Early combination with mycophenolate mofetil for immune-related hepatitis in patients with solid tumors treated with immune checkpoint inhibitors.

Abstract

12133 Background: Hepatitis, as an immune-related adverse event (irAE), occurs in 2%-10% of patients treated with immune checkpoint inhibitors (ICIs). Although guidelines recommend the use of mycophenolate mofetil (MMF) for steroid-refractory and steroid-resistant ir-hepatitis, there has been no evidence on the efficacy of MMF. Methods: We retrospectively reviewed consecutive patients with solid tumors who developed grade 2 or higher ir-hepatitis requiring systemic steroids after ICIs (nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab and ipilimumab) between January 2015 and August 2023. The changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin level, according to the CTCAE version 5.0, were used to assess ir-hepatitis. ALT improvement was calculated as the ratio of the change in ALT values from onset to day 7, normalized by the ALT values at onset. Results: Among 4405 patients treated with ICI during the study period, 130 patients (3%) developed grade 2 or higher ir-hepatitis requiring systemic steroids. The median age was 62 (range: 19-85) years-old, and 122 patients (94%) had an ECOG performance status (PS) 0/1. These patients included 67 (52%) with melanoma, 35 (27%) with lung cancer, 7 (5%) with esophageal cancer, and 21 (16%) with other cancers. Among 123 evaluable patients, 46 patients (46/123, 37%) received MMF including 20 patients experiencing steroid-refractory and 26 steroid-resistant. The median duration from the start of systemic steroids to MMF was 11 days (range: 0-113 days). Improvement of hepatitis to grade 1 with MMF was observed in 40 patients (40/46, 87%) with a median time of 18 (range: 3-176) days. Of the patients evaluated for the impact of the timing of MMF on the improvement of ir-hepatitis (n=38), ALT improvement at day 7 after ir-hepatitis onset in patients who initiated MMF within 3 days of ir-hepatitis onset (early combination group, n=8) was significantly higher compared with the patients who initiated MMF after 3 days of ir-hepatitis onset (late combination group, n=30) (72.3% vs. 41.7%, p=0.02). Additionally, among patients evaluable for systemic steroid dosage (n=45), the total systemic steroid dosage in patients in the early combination group (n=8) was significantly less than in the late combination group (n=37) (median: 2120mg vs 4005 mg, p=0.02). Conclusions: MMF was effective for both steroid-refractory and steroid -resistant ir-hepatitis. Early combination with MMF in addition to systemic steroids can lead to a more rapid improvement of ir-hepatitis compared to late combination with MMF consequently reducing the total systemic steroid dosage. [Table: see text]