomarkers beyond HER2,” says Janjigian, who is an investigator for the Opdivo trials. More in-depth data on that drug will be released this summer, which will clarify the potential role of PD-L1 inhibition in treating gastric cancer, she says.

Using genomic sequencing to identify patients whose gastric tumors have hundreds of mutations — and therefore might be most susceptible to treatment with immunotherapy — is an approach that some oncologists have started to embrace, Janjigian adds.

Even though targeted antibodies haven’t produced much of a survival benefit on their own, or in combination with chemotherapy, oncologists have observed that they seem to activate the immune system. The hope is that combining them with checkpoint inhibitors will strengthen that response. Memorial Sloan Kettering is planning a trial, for example, combining Herceptin and Keytruda in HER2-positive gastric cancer patients.

A wide range of combination treatments are being tested across all of the GI cancers. Opdivo is in an early trial in combination with Yervoy (ipilimumab), which inhibits another checkpoint called CTLA-4, in patients with colon cancer. And Roche is currently testing its drug Avastin with an experimental anti-PD-L1 antibody, atezolizumab, in esophageal cancer.And it’s not just drug treatments that can activate the immune system to combat GI tumors. One of the biggest developments in cancer immunotherapy in recent years is the ability to take immune-boosting T cells from the blood of patients, re-engineer them to be able to recognize unique antigens, or proteins on cancer cells, and then infuse them back into the body so they can home in on tumors and destroy them.

The technology, known as chimeric antigen receptor T cell (CAR T cell) therapy, has worked well in blood-based cancers like leukemia and lymphoma — even curing some patients in clinical trials who had failed all other therapies — but it has been difficult to translate to GI cancers and other solid tumors because there is no single antigen that drives them.

Scientists at the National Cancer Institute (NCI) are working on a method for engineering cells that might get around that problem. The technique, called “adoptive cell transfer,” involves removing tumor samples from individual patients and isolating tumor-reactive lymphocytes, which are naturally occurring white blood cells that can recognize the specific mutations in that cancer and launch an immune attack against them. The cells are then grown outside the body, engineered to enhance the immune response, and infused back into patients.

The technique has been used only in a small number of patients with gastrointestinal cancers, including one with a type of GI cancer called cholangiocarcinoma, or bile duct cancer, who had failed multiple chemotherapy regimens. The patient’s lung and liver metastases have shrunk by greater than 80 percent, and she remains progression-free more than two years after treatment. Researchers continue to perfect the technique, says Steven Rosenberg, a senior investigator at the NCI who is leading the research.

“It’s highly personalized — we have to create a new drug for each patient,” Rosenberg says. “But 90 percent of all patients who die of cancer die of solid tumors, so we’re in desperate need of new treatments. In my view, cell-transfer therapy is a promising area.”