Maureen Sideris, seated, with her sister Marion, receiving the 8th of 9 immunotherapy infusions during successful treatment for early-stage gastroesophageal junction cancer at Memorial Sloan Kettering Cancer Center. Maureen took part in a clinical trial that gave immunotherapy alone to patients with several types of cancer sharing a particular mutation, meaning they did not have to undergo surgery, radiation, or chemotherapy.
An approach pioneered at Memorial Sloan Kettering Cancer Center (MSK) that caused rectal cancer tumors with a specific genetic mutation to disappear in 100% of clinical trial participants has been expanded to treat other types of cancer, including stomach (gastric), colon, esophageal, urothelial, and others.
The new results from the larger clinical trial saw nearly 80% of patients with several types of cancer successfully treated with only immunotherapy, which harnesses the body’s own immune system to fight cancer.
That meant people in this clinical trial who responded positively to treatment did not require surgery to remove an organ tumor and did not have to undergo chemotherapy or radiation.
“This is very exciting and shows that a broad range of tumors with this genetic mutation, called MMRd, can be treated with immunotherapy replacing surgery and radiation, giving patients better quality of life,” says the leader of the trial, gastrointestinal oncologist Andrea Cercek, MD, who oversaw the trial with gastrointestinal oncologist Luiz Diaz Jr., MD.
- 103 patients in clinical trial, including rectal and several other cancer types
- Overall: 80% of all patients only needed immunotherapy — no surgery, radiation, or chemotherapy
- 100% of rectal cancer patients successfully treated using only immunotherapy
- Nearly two-thirds of patients with other cancer types successfully treated using only immunotherapy
- All patients had a tumor mutation called MMRd, which is particularly vulnerable to immunotherapy
- Patients ranged from 26 to 87 years old
Maureen Sideris was diagnosed with gastroesophageal junction cancer in 2022 and joined the trial soon after the results from the first trial were announced. “My husband, Tommy, and I were preparing for the worst,” she recalls. “But after being treated with only immunotherapy, I had no evidence of cancer and didn’t have to undergo surgery or chemo or radiation. I felt like I won the lottery!”
The results of the larger study were simultaneously published in The New England Journal of Medicine in April 2025 and presented by Dr. Cercek at a top medical conference, the American Association of Cancer Research (AACR) Annual Meeting.
How the Immunotherapy-Only Approach Improves Quality of Life: No Ostomy Bags, Preserved Sexual Functions and More
Dr. Cercek and Dr. Diaz developed this approach in part because standard treatment for some cancers can severely affect quality of life.
Gastrointestinal medical oncologist Andrea Cercek, MD
“Using the standard-of-care treatment of surgery, radiation, and chemotherapy to treat rectal cancer is effective,” explains Dr. Cercek. “But the treatments can leave people infertile and severely affect bowel, urinary, and sexual functions as well as other aspects of daily life.” Some people also need a lifelong ostomy — a bag outside the body for collecting waste.
The doctors had observed that in some cases, immunotherapy alone could shrink rectal tumors dramatically. They designed a clinical trial to closely monitor patients who responded well to immunotherapy to see if surgery and other treatments could be deferred until after immunotherapy — and hopefully never used at all.
Targeting MMRd: The Mismatch Repair-Deficient Mutation in Tumors
In both clinical trials led by Drs. Cercek and Diaz, patients had tumors that were stage I-3, meaning they had not spread (metastasized).
The tumors also had a genetic mutation called mismatch repair-deficient (MMRd).
Gastrointestinal medical oncologist Luis Diaz, Jr., Head of the Division of Solid Tumor Oncology
The MMRd mutation makes tumors particularly vulnerable to a type of immunotherapy called checkpoint inhibitors. This therapy “unmasks” tumor cells, making it easier for the patient’s own immune system to recognize and kill cancer cells.
- 5-10% of rectal tumors are believed to be MMRd
- 2-10% of other types of solid tumors in the trial are thought to be MMRd
The checkpoint inhibitor used in the trials is Jemperli (dostarlimab) made by GSK.
Expanding the Immunotherapy-Only Approach to Other Cancers
The first clinical trial at MSK to investigate the approach started small, with only 18 patients. But the trial’s 100% success rate using immunotherapy alone made headlines around the world when results were published in 2022.
That success spurred Dr. Cercek and Dr. Diaz to explore if the approach would be successful against other cancers.
“We knew there was a broad range of cancer types that had this same MMRd genetic mutation,” explains Dr. Cercek. “And standard treatment for some of these other cancers, including surgery, radiation, and chemotherapy, can also have life-altering side effects. We hoped this approach could help people facing these other cancers too.”
Maureen’s thoracic oncologist near her home in upstate New York, Dr. Faisal Waheed Paracha, knew of the success of the original rectal cancer trial. He contacted MSK thoracic surgeon David Jones, MD, who connected Maureen with MSK gastrointestinal medical oncologist Steven Maron, MD. Dr. Maron became Maureen’s main care provider at MSK and helped her join the clinical trial.
“I can honestly say that every single person I met at MSK was amazing,” says Maureen. “Everyone was so warm and positive and just nice humans, including all the doctors, nurses, and technicians.”
Results of the New Clinical Trial and Cancer Types Involved
103 patients with stage I-3 tumors that have the MMRd mutation participated in the expanded trial:
- 49 rectal cancer patients
- 54 patients with other types of solid tumor cancers
- Participants received checkpoint inhibitor infusions for six months
- Side effects from the immunotherapy “were well-tolerated”
Clinical Trial Results for Non-Rectal Cancer Patients
The non-rectal group included 54 patients with a variety of cancers that had early-stage MMRd tumors, including:
- Esophageal
- Stomach
- Colon
-
Hepatobiliary
- Periampullary
- Cholangiocarcinoma
- Urothelial
- Endometrial
- Prostate
Of these 54 patients, 35 experienced a complete clinical response — meaning all signs of their cancer disappeared, according to a variety of tests.
Overall, Dr. Cercek says, nearly 2 out of 3 patients with types of cancer other than rectal were able to preserve their organs and their quality of life
“This is a very significant response, and the results were even better than we had hoped,” says Dr. Cercek. “We found that some cancer types responded extremely well to the immunotherapy, including colon and stomach cancer.”
Dr. Cercek notes that in those 20% of non-rectal cancer patients who did end up needing surgery, “we often saw that the immunotherapy shrunk the tumor and sometimes even lowered the staging assigned to the cancer. We also saw lower rates of cancer recurrence, suggesting that even if the effect wasn’t a home run, it helped most patients.”
Dr. Cercek says in no cases where patients ended up needing surgery was their outcome compromised by first trying immunotherapy alone.
Clinical Trial Results for Rectal Cancer Patients
In all 49 rectal cancer patients, there was no evidence of cancer after immunotherapy.
Dr. Cercek explains that two of the rectal cancer patients presented special challenges. “One patient had regrowth locally, so we resumed immunotherapy and it disappeared completely. Another patient had growth in a lymph node, which we surgically removed. However, that patient kept their rectum, as did everyone else in the rectal group.”
Understanding Why Certain Cancers Respond to Immunotherapy
“We’re really excited to help more people,” Dr. Cercek says. “And we are already exploring why rectal tissue seems to have such an extraordinary response to immunotherapy and how we can use that knowledge to help with other cancer types.”
One working hypothesis, she says, is the area in which the cancer sits, called the tumor microenvironment. “In some areas there could be bacteria or certain types of immune cells that influence how the tumor reacts to immunotherapy.”
How This Approach Is Changing Cancer Care
Based on the results of the original trial with rectal patients, the “immunotherapy alone” approach has been incorporated into the treatment guidelines of the National Comprehensive Cancer Network, the doctor’s group that sets cancer treatments in the United States.
Dr. Cercek reports that the approach pioneered at MSK “has been adopted by many doctors in the U.S. and around the world. I get letters thanking us from America, Australia, Ireland, and other countries, which is really gratifying.”
There has even been a small baby boom. “Three people who participated in the original MSK trial have had healthy babies since finishing treatment,” says Dr. Cercek, who met one of these newborns days after her birth. “That would have been nearly impossible for women treated with the standard treatment of surgery, radiation, and chemotherapy — which can make both genders infertile.”
Maureen says her successful treatment on the trial improved her life dramatically, in ways big and small. “I’m a chatterbox,” Maureen says with a laugh. “I was afraid that if I got surgery on my esophagus, I wouldn’t be able to talk for a while, which would be awful. To have immunotherapy alone was just amazing.”
Now 71, Maureen is enjoying an active retirement after a 40-year career, much of it in the technology field. “I love to read, cook, walk, dote on our French Brittany, Odin, and volunteer at my local library,” she says.
FDA “Breakthrough Designation”
The original clinical trial also led the U.S. Food and Drug Administration (FDA) to give “Breakthrough Therapy Designation” to Jemperli (dostarlimab) — the checkpoint inhibitor used in the trial — in December 2024.
Dr. Cercek points out that this treatment has proved very durable, with some original trial participants still cancer-free after four years and counting.
Immunotherapy Alone Approach Proving Helpful for Lynch Syndrome Cancers
The treatment has proved particularly helpful for people whose tumors are caused by Lynch syndrome, an inherited condition that makes people much more likely to develop colorectal and other cancers.
“People with Lynch syndrome usually don’t respond well to chemotherapy, so this gives them an important new option for treatment of early-stage disease,” says Dr. Cercek.
Next Steps: Expanding Trials and Targeting Tumors Beyond MMRd
The next step, says Dr. Cercek, is to expand the research even further, with clinical trials that have more patients and involve other hospitals.
Ultimately, she says, “I want to see if we can bring this approach to people who do not have the MMRd mutation, to help as many people facing cancer as possible.”
For Maureen, this spirit of innovation at MSK works hand in hand with another key to her recovery — compassion.
“My sister Marion was my angel and came to every appointment with me. She carried a bag full of little silver angels and hearts with her and gave them out to everyone who interacted with us. I think half of MSK has a little silver angel or heart now, because everyone who took care of me couldn’t have been nicer and more concerned about helping me get well.”
The study was funded by Swim Across America, SU2C, R21 CA252519-01A1 and GlaxoSmithKline.
Dr. Cercek discloses the following: Advisory board Amgen, Agenus, Abbvie, Daiichi Saynko, Jansses, Merck, GSK, Pfizer, 3T Biosciences, Summit, Regeneron. Research funding: GSK, Pfizer. Pending patent neoadjuvant therapy of mismatch repair-deficient rectal cancer.