A pioneering approach using immunotherapy alone has successfully treated multiple cancer types carrying a specific genetic mutation, allowing patients to avoid surgery, radiation, and chemotherapy while maintaining their quality of life, according to new clinical trial results from Memorial Sloan Kettering Cancer Center (MSK).
The phase 2 clinical trial, led by gastrointestinal oncologists Dr. Andrea Cercek and Dr. Luis Diaz Jr., found that nearly 80% of patients with mismatch repair-deficient (MMRd) tumors experienced complete clinical responses after six months of immunotherapy treatment, meaning all signs of their cancer disappeared.
Results were simultaneously published in The New England Journal of Medicine and presented at the American Association of Cancer Research (AACR) Annual Meeting in April 2025.
Expanding Beyond Rectal Cancer Success
The new trial builds upon MSK's groundbreaking 2022 study that made headlines worldwide when 100% of rectal cancer patients with the MMRd mutation experienced complete responses to immunotherapy alone.
"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," said Dr. Cercek, who is also co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancer at MSK.
The expanded trial included 103 patients with stage 1-3 cancers:
- 49 patients with rectal cancer (100% complete response)
- 54 patients with other cancer types (65% complete response)
Non-rectal cancers in the trial included stomach, colon, esophageal, hepatobiliary, periampullary, cholangiocarcinoma, urothelial, endometrial, and prostate cancers.
Preserving Organs and Quality of Life
Standard treatments for many of these cancers typically involve surgery, radiation, and chemotherapy, which can severely impact quality of life. Surgery often requires removing organs or creating permanent ostomies, while radiation and chemotherapy can cause infertility and impair bowel, urinary, and sexual functions.
"Using the standard-of-care treatment of surgery, radiation, and chemotherapy to treat rectal cancer is effective," explained 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."
Maureen Sideris, a 71-year-old trial participant diagnosed with gastroesophageal junction cancer in 2022, experienced the benefits firsthand. "My husband, Tommy, and I were preparing for the worst," she recalled. "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!"
How the Treatment Works
The trial utilized Jemperli (dostarlimab), a checkpoint inhibitor made by GSK, administered over six months. This immunotherapy "unmasks" tumor cells, making it easier for the patient's immune system to recognize and kill cancer cells.
All patients in the trial had tumors with the mismatch repair-deficient (MMRd) mutation, which makes them particularly vulnerable to checkpoint inhibitors. This genetic mutation occurs in:
- 5-10% of rectal tumors
- 2-10% of other solid tumors
Dr. Diaz noted, "The majority of patients in the trial saw their tumors completely disappear. These results could change how we treat some cancers."
Remarkable Response Rates
The trial results demonstrated impressive outcomes:
- 100% of rectal cancer patients (49 of 49) achieved complete clinical response
- 65% of patients with other cancer types (35 of 54) achieved complete clinical response
- Overall, 82 of 84 patients with complete responses avoided surgery entirely
Dr. Cercek emphasized that even in the 20% of non-rectal cancer patients who eventually needed surgery, "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."
Importantly, no patients who tried immunotherapy first had compromised outcomes if they later required surgery.
Early Detection of Treatment Response
The study also found that circulating tumor DNA (ctDNA) testing using Haystack MRD™ could reliably identify complete responses as early as 1.4 months into treatment. This suggests ctDNA will play an important role in assessing treatment responses as novel therapies expand, particularly for tumors in locations where direct visualization or biopsy is challenging.
Impact on Treatment Guidelines and Patient Lives
Based on the results of the original rectal cancer trial, the "immunotherapy alone" approach has been incorporated into the National Comprehensive Cancer Network treatment guidelines, which set cancer treatment standards in the United States.
In December 2024, the U.S. Food and Drug Administration (FDA) granted "Breakthrough Therapy Designation" to dostarlimab for the treatment of MMRd rectal cancer.
The approach has proven particularly beneficial for patients with Lynch syndrome, an inherited condition that increases the risk of 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," Dr. Cercek explained.
Life-Changing Outcomes
The treatment's durability has been remarkable, with some original trial participants remaining cancer-free after four years. Dr. Cercek also reported that three women from the original trial have had healthy babies since completing treatment—an outcome that would have been nearly impossible with standard treatments that often cause infertility.
For Maureen Sideris, the benefits extended beyond cancer treatment. "I'm a chatterbox," she said 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."
Future Directions
Drs. Cercek and Diaz are now working to expand this approach further, with plans for larger clinical trials involving more patients and additional hospitals.
"We're really excited to help more people," Dr. Cercek said. "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 hypothesis focuses on the tumor microenvironment—the area surrounding the cancer—where bacteria or certain immune cells might influence how tumors react to immunotherapy.
Ultimately, Dr. Cercek hopes to extend this approach beyond MMRd tumors: "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."
The study was funded by Swim Across America, Stand Up To Cancer, the National Institutes of Health, and the National Cancer Institute, with support from GSK, which provided dostarlimab, and Haystack Oncology, a Quest Diagnostics company, which provided ctDNA testing.
