Vedolizumab Induces Remission of Immunotherapy-Related Diarrhea, Colitis

Vedolizumab (Entyvio) induced clinical, endoscopic, and histologic remission of steroid-refractory, immune-mediated enterocolitis in patients receiving immune checkpoint inhibitors (ICIs) for cancer treatment, according to the results of a small retrospective study presented at the 2018 American College of Gastroenterology Annual Meeting.

The clinical remission rate was 86%; the endoscopic remission rate, 54%; and the histologic remission rate, 29%. Two patients (8%) experienced adverse events (AEs).¹

Hamzah Abu-Sbeih, MD, a research fellow at The University of Texas MD Anderson Cancer Center in Houston, presented findings from 28 adult patients treated at MD Anderson and Medstar Georgetown University Center in Washington, DC, from December 2016 to February 2018. He said that investigators noticed that endoscopic remission was a predictor for clinical remission.

“Vedolizumab is an effective alternative treatment for immune-related enterocolitis that is refractory to steroids, with a favorable safety profile,” Abu-Sbeih said. “However, our study is limited by the sample size and its retrospective nature. Therefore, large-scale prospective studies validating our findings are warranted.”

Up to 14% of patients receiving ICIs experience enterocolitis, Abu-Sbeih said. Immune-related AEs (irAEs) are the most common cause of treatment discontinuation among patients being treated with ICIs.²Previous studies showed that 60% to 85% of patients assigned to 3 mg/kg of ipilimumab (Yervoy) experience irAEs, and 10% to 27% develop grade 3/4 toxicities. In the adjuvant setting, 41.6% of patients experienced grade 3/4 irAEs when treated with 10 mg/kg of ipilimumab followed by a maintenance dose.³

Results from a retrospective analysis of data collected in Vigilyze, the World Health Organization’s pharmacovigilance database, showed that irAEs led to death in 0.3% to 1.3% of patients treated with ICIs. Colitis/diarrhea accounted for 70% (135 of 193) of deaths in patients assigned to ipilimumab monotherapy. Colitis was also responsible for 17% (58 of 333) of deaths among patients treated with anti-PD-1/PD-L1 therapy and 37% (32 of 87) of patients treated with the combination of anti— PD-1/PD-L1 plus anti–CTLA-4.⁴

Current guidelines recommend using steroids in the first line to treat enterocolitis and infliximab (Remicade) for those who are refractory to steroids, but these agents can cause significant morbidity and may counteract the antitumor effect of immunotherapy. Abu-Sbeih et al theorized that vedolizumab, a gut-targeted anti-integrin agent, might be effective for immune-mediated enterocolitis that would not induce immunosuppression.

The primary endpoint was clinical remission, defined as an improvement in clinical symptoms to grade ≤1. Secondary endpoints included endoscopic and histologic remission.

Among the participants, 27 patients (71%) were men and 25 were white, and the median age was 63 years. Melanoma was the most common diagnosis (25%). Twelve patients (43%) had received anti—PD-1 or PD-L1 therapy, and 16 (57.1%) had received anti–CTLA-4 therapy.

All patients in the study had experienced diarrhea; 13 (46.4%) had grade 3/4 symptoms, and 15 (53.6) had grade 1/2. The median time to onset was 10 weeks. Fourteen patients reported abdominal pain at presentation.

On endoscopy, 13 patients reported nonulcerative inflammation, and 8 had mucosal ulceration. Endoscopy was normal for 7 patients. Among those with an abnormal endoscopy, 14 had extensive endoscopic distribution. All patients had active inflammation on initial evaluation, 14 (50%) had features of chronicity, and 10 (36%) had microscopic colitis.

The median duration of steroid treatment was 96 days. All patients were refractory to steroids, and 7 were refractory to both steroids and infliximab.

Vedolizumab was infused at a dose of 300 mg, and patients received a median of 3 doses (interquartile range, 1-4). The mean duration of follow-up was 15 months.

Four patients did not respond to vedolizumab treatment. At initial endoscopy, 3 had large/deep ulcers but no evidence of inflammation or small/ superficial ulcers. The overall duration of disease in this group was 8 months compared with 5 months for responders.

Mean fecal calprotectin value may represent a predictive biomarker. Nonresponders had higher mean fecal calprotectin value at the time of onset compared with responders (586 vs 299, respectively) and after vedolizumab treatment (487 vs 108).

“The mean fecal calprotectin value at the time of presentation was almost double in patients who failed to respond to treatment compared with those who had clinical remission,” Abu-Sbeih said. “Therefore, fecal calprotectin could be used as a predictor for vedolizumab efficacy.”

Nonresponders were also more likely to have ulceration on initial endoscopy (75% vs 25%) and on last repeat endoscopic findings (75% vs 8%). Responders were more likely to have nonulcerative inflammation (46% vs 0%) or normal mucosa (46% vs 25%).

References:

1. Abu-Sbeih H, Ali FS, Alsaadi D, et al. Outcomes of vedolizumab treatment in patients with immune checkpoint inhibitor-induced diarrhea and colitis: a multi-center study. Presented at: 2018 American College of Gastroenterology Annual Meeting; October 5-10, 2018; Philadelphia, PA. Abstract 61.
2. Wang Y, Abu-Sbeih H, Mao E, et al. Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson. J Immunother Cancer. 2018;6:37. doi: 10.1186/ s40425-018-0346-6.
3. Haanen JBAG, Carbonnel F, Robert C, et al; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv119-iv142. doi: 10.1093/annonc/mdx225.
4. Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis [published online September 13, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.3923.