Concurrent Immunosuppressive Therapy With Restart of Checkpoint Inhibitor Reduces Risk of Recurrent Immune-related Enterocolitis

Immune-related enterocolitis (irEC) is a common adverse event during cancer therapy with immune checkpoint inhibitors (ICIs). National Comprehensive Cancer Network guidelines recommend initiating glucocorticoid therapy and continuing it for at least four to six weeks after the resolution of irEC.

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However, recent retrospective analyses of patients who received selective immunosuppressive therapies (SIT) for severe irEC, including tumor necrosis factor α inhibitors or vedolizumab, have shown these agents led to earlier symptomatic improvement than glucocorticoids. Small case series suggest that continued use of SIT may also reduce the risk of recurrent irEC if ICI therapy is restarted.

Now, the first multicenter retrospective study of that approach, reported in The Journal for ImmunoTherapy of Cancer, has indicated its efficacy and safety.

The authors are David M. Faleck, MD, of Memorial Sloan Kettering Cancer Hospital; Yinghong Wang, MD, PhD, and Fangwen Zou, MD of MD Anderson Cancer Center; Michael Dougan, MD, PhD, a physician in the Division of Gastroenterology and director of the GI Center for Cancer Complications at Massachusetts General Hospital and the Mass General Cancer Center, and Yousef R. Badran, MD, a clinician and research fellow in the Division; and colleagues.

Methods

The three-center study included 138 cancer patients who received ICI therapy between May 2015 and June 2020, developed irEC, and received infliximab or vedolizumab for initial symptom control or to facilitate steroid tapering:

• 77 patients were subsequently restarted on ICI with continued infliximab (n=33) or vedolizumab (n=44)
• 61 patients (controls) were restarted on ICI therapy without concurrent SIT (46 received infliximab, 11 received vedolizumab, and 4 received infliximab and vedolizumab sequentially before restarting ICI)

ICI therapy was held for a similar duration in both groups.

Symptom Recurrence

After re-initiation of ICI, patients on concurrent SIT therapy had a significantly lower average rate of grade 3–4 diarrhea recurrence compared with controls (17% vs. 34%; P=0.028). The same trend was seen for grade 3–4 colitis (29.5% vs 18.2%, p=0.155).

The primary outcome was the recurrence of severe irEC, defined as the composite of grade 3–4 colitis or diarrhea. On multivariate analysis, concurrent SIT use was associated with a significantly lower risk of recurrence (OR, 0.34; P=0.034).

Malignancy type, duration of steroid exposure for the initial episode of irEC, duration for which the ICI regimen was held, and ICI regimen changes were not associated with the rate of irEC recurrence. SIT administration was also associated with better endoscopic outcomes.

Safety

There were no differences in overall survival or cancer progression rates between the control group and patients receiving concurrent SIT. No differences in survival outcomes were seen when concurrent infliximab and concurrent vedolizumab were compared against each other and against control.

Managing Recurrent irEC

Data were incomplete in this study about how second episodes of irEC were managed and the outcomes. However, stopping ICI therapy after recurrent irEC was not observed to be associated with refractory colitis: recurrence was manageable after the resumption of systemic glucocorticoids and transition to an alternative form of SIT.

The decision to continue or stop ICI therapy after recurrent irEC was at the discretion of the treating physician after considering multiple factors. The difficulty in managing recurrent irEC was presumably one of those considerations.

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