Immune-based treatments for cancer have become the biggest new advance in tackling tumors, and the latest approval could make a big difference for some people with rectal cancer.
On Oct. 19, the U.S. Food and Drug Administration (FDA) approved dostarlimab (brand name: Jemperli) to treat a specific type of rectal cancer called microsatellite instability-high (MSI-H)/mismatch repair deficient cancer. This cancer is caused by the accumulation of certain genetic mutations that prevent rectal cells from repairing DNA damage and accounts for 5-10% of rectal cancers. In a study of 154 people with this type of rectal cancer who were treated with dostarlimab, 68% had a complete clinical response at one year, which meant doctors could not see evidence of tumors on imaging or other methods for tracking the tumors. In the study, which the drug's manufacturer, GSK, submitted to the FDA, people received nine infusions of the drug: once every three weeks for six months.
“Not only did they reach clinical complete response, but they maintained that for a year,” says Dr. Andrea Cercek, section head of colorectal cancer at Memorial Sloan Kettering Cancer Center and principal investigator of the study. (Some of the earliest patients have continued to remain tumor-free for even longer. ) “That really suggests that the response is durable and real.”
Dostarlimab is a checkpoint inhibitor, which means it releases the brakes that hold back the immune system from recognizing and attacking tumors. The drug allows immune cells to destroy cancer, making it a powerful weapon for seeking out cancer cells no matter where they spread or hide.
“We have completely leapfrogged over standard of care with a simple immunotherapy that melts the tumor away,” says Dr. Luis Diaz, head of solid tumor oncology at Memorial Sloan Kettering and one of the trial investigators.
The benefits of avoiding standard rectal-cancer treatment
Standard treatment for rectal cancer involves chemotherapy, radiation, and surgery to remove the rectum that requires patients to wear colostomy bags for the rest of their lives. The dostarlimab approval means more patients whose tumors have specific mutations could avoid those aggressive therapies altogether. “We have patients who would have lost the ability to bear children who have had children because this therapy replaced chemotherapy, radiation, and life-altering surgery in one swoop," Diaz says. "That’s a big deal.”
Kelly Spill is one of them. Diagnosed in 2020 when she was 29, shortly after having her first baby, Spill spent nearly nine months trying to figure out why she continued to have constipation and see bloody discharge in the toilet. Because she had recently given birth, doctors first attributed the symptoms to her pregnancy, and when they persisted after delivery, to internal hemorrhoids. It wasn’t until a doctor ordered a colonoscopy that they found a tumor.
“The doctor told me it was Stage III colorectal cancer, and that the treatment plan would include chemo, radiation, and surgery. And that I would never carry another baby again, and would most likely have a colostomy bag for the rest of my life,” says Spill. “It didn’t seem real until I heard the words that I was not going to carry another baby. I immediately stopped thinking about me, and started thinking about my husband and what it meant for my son. We had just started our lives together; we were supposed to have all these kids.”
Sascha Roth also faced devastating news when she was diagnosed with rectal cancer in 2019 after seeing blood in her stool. A resident of Washington, D.C., she had a friend with a similar diagnosis who had received chemotherapy, radiation, and surgery and recommended his surgeon at Memorial Sloan Kettering. Roth assumed she would follow the same strategy, but she learned that she had Stage III cancer and that she wasn’t a good candidate for surgery because the tumor was located so low in the rectum. Her tumor also had mutations that suggested it wouldn’t respond well to chemotherapy.
“It was a double whammy that threw me down,” she says. But the surgeon introduced her to Cercek, who was waiting to hear from the FDA about starting an immunotherapy trial for patients like Roth. “They told me I would be the first patient in the study, and there wasn’t scientific evidence that it would work.” Still, Roth wanted to try. She agreed to become Memorial Sloan Kettering’s first patient on the study, and then spent two months waiting for the FDA to greenlight the trial so she could begin receiving the drug. “I was calling Sloan Kettering incessantly to see if the FDA approved [the study],” she says. “The second the FDA gave its stamp of approval, Dr. Cercek’s team called me to New York to start the first round of treatment less than a week later.”
Not long after that, at Spill's first appointment at Memorial Sloan Kettering to discuss chemotherapy, she learned that the mutations on her tumor made her a good candidate for a study they had just begun. Only three patients had enrolled ahead of her (including Roth), so there was no data on whether it would actually treat her cancer. Spill, who was at the appointment with her mother, decided she had nothing to lose by joining the trial. “If it doesn’t go well, we could go back to option A,” Spill remembers her mother saying.
By her second infusion, Spill felt the tumor was shrinking because she no longer had major constipation. By the fourth infusion, scans showed the tumor had shrunk by 50%. The study originally called for patients to get chemotherapy, radiation, and surgery if needed after six months on dostarlimab. But a nurse pulled Spill’s mother aside after that appointment to tell her that the first three patients in the study did not need any additional treatments because their tumors had disappeared. Following Roth’s results, the study was revised to make chemotherapy, radiation, and surgery an option only if needed: if the tumors hadn’t gone away. It wasn’t a guarantee that Spill would have the same results as those first patients, but “it gave me hope, and all I could think about was maybe I could have another baby,” she says.
After all of her dostarlimab infusions, Spill, too, no longer had any tumor left and was declared cancer-free. Her doctors advised her to wait two years before trying to get pregnant again to ensure the cancer wouldn’t return. Once she was cleared, she got pregnant and gave birth to a girl in 2023, and later a boy in 2025. “I am now five years cancer-free, and last September got the boot from Memorial Sloan Kettering,” she says, meaning she no longer needs to follow up with her oncologists there. She now sees her primary care doctor for colonoscopies every two years.
“I see beauty in absolutely everything in life now,” Spill says.
What comes next for dostarlimab
Not only does the immunotherapy appear to work well in treating these rectal cancers, but it also comes with relatively few side effects. About 20% of those in the study reported fatigue, rash, diarrhea, and uncontrollable itching. Roth, who received her infusions during the COVID lockdown, drove from D.C. for her treatments and was able to make the roundtrip in one day. "It's just proof that you can really do the things you want to do. I didn't feel tired or sick after [the treatment], and there was never a time when I was at home recovering," she says. "I watched my mom and dad go through standard chemo and radiation and anticipated that would be what my treatment was like. It was nothing like that."
Cercek says the results point toward a potentially new model for managing some rectal cancers, which may include relying on immunotherapy like dostarlimab and monitoring patients more carefully before automatically turning to chemotherapy, radiation, or surgery. Some of the patients in the trial who were treated on dostarlimab underwent surgery after finishing their infusions if their doctors still felt there might be tumors remaining. Among them, despite the doctors’ suspicions, 80% did not turn out to have evidence of tumors in their specimens, says Cercek.
Dostarlimab is already approved to treat endometrial cancers with the same mutations and costs $10,000 to $12,000 per dose out of pocket, although GSK has a manufacturer's savings program to cover that cost for some patients.
“We still have a lot of learning about what complete clinical response means,” she says, and with immunotherapy, that might mean a more patient-centric, individualized approach that involves more time for the immune system to respond to the immunotherapy and become trained to attack the cancer. “If it looks like the tumor is responding, we need to give it more time with better techniques to determine whether or not the tumor is truly gone.”
Cercek and her team are studying the best ways to monitor how tumors respond to dostarlimab by looking at snippets of genetic information that tumors shed in the blood, or more advanced imaging to accurately capture changing tumor sizes. “We need to improve on those techniques but also to teach the oncology community that there is a very, very high chance that the tumor might disappear, even if it might not look like it at six months. We need to continue watching and waiting and giving it time.”