JUST AFTER LABOR DAY in 2019, Sascha Roth, who was 38 years old, was diagnosed with stage III rectal cancer. Roth co-owns and operates Urban Country Designs, a furniture and interior design company in Bethesda, Maryland. After noticing some rectal bleeding, she had a sigmoidoscopy, and a growth in her rectum was removed. When her gastroenterologist called to let Roth know that the growth was malignant, the small-business owner’s first instinct was to gather extra information from a friend who was diagnosed with colorectal cancer two years earlier.

Her friend, who had surgery at Memorial Sloan Kettering Cancer Center in New York City, recommended that Roth make the trip north for a consultation in addition to going to the cancer center close to her. Typically, treatment for stage III rectal cancer includes some combination of radiation, chemotherapy and surgery. In many cases, oncologists recommend starting treatment with chemotherapy and radiation to shrink the tumor before surgery—an approach known as neoadjuvant therapy.

Surgery for rectal cancer can involve removing the rectum, which means a person might need an ostomy bag, either temporarily or permanently. After surgery, “gastrointestinal function is never the same,” says physician-scientist Luis Diaz Jr., a medical oncologist at Memorial Sloan Kettering. Radiation also carries the risk of long-term effects including incontinence and problems with sexual function.

Roth tried to assure herself that she would handle whatever treatment she needed, but after genetic testing at Memorial Sloan Kettering, she learned she had Lynch syndrome, an inherited condition that is caused by mutations in DNA mismatch repair genes. When functioning normally, these genes help correct mistakes when DNA is copied. People with Lynch syndrome have increased risk of developing many cancers, including colorectal cancer. Roth’s oncologist, Andrea Cercek, didn’t recommend chemotherapy. She noted that some research suggests chemotherapy doesn’t work as well in patients who have tumors like Roth’s, which are considered mismatch-repair deficient. In addition, Roth’s tumor was located low in her rectum, which meant she would likely need a permanent ostomy bag after surgery.

Cercek offered another option: a small phase II clinical trial testing whether neoadjuvant immunotherapy given before radiation, chemotherapy or surgery could help shrink the tumor. Immunotherapy works by taking the brakes off immune cells known as T cells so they can attack the cancer at full tilt. The researchers in the trial also hoped that those unbridled T cells would help to fight cancerous cells left in the body even after immunotherapy treatment stopped.

The clinical trial was open to people with stage II or III rectal cancer whose tumor tested positive for DNA mismatch repair deficiency, or dMMR. Roth met the enrollment criteria and started the clinical trial in December 2019. She received an experimental immunotherapy intravenously every three weeks for six months. In May 2020, just as she was preparing to start radiation therapy, Cercek called to tell Roth that her MRI scans showed no traces of cancer. No signs of cancer meant no need for chemotherapy, radiation or surgery, the doctor said, at least at that moment. It also meant no debilitating side effects and no ostomy bag.

It wasn’t just Roth. As of March 2023, almost 40 people with rectal cancer had enrolled in the trial, and 23 of them had completed treatment with a 100% success rate, which means their cancer had not returned. Diaz, who led the trial with Cercek, says this type of success is almost unheard of in cancer research. “It’s pretty astounding,” he says.

Hope and Reality

By some estimates, about 44% of cancer patients are eligible for immunotherapy treatment, but only about 12% of those people will respond to the treatment. For most cancers, traditional treatments such as chemotherapy, radiation and surgery are the mainstay, says thoracic oncologist Jay Lee at UCLA Health in Los Angeles. Lee has been studying the use of neoadjuvant immunotherapy for people with non-small cell lung cancer (NSCLC), which is known to exhibit resistance to chemotherapy and to frequently recur.

In the past decade or so, immunotherapy drugs called immune checkpoint inhibitors, or ICIs, have revolutionized treatment for some patients with NSCLC and other cancers. In some cases, patients have had extraordinary outcomes. A person diagnosed with metastatic melanoma six years ago, for example, could expect to live six to nine months. Now, largely because of ICIs, median overall survival for someone with metastatic melanoma is nearly six years. Immunotherapy has generally been offered after other treatments fail or in advanced stage cancer, but promising results are driving researchers to ask whether it might be useful before standard treatments—even if in a fraction of patients whose tumors have certain mutations.

Roth was already familiar with clinical trials through experience with her family. When she was 16, her father was diagnosed with a brain tumor and joined a clinical trial for an experimental therapy. “While he had to withdraw after six months due to adverse health effects, we truly believe that the trial helped to extend his life,” she says, noting that her father lived for a year and a half following his cancer diagnosis, even though doctors had predicted he had three to six months left. She didn’t hesitate to join a trial after her own diagnosis. “It didn’t even occur to me not to do it,” she says. “It felt like the best option.”

Now Enrolling

Various trials are testing whether upfront immunotherapy benefits patients.

The experimental immunotherapy drug that Roth took in the trial eventually gained Food and Drug Administration (FDA) approval under the brand name Jemperli (dostarlimab) in April 2021 to treat patients who had recurrent or advanced endometrial cancers with dMMR. In August 2021, Jemperli received accelerated approval to treat any recurrent and previously treated cancers with dMMR, no matter where in the body they occur. The success of the trial testing this drug in a neoadjuvant setting for rectal cancer begs other questions, like whether giving other immunotherapies earlier could benefit patients with dMMR tumors at other organ sites, including the prostate, pancreas, stomach and esophagus, Diaz and Cercek say.

Extending the Benefits

While these questions hold possibility for patients, medical oncologist James Gulley, who co-directs the National Cancer Institute’s Center for Immuno-Oncology in Bethesda, cautions that the results from this small study in carefully selected patients can also cause false hope. Many people treated with immunotherapy can develop resistance, and the cancer could return, he adds. “Additional time will be required to see what proportion of patients respond and if the response is durable,” he says.

But if the results seem too good to be true, they are also too exciting to ignore, he says. If immunotherapy proves to be as effective in treating stage II and stage III cancers as standard treatments like surgery, it could save patients from undergoing difficult operations for conditions like advanced bladder cancer, for example. “These are long, involved surgeries, and if you can avoid it, you can help patients,” Gulley says. He also notes that chemotherapy, radiation and surgery often leave people who have head and neck cancers with serious problems, including the inability to swallow, which necessitates a feeding tube. “This really opens up avenues for new and better ways to treat patients,” Gulley says.

Doctors do not yet have enough evidence for widespread use of neoadjuvant immunotherapy in most cancers. “That is something for the future, but not something for right now,” Gulley says. “We still need more data.”

Gathering Findings

The FDA has approved immunotherapy and chemotherapy as a neoadjuvant treatment in high-risk breast cancer and non-small cell lung cancer in the U.S. In July 2021, the FDA approved Keytruda (pembrolizumab) and chemotherapy as a treatment before surgery for people diagnosed with high-risk, early-stage triple-negative breast cancer. And in March 2022, the FDA approved Opdivo (nivolumab), a PD-1 inhibitor, to be given with chemotherapy prior to surgery in patients with early-stage NSCLC. In Europe, Keytruda was approved in 2017 as a single-agent first-line treatment for patients with early-stage NSCLC that produces high levels of the protein that blocks PD-1.

Lee, at UCLA Health, who is comparing the effectiveness of combined neoadjuvant Opdivo and chemotherapy to neoadjuvant chemotherapy alone in patients with early-stage NSCLC, says the way oncologists think about the timing of immunotherapy use is evolving as more findings become available. Now researchers want to mobilize the immune system to treat cancer as soon as possible instead of waiting until it metastasizes. “You can prime and activate those T cells,” Lee says. “There’s a lot of data to suggest that it’s better to give [immunotherapy] neoadjuvantly.” Researchers suspect that immunotherapy given up front can help the immune system recognize the initial tumor and remain vigilant against new malignant growths.

Presenting at the European Lung Cancer Congress in March 2023, researchers described the results from a trial comparing chemotherapy alone with chemotherapy combined with Opdivo given before surgery in 358 participants with stage I through III NSCLC. At three years, 28% of patients who had received the combination before surgery had had a recurrence, compared with 42% of those who received chemotherapy alone before surgery. While overall survival data are not yet available, the researchers reported that patients with certain tumor mutations in a group of four genes, all related to the immune system, were more likely to respond to Opdivo than patients with other mutations. In addition, research suggests patients with tumors driven by mutations in so-called “driver” genes, which are directly linked to cell growth and division, are less likely to respond to immunotherapy, Lee says. These patients should start immediately with other therapies.

Georgina Long, a medical oncologist at Melanoma Institute Australia, University of Sydney and Royal North Shore Hospital, has been studying the impact of neoadjuvant immunotherapy combined with targeted therapy for people diagnosed with melanoma. She stresses the importance of clinical trials for patients. “Ask your physician about them,” she advises. “To move the field forward, we have to be doing clinical trials.”

For Roth, in Bethesda, her participation in a clinical trial helped advance research and also materialized into a lasting remission. And more than three years after stopping Jemperli, Roth still has clear scans, including her most recent one in June 2023. She knows how lucky she is to have found the clinical trial testing Jemperli. Roth encourages all patients with colorectal cancer to explore the potential of clinical trials.

For Diaz, the clinical trial showed that immunotherapy given as the first treatment can change the natural history of the disease—and, most importantly, patients’ lives. That’s the most exciting prospect, he says. “We want to omit surgery and radiation when possible. That’s where the real advance is,” Diaz says. “Those are the bars we have to reach for.”

Stephen Ornes lives and works in Nashville, Tennessee.