Immunotherapy Breakthrough Offers Hope for Rare Cancer Patients

When Maureen Sideris, 71, was diagnosed with gastroesophageal junction cancer in 2022, she was confronted with the grim prospect of surgery that could strip away her ability to speak or savor her favorite foods. Choosing a different path, Sideris joined a clinical trial investigating an immunotherapy drug designed for rare cancer types. After undergoing nine rounds of intravenous treatments over six months, her tumors remarkably shrunk and then vanished entirely.

"I was in shock—I felt like I’d won the lottery," Sideris expressed to Verywell. "Right up until the very end, you're almost thinking that another shoe is going to drop."

The clinical trial, conducted at Memorial Sloan Kettering Cancer Center, administered the drug dostarlimab to 117 patients with tumors characterized by mismatch repair mutations—a rare genetic anomaly present in approximately 2% to 3% of cancers. The results were impressive, with 80% of participants achieving remission without the need for surgery.

The study, presented at the annual meeting of the American Association for Cancer Research and published in the New England Journal of Medicine, also explored the drug’s efficacy on mismatch repair-deficient (MMRd) tumors in various organs, including the stomach, esophagus, liver, endometrium, urinary tract, and prostate. Among 54 patients, tumors disappeared in 35.

"This is really powerful data," remarked Dr. Benjamin Schlecter, a senior physician at the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute. "It shows us that different cancers respond quite differently. It turns out, it doesn’t work as well in some cancers, despite their biological similarities."

Complete resolution was achieved in just over half of those with gastric cancer, with lower success rates for gastroesophageal cancer. Schlecter noted that there wasn’t sufficient data to alter treatment protocols for pancreatic, urothelial, small intestine, or prostate cancers at this time.

Additionally, the study offers insights into treatment failures: Cancer recurrence was often found in the lymph nodes rather than the primary tumor site, potentially guiding decisions about surgical interventions.

Traditionally, immunotherapy for localized solid tumors involves a few doses followed by surgery. This large-scale study, however, indicates that immunotherapy alone could suffice for most patients, potentially "upending the standard paradigm" for treating MMRd cancer, according to Dr. Michael Overman of the MD Anderson Cancer Network.

A phase 3 clinical trial is in progress to assess dostarlimab for MMRd colon cancer prior to surgery. Dr. Overman sees potential for the therapy to sufficiently shrink tumors, rendering surgery unnecessary in some cases.

Dostarlimab works by enabling the immune system to recognize tumors that typically hide behind PD1 proteins. Initially approved for endometrial cancer with mismatch repair mutations, it later gained approval for MMRd rectal cancer. In 2024, guidelines were updated to recommend immunotherapy as the preferred first-line treatment for MMRd rectal cancer.

"The crucial takeaway is to get tested for MMRd cancers," Schlecter stressed. "It's important because this could indicate a familial trait, and immune therapy might be an option before considering surgery that affects bowel function."

Furthermore, many with MMRd cancers could have Lynch syndrome, highlighting the importance of genetic testing.

Despite lacking the hair loss and mouth sores typical of chemotherapy, immunotherapy can cause side effects like skin rashes and gastrointestinal issues. It may not be suitable for those with autoimmune conditions.

A notable challenge in using immunotherapy as an initial treatment lies in adequate surveillance. Unlike rectal cancers detectable with MRI, other types pose greater challenges. "How do you monitor a colon cancer not scheduled for surgery?" Overman questioned, pointing out the limitations of CT scans versus MRI.

As researchers continue honing care for MMRd patients and seek to expand immunotherapy applications, Sideris voiced a plea for ongoing support. "My success and that of the rectal cancer patients indicate that this wouldn't have been possible without funding. We need to keep pushing forward."