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A small but heralded clinical trial at Memorial Sloan Kettering Cancer Center (MSK) that saw rectal cancer disappear in 100% of people who took part has taken a step towards approval by the Food and Drug Administration (FDA).
The form of immunotherapy used in the trial, called Jemperli (dostarlimab) and produced by the drug company GSK, received the FDA’s “Breakthrough Therapy Designation” on December 16, 2024, for treating people with a particular type of rectal cancer.
The FDA says this breakthrough designation aims to “expedite the development and review of drugs that are intended to treat a serious condition” where clinical data show “substantial improvement over available therapy.”
This trial’s new approach, which uses immunotherapy alone, benefits a subset of patients who have tumors with specific genetic characteristics known as mismatch repair-deficient (MMRd) or microsatellite instability-high (MSI).
Using immunotherapy alone means that people are spared the standard treatment for rectal cancer, which includes surgery, radiation, and chemotherapy. These therapies, while generally effective, can have life-altering side effects, including infertility, incontinence, and more.
“Everyone on the clinical trial is doing great,” says MSK gastrointestinal oncologist Andrea Cercek, MD, who led the clinical trial with gastrointestinal oncologist Luis Diaz, MD.
They reported updated results in June 2024, more than doubling the number of patients who have been have been successfully treated. “So far, 42 people have completed treatment, and all of them have no evidence of disease. Side effects were quite mild and well tolerated.”
She adds: “This new treatment is also proving very durable. Most people on the trial have been free of cancer for at least a year, and the original participants have been healthy for up to four years and counting. The success rate remains 100%.”
Changing Practice Around the World
Dr. Cercek reported the updated results in June 2024 at ASCO, the country’s premier conference on cancer. When she announced the first set of results at the same conference in 2022, the news made headlines around the world and were simultaneously published in the New England Journal of Medicine.
Since then, 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.”
The National Comprehensive Cancer Network, the doctors’ group that sets guidelines for cancer treatments in the U.S., officially changed their directives for treating rectal cancer as a result of the clinical trial, which makes insurers more willing to cover the approach.
The trial has even sparked a small baby boom. “Three people who participated in the 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.”
Clinical Trial Success with the First Patient
Sascha Roth, the first patient in the clinical trial, remembers getting a momentous phone call on a hectic Friday evening.
She was racing around her home in Washington, D.C., to pack for New York, where she had been scheduled to undergo weeks of radiation therapy for rectal cancer.
Sascha, then 38, had undergone six months of immunotherapy in the clinical trial. And Dr. Cercek had called to relay the happy news that her latest tests showed no evidence of cancer.
The call changed everything, Sascha says, and left her “stunned and ecstatic — I was so happy.”
Immunotherapy harnesses the body’s own immune system as an ally against cancer. The MSK clinical trial was investigating — for the first time ever — if immunotherapy alone could beat rectal cancer that had not spread to other tissues, in a subset of patients whose tumor contain a specific genetic mutation.
Listen to how immunotherapy is transforming the treatment of cancers at MSK.
“Dr. Cercek told me a team of doctors examined my tests,” recalls Sascha. “And since they couldn’t find any signs of cancer, Dr. Cercek said there was no reason to make me endure radiation therapy.”
100% Remission of Rectal Cancer
These same remarkable results would be repeated for all 42 people — and counting — in the MSK clinical trial. In every case, the rectal cancer disappeared after immunotherapy — without the need for the standard treatments of radiation, surgery, or chemotherapy. And the cancer has not returned in any of the patients, who have been cancer-free for up to four years.
“It’s incredibly rewarding,” says Dr. Cercek, “to get these happy tears and happy emails from the patients in this study who finish treatment and realize, ‘Oh my God, I get to keep all my normal body functions that I feared I might lose to radiation or surgery.’ ”
Her co-investigator, MSK medical oncologist Luis Diaz, Jr. MD, is equally thrilled. He’s spent his career studying how to defeat cancer with immunotherapy. “It’s really exciting,” says Dr. Diaz, a member of the White House’s National Cancer Advisory Board. “I think this is a great step forward for patients.”
Using Immunotherapy Earlier To Target a Genetic Mutation
Drs. Cercek and Diaz explain that their team’s research was sparked by two key ideas.
The first premise, says Dr. Diaz, is to figure out precisely which patients benefit most from immunotherapy, so they can receive it right away. “Immunotherapy has proven successful in treating a subset of patients with colon and rectal cancer that has metastasized, meaning spread to other tissues.”
The patients in this subset, Dr. Diaz explains, have tumors with a specific genetic makeup known as mismatch repair-deficient (MMRd) or microsatellite instability (MSI).
Between 5% and 10% of all rectal cancer patients are thought to have MMRd tumors, including all the patients in the MSK clinical trial that Sascha participated in. There are 45,000 Americans diagnosed a year with rectal cancer.
“An MMRd tumor develops a defect in its ability to repair certain types of mutations that occur in cells. When those mutations accumulate in the tumor, they stimulate the immune system, which attacks the mutation-ridden cancer cells,” says Dr. Diaz, who heads the MSK division of Solid Tumor Oncology and holds the Grayer Family Chair.
But cancer has a trick up its sleeve to stop the immune system from doing its job.
Helping the Immune System Overcome Rectal Cancer
Immune cells contain a safeguard called a checkpoint to prevent them from attacking normal cells. Cancer cells can trip this safeguard and shut down immune cells, allowing a tumor to hide and grow.
However, immunotherapy can turn the tables yet again.
An immunotherapy agent called a checkpoint inhibitor releases the brake on an immune cell, freeing it to recognize and attack cancer cells. “When the brakes are taken off the immune cells, MMRd cells look especially strange because they have so many mutations. So the immune cells attack with much more force,” explains Dr. Cercek.
Dr. Diaz’s pioneering research in treating cancer with immunotherapy had already shown that checkpoint inhibitors could “help people with MMRd colorectal tumors that have spread,” he says. “We thought, ‘Let’s try it before cancer metastasizes as a first line of treatment.’ ”
Avoiding Life-Altering Side Effects
The second premise of the clinical trial was to avoid the toxicity often associated with treatment for rectal cancer.
Dr. Cercek explains: “Our first duty is to save our patient’s life. But the standard treatment for rectal cancer with surgery, radiation, and chemotherapy can be particularly hard on people because of the location of the tumor.” She continues, “They can suffer life-altering bowel and bladder dysfunction, incontinence, infertility, sexual dysfunction, and more.”
Dr. Diaz adds, “Obviously, that can lead to a lot of self-esteem and psychiatric issues as well.”
To avoid these toxicities, many approaches to rectal cancer try to shrink the tumor as much as possible with chemotherapy and radiation to facilitate surgery. Drs. Cercek and Diaz surmised that immunotherapy in MMRd patients could similarly shrink the tumor to enable a more successful surgery.
But Dr. Cercek proposed going further: In patients where the immunotherapy caused the cancer to completely disappear, doctors would omit chemotherapy, radiation, and surgery — and, instead, closely monitor for any signs of recurrence. Dr. Diaz says this decision by Dr. Cercek was “a world-class moment” that promised to change the lives of patients — if it worked.
All patients in the trial must have stage 2 or 3 rectal tumors that are MMRd — which makes their cancer particularly sensitive to immunotherapy. The patients were given the checkpoint inhibitor dostarlimab (Jemperli) intravenously every three weeks, for six months.
Their tumors were closely tracked, Dr. Diaz explains, “using imaging, visualization such as endoscopy, as well as other methods.”
No More Symptoms of Rectal Cancer
The results surprised even Drs. Cercek and Diaz.
“The immunotherapy shrank the tumors much faster than I expected,” says Dr. Cercek. “My research nurse Jenna Sinopoli would tell me, ‘The patient has only received one treatment and already they’re not bleeding anymore and their terrible pain has gone away.’ ” Dr. Cercek recalls: “Patients came to my office after just two or three treatments and said, ‘This is incredible. I feel normal again.’ ”
Since Sascha was the first patient to enroll in the trial, the research team worried that her experience might prove to be an outlier. Sascha says: “Before I came to MSK, oncologists at another medical center told me I needed chemo, radiation, and surgery. To instead get immunotherapy infusions every few weeks in New York with no side effects seemed like a cakewalk in comparison.”
It turned out Sascha was not an exception. Dr. Diaz recalls his growing excitement as “the first patient had a complete response to therapy and didn’t need anything else. Then the second patient didn’t need surgery or radiation. Then the third. Pretty soon we’re at the 10th patient that had a complete response. That is incredible.”
Patients, of course, were even more thrilled. “One young man and his family just sat in stunned silence when I told them his cancer had disappeared,” recalls Dr. Cercek. “Then they thanked us over and over.” She continues, “A young woman looked at the screen during an examination and asked, ‘Where is the tumor?’ ‘It’s gone,’ we told her.”
Dr. Cercek says: “The most exciting part of this is that every single one of our patients has only needed immunotherapy. We haven’t radiated anybody, and we haven’t put anybody through surgery.” She continues, “They have preserved normal bowel function, bladder function, sexual function, fertility. Women have their uterus and ovaries. It’s remarkable.”
Meet four patients who were successfully treated for rectal cancer thanks to a clinical trial involving immunotherapy at MSK
Next Steps for Study Patients
Drs. Cercek and Diaz want people with rectal cancer tumors that are MMRd to know the clinical trial continues to enroll patients and is growing. Dr. Diaz says, “Our message is: Get tested if you have rectal cancer to see if the tumor is MMRd. No matter what stage the cancer is, we have a trial at MSK that may help you. And MSK has special expertise that really matters.”
That’s particularly important for people at high risk of rectal cancer. Sascha, like eight of the people in the study, was found to have Lynch syndrome, an inherited condition that puts people at significantly higher risk of rectal, colon, and other cancers.
Lynch syndrome is associated with poorer outcomes from chemotherapy and surgery, so treatment with immunotherapy may be an important new tool.
Similarly, there has been a disturbing rise in the number of people younger than 50 who are diagnosed with colorectal cancer — particularly rectal cancer. Dr. Cercek says: “We are seeing more and more young people with rectal cancer, including people in their 20s in our trial. Immunotherapy might be an important new option for them.”
Another way MSK is trying to help the growing number of younger patients with cancer is the Center for Young Onset Colorectal and Gastrointestinal Cancer. It’s the first center in the world devoted to the specific needs of people under 50 and is co-led by Dr. Cercek.
Potential Help for Other Cancers
As MSK’s rectal cancer trial continues, Dr. Diaz hopes “it’s the tip of the iceberg.” He explains: “We are investigating if this same method may help other cancers where the treatments are often life-altering and tumors can be MMRd. We are currently enrolling patients with gastric (stomach), prostate, and pancreatic cancers.”
Dr. Diaz has coined a term for this new method of using immunotherapy alone to target MMRd tumors, calling it “immunoablative” therapy — that means using “immunotherapy to replace surgery, chemotherapy, and radiation to remove cancer.” He adds, “That might sound futuristic — but in this trial, we have a clinical example where that happened.”
Today, four years after she began the trial, Sascha remains cancer free and continues to live a normal life. She runs a family-owned home-furnishing and interior design business and often speaks to people facing rectal and other cancers.
“My whole experience has been like a dream,” she says. “MSK research and cancer care is simply years and years ahead of where other hospitals — even really good ones — are or should be.”
This research receives essential philanthropic support from the MSK Giving community, including The Society of MSK, Bob and Anna Lou Schaberg, the Frechette Family Foundation, and Jackie and Richard Emmet (Cercek), and Kate and Andrew Davis & The Shelby Cullom Davis Charitable Fund, Stand Up To Cancer, and Swim Across America (Diaz).
Dr. Diaz holds the Grayer Family Chair.
- This clinical trial is for patients with Stage II or III locally advanced cancers, whose tumors have a particular genetic makeup known as mismatch repair deficient (MMRd) or microsatellite instability (MSI).
- Patients who don’t know whether they have this specific kind of tumor should ask their doctor to get their tumor tested.
- MSK experts would be happy to talk with patients who do not have this mutation.
- MSK can help patients diagnosed with any stage 1, 2, 3 or 4 cancer of any kind.
