CHARLOTTE, N.C.—For immune-mediated diarrhea and colitis that is refractory to standard therapy, fecal microbiota transplantation may be an effective next line of treatment. Investigators from The University of Texas MD Anderson Cancer Center, in Houston, also found evidence to support the procedure as a first-line approach.
“The majority of patients we have treated with FMT have had symptom improvement. We are seeing a lot of promising signals in applying FMT, not only for compassionate cases but also for front-line treatment for immunotherapy-related colitis. FMT avoids long-term steroid dependency and immunosuppression. It’s effective in maintaining remission and has a low complication rate,” said Yinghong Wang, MD, PhD, the director of Fecal Microbiota Transplantation and director of Inflammatory Bowel Disorders at the cancer center.
The current recommendation for immune-mediated diarrhea and colitis (IMC) is to initiate corticosteroids for diarrhea/colitis of grade 2 or higher and biologics for steroid-refractory disease. But these treatments can have long-lasting complications. The increasing use of immune checkpoint inhibitors that pose a risk for colitis presents a growing need for evolving management strategies, Dr. Wang noted.
Clinical Characteristics Of Study Patients
In a presentation at the 2022 annual meeting of the American College of Gastroenterology, Dr. Wang and her co-investigators reported on data on the use of FMT in 37 patients with IMC, most of whom had stage IV disease, mainly genitourinary cancers (35%) or melanoma (27%) (abstract D0397). More than 78% of patients had been hospitalized, for a median of eight days. Almost all of them were treated with a steroid and either infliximab or vedolizumab (Entyvio, Takeda).
Cancer treatment consisted of either PD-1/L1 inhibitors or a combination of PD-1/L1 inhibitors plus the anti–CTLA-4 agent ipilimumab (Yervoy, Bristol-Myers Squibb); two patients received ipilimumab alone. All patients stopped treatment because of colitis, after a median of seven doses.
Symptom Improvement With Transplant
Of the 37 patients, 32 (86%) reported improvement in symptoms after FMT, at a median of five days post-treatment. Four patients (11%) required immunosuppressants for recurrent or refractory colitis after FMT, and 30% resumed their cancer treatment. Complications related to FMT within seven days were reported by 16% of patients, and complications within 30 days were reported by 5%. The complications were mostly mild and self-limited. At the end of the study period, 95% of patients were in clinical remission and 5% had persistent symptoms. At the last follow-up, 46% of the patients had died, mainly from progressive disease.
This is the largest study to date supporting the effectiveness of FMT in managing immune-related diarrhea and colitis refractory to standard treatment and showing an improvement in patient-reported outcomes, Dr. Wang noted.
“Our results show FMT is a safe and promising treatment option, with a low complication rate. The majority of patients had symptom improvement, and a very small proportion required additional treatment,” she said. “The results also potentially support a lower threshold for resorting to FMT in difficult-to-manage cases. This is important as it avoids the long-term immunosuppression these patients usually receive and [its] corresponding complications.”
First-line Therapy With FMT
The “lower threshold” for using FMT was examined in another study that Dr. Wang and her team presented at ACG (D0418). Three patients, with metastatic kidney cancer and on immune checkpoint inhibitors, received FMT before receiving any steroids or biologic agents.
All the patients presented with abnormal lactoferrin and calprotectin values, which subsequently improved after FMT. They reported symptom improvement after FMT, and only one had a recurrence of symptoms. The latter patient was slated for a second FMT but, due to underlying end-stage renal disease, he developed worsening hypotension and cardiac deterioration and died six weeks later. The other two patients have had sustained clinical responses for 10 and 13 months, at the time of the meeting.
Co-investigator Malek Shatila, MD, a research fellow at MD Anderson, described the rapid response in one patient who had persistent grade 2 diarrhea. “The very next day after FMT, she had symptom improvement, and endoscopically we saw a significant mucosal healing inside of two months,” he said.
Dr. Wang said this early evidence of benefit up front has “opened a new path for us.” She added, “We are seeing better acceptance from our patients and oncologists. Now, they are checking with me when they have new cases …. They are starting to be more open-minded and feel more comfortable in considering this new approach.”
“There is growing interest in the role of the microbiome in both the efficacy and toxicity of immunotherapy. Immune-related colitis is one of the most common and severe toxicities that results from the use of checkpoint inhibitors in cancer, and is the most common toxicity leading to treatment discontinuation,” said David Faleck, MD, the director of Inflammatory and Immune-Related Bowel Diseases at Memorial Sloan Kettering Cancer Center, who is conducting a phase 1 trial of FMT for immune-related colitis (ClinicalTrials.gov Identifier: NCT04883762).
“Dr. Wang’s work on the role of FMT for the treatment of immune-related colitis is novel and exciting, and it paves the way for future studies of microbiome therapeutics in the growing field of immune-related toxicities,” Dr. Faleck said. “Larger, multicenter studies—ideally randomized trials with control arms—will be important to understand the role and optimal positioning of FMT in the management of immune-related colitis.”
—Caroline Helwick
Dr. Faleck reported financial relationships with AzurRx, Equillium, Kaleido and Mallinckrodt. Dr. Shatila reported no relevant financial disclosures. Dr. Wang reported financial relationships with AxurRx, Ilya, MabQuest SA, Sanarentero and Sorriso.
This article is from the January 2023 print issue.