ICEMELT: Risk factors of immune-checkpoint inhibitors mediated liver, gastrointestinal, endocrine and skin toxicity

Immuno-oncology (IO) is a novel treatment that invigorates the anti-tumour response by boosting the T cell immunity. Inhibition of immune checkpoints can significantly strengthen the cancer-specific cytotoxic T cell response, resulting in improved tumour destruction. While IO has become a well-accepted treatment in some solid malignancies such as melanoma, liver cancer 1, colorectal cancer 2, the widespread clinical implementation of immune-checkpoint inhibitors (ICIs) has been hampered by their high cost in combination with commonly occurring immune-related adverse events (irAEs).

Gastrointestinal toxicities are the second most common irAEs and can occur in up to 5% of patients treated with single PD-1 (programmed cell death antigen-1) inhibitor and up to 55% of patients treated with a combination of PD-1 + CTLA-4 (cytotoxic T-lymphocyte associated antigen-4) inhibitors. To date, (1) we cannot predict irAE risk reliably at patient level and (2) irAEs remain a diagnosis of exclusion as there are no specific clinical or biological markers. Thus, irAEs result in treatment delay/disruption, and may even prevent patients from receiving more potent dual therapy to begin with due to the concern of higher toxicity risk. Thus, it is of utmost importance to understand the underlying mechanisms and risk factors of irAEs. One day it may facilitate developing strategies for their prevention and diagnosis. With no established markers of its onset and development, irAEs remain a major challenge in cancer immunotherapy and present a crucial barrier for developing more effective combinatorial therapies or expanding IO usage to earlier stages i.e., adjuvant and particularly, neo-adjuvant context.

ICEMELT is a prospective multicentre cohort study. It recruits patients with solid malignancies who are scheduled to receive ICI therapy at one of the participating study sites. Patients are divided into groups: (1) single ICI; (2) Ipilimumab + Nivolumab; (3) ICIs + platinum-based chemotherapy; (4) Atezolizumab + Bevacizumab (VEGF [Vascular endothelial growth factor] inhibitor). Considering the incidence of irAEs in patients treated with abovementioned ICI-based regimens, power of 0.8 and significance level of 0.05, we need to recruit n=44; n=32; n=37 patients in groups 1, 3 and 4 respectively (distribution ratio 2:1) and n=148 to group 2 (distribution ratio 1:1). In the past 2.5 years ICEMELT study recruited: n=35; n=114; n=23 and n=34 into groups 1, 2, 3 and 4 respectively.