Maureen Sideris was driving to Maine for a wedding when she realized she couldn’t swallow the sandwich she was having for lunch.
The 71-year-old was soon diagnosed with gastroesophageal cancer. It was August 2022. The tumor, she said, blocked off a portion of her esophagus, the tube that carries food from the mouth to the stomach, making it difficult to swallow food.
The standard treatment approach for esophageal cancer — chemotherapy and radiation, followed by surgery to remove part of the esophagus and stomach — “is quite devastating,” said Dr. Luis Diaz, the head of solid tumor oncology at Memorial Sloan Kettering Cancer Center in New York City. “One can overcome that, and there’s a new normal after that, but it’s not like what it was before.”
Going through all of those treatments, Sideris said, “would have been horrendous.”
Instead, she received just one treatment — immunotherapy — as part of a clinical trial at Memorial Sloan Kettering. It’s been two years since she completed her treatment and she’s in remission.
Diaz, the senior researcher on the clinical trials, said when the first person in the trial responded to the immunotherapy, it was exciting.
“You can say, ‘Hey, you’re done. You don’t need chemotherapy, radiation or surgery,’” Diaz said.
The approach won’t work for everyone. The Phase 2 trial focused on people whose tumors had what’s known as mismatch repair deficiency, a mutation that means mistakes in the DNA aren’t fixed when cancer cells replicate. This leads to even more mutations.
For the treatment to work, “the tumors need to have this mutation,” said Dr. Andrea Cercek of Memorial Sloan Kettering. Cercek led the clinical trial and presented the findings at the American Association for Cancer Research’s annual meeting on Sunday in Chicago. The research was simultaneously published in The New England Journal of Medicine.
Mismatch repair deficiency occurs more frequently in some cancers than in others. About 16% of ovarian cancers and as much as 30% of endometrial cancers have the mutation, compared to 10%-20% of colorectal cancers. Between 8% and 22% of nonmetastatic gastroesophageal cancers are mismatch repair deficient.
Immunotherapy drugs work by teaching a person’s immune system to recognize and attack cancer cells. The drugs have been found to work particularly well against tumors with mismatch repair deficiencies, because the many mutations provide more targets for immune cells.
However, the drugs typically aren’t used as a first-line treatment for these cancers. Instead, they’re brought in if approaches like chemotherapy and radiation don’t work, or if a cancer returns or has already spread.
The new trial expanded on a smaller study from Cercek that used the immunotherapy drug dostarlimab as the first treatment in 12 people with rectal cancers that were advanced but had not spread elsewhere in the body. All of the people’s tumors had mismatch repair deficiencies. Everyone underwent immunotherapy treatment for at least six months. At the end of that time, all 12 had a complete response, meaning there was no evidence of the tumor remaining. None of them had to undergo other cancer treatments that would usually be used to treat these types of cancer, including surgery.
The researchers started with rectal cancers because the treatments, and in particular the surgery, can be life-changing. Surgery may involve removing the rectum — the final portion of the large intestine before the anus. Patients who undergo this surgery must have a colostomy, an operation where the intestine is rerouted to a hole made in the abdomen for stool to pass out of the body into what’s known as an ostomy bag. “This will have a significant impact on your quality of life,” Diaz said.
The second part of the trial expanded the treatment to more people, including patients with other cancers known to have mismatch repair deficiencies, including cancers of the esophagus; endometrium; kidney and ureters; and liver, gallbladder and bile ducts. Everyone enrolled in the trial had early-stage cancer, meaning it hadn’t spread to other organs.
Sideris was one of the first people with a noncolorectal cancer to be cleared for the treatment in the trial.
During her first appointment, Sideris was hooked up to an IV that dripped the immunotherapy into her bloodstream. “Within 45 minutes, it’s done,” she said.
Sideris repeated the process every three weeks over the next six months as Cercek and her team enrolled other people who had recently been diagnosed with cancer. They were divided into two categories: those with colorectal cancers, and those with the other types.
The first group, rectal cancers, included 49 patients who completed six months of immunotherapy. All of them responded to the therapy and didn’t need surgery, chemotherapy or radiation. About 75% of them were still cancer-free a year or more after completing the treatment.
In the second group, 54 people completed the six-month treatment, and 35 — about 61% — had complete responses and didn’t need to undergo further treatment. The researchers didn’t look at data on the patients’ 12-month results.
Sideris said she’s grateful she didn’t have to endure the side effects of chemotherapy, but the immunotherapy did cause kidney failure, a known side effect of the drug. She’s now taking medication to manage the condition.
Still, Sideris said, “it was like winning the lottery.”
Dr. Suneel Kamath, a gastrointestinal medical oncologist at the Cleveland Clinic, cautioned that mismatch repair deficiencies only account for “1%-2% of cancers at most.”
“Unfortunately, this is not going to be something that is a cure-all,” he said.
But for people who do have this type of cancer, the findings offer substantial hope: Cancer surgery can often be “life-altering,” Kamath said. “A huge number might not need surgery at all and can be cured from the immunotherapy alone.”
Diaz said that for patients with mismatch repair deficiency, it may be possible to avoid 80% of surgeries.
Being able to preserve people’s organs by avoiding surgery can have a huge effect on quality of life. Depending on the surgery, patients could experience sexual dysfunction, loss of bowel control, acid reflux and infertility. Chemotherapy and radiation can also hurt fertility. This is particularly important at a time when more young people are being diagnosed with cancer, Cercek said.
The research also suggests that immunotherapy could possibly be used as a first-line treatment for early-stage mismatch repair deficient cancers.
“Immune therapies have a ton of potential. This shows we might be able to start with that,” said Dr. Heather Yeo, a surgical oncologist at Weill Cornell Medicine in New York City.
Diaz said that while larger studies are needed to confirm the trial’s findings, using immunotherapy in place of surgery, radiation and chemotherapy may not be far off for certain patients.
“I think it’s a short step from this report to application of standard of care,” he said.