# Mycophenolate Mofetil for Treatment of Ipilimumab-Induced Colitis in Patients with Metastatic Melanoma

## TL;DR

This study shows that mycophenolate mofetil (MMF) is an effective oral treatment for severe colitis caused by immunotherapy in melanoma patients, similar to infliximab.

## Contribution

The study provides evidence that MMF is a viable alternative to infliximab for treating steroid-refractory immune-related colitis in melanoma patients.

## Key findings

- MMF and infliximab both effectively resolved symptoms of immune-related colitis in patients.
- MMF was well-tolerated and did not impair oncological outcomes like progression-free or overall survival.
- MMF is a suitable alternative when infliximab cannot be used.

## Abstract

Treatment with immune checkpoint inhibitors (ICIs) has improved survival in patients with advanced melanoma but can also induce immune-related (ir) adverse events such as severe colitis. Steroid-refractory patients are most commonly managed with additional infliximab, while data for other immunosuppressants are sparse. In this retrospective study, we compared mycophenolate mofetil (MMF) with infliximab in patients with steroid-refractory ir colitis. Our study demonstrates that patients can be effectively managed not only with infliximab but also with MMF, without prolongation of time to resolution or impairment of oncological outcomes. The data point to MMF as a well-tolerated, oral treatment alternative for patients with ICI-induced ir colitis, especially in patients where infliximab is contra-indicated.

Background/Objectives: Treatment with immune checkpoint inhibitors (ICIs) in patients with advanced melanoma has greatly improved clinical outcomes but can induce immune-related adverse events (irAEs). ICI-induced immune-related (ir) colitis is one of the most common severe irAEs and is primarily managed by treatment with high-dose corticosteroids. Some patients are steroid-refractory and require additional immunosuppressants. Infliximab is commonly used as the additional treatment of choice, while data for other immunosuppressants such as mycophenolate mofetil (MMF) are sparse. Methods: We used MMF to treat ir colitis in a cohort of patients in Heidelberg and compared clinical data with patients who received standard irAE management with infliximab in the Cancer Centers of Heidelberg, Hannover, Mainz, and Kiel. Outcome measures included response rate, time to response, duration and amount of steroid intake, and recurrence of colitis, as well as progression-free survival (PFS) and overall survival (OS) measured from the start of steroid intake. Results: Out of 52 patients refractory to steroids, 31 were treated with additional MMF and 21 with additional infliximab. A total of 24 out of 31 patients (77.4%) experienced bowel habit normalization during treatment with MMF after a median of seven days. Seven patients required additional infliximab to achieve a resolution of symptoms. Twenty out of 21 patients (95.2%) showed a normalization of stool frequency with infliximab after a median of eleven days. One patient required additional MMF to achieve a normal bowel habit. Hence, resolution of symptoms was achieved during both treatment regimens (p = 0.081) in a comparable period of time (p = 0.858). Neither recurrence of colitis after additional immunosuppression (p = 0.760) nor rate of CMV positivity after recurrence of colitis (p = 0.898) differed between groups. We observed a tendency towards longer treatment duration (108 vs. 85 days, p = 0.052) and significantly higher cumulative corticosteroid intake (7585 mg vs. 3485 mg, p = 0.002) in the MMF group compared to the infliximab group. However, we observed significantly higher cumulative steroid intake and a longer duration of corticosteroid therapy in patients treated at the Heidelberg center compared with those treated at the other participating centers within the infliximab group. In contrast, no significant differences in corticosteroid duration or cumulative dose were observed in the center-internal comparison between MMF- and infliximab-treated patients at Heidelberg. These subgroup analyses may indicate that the observed differences in corticosteroid exposure are more likely related to center-specific management strategies rather than substance-specific effects. Neither median PFS nor OS differed between the groups (mPFS: MMF: 3.2 months; infliximab: 2.1 months (p = 0.978); mOS MMF: 12 months; infliximab: 9.5 months (p = 0.561)). Conclusions: The data point to MMF as a well-tolerated, oral treatment alternative for patients with ICI-induced ir colitis, especially in patients where infliximab is contra-indicated.