S. Lew1,2, R. Chamberlain1,2,3 1Saint Barnabas Medical Center,Surgery,Livingston, NJ, USA 2Saint George’s University,Grenada, Grenada, Grenada 3University Of Medicine And Dentistry Of New Jersey,Surgery,Newark, NJ, USA
Introduction:
Cancer cells employ diverse mechanisms to evade anti-tumor immune responses, one of which expresses a ligand activating negative costimulatory molecules which downregulate the T cell immune response; lymphocyte antigen-4 (CTLA-4). Many studies with CTLA-4 monoclonal antibody have demonstrated antitumor activity in advanced melanoma and other solid tumors with varying degrees of treatment related gastrointestinal (GI) adverse effects. This study sought to determine the incidence of CTLA-4 blockade-associated severe GI adverse effects, risk stratified by the type of malignancy treated, and to investigate dosage related risk of severe diarrhea or colitis.
Methods:
A comprehensive literature search of PubMed, Google Scholar and the Cochrane Central Registry of Controlled Trials was completed. Keywords searched were ‘ipilimumab’, ‘Yervoy’, ‘MDX-010′, ‘MDX101′, ‘tremelimumab’, ‘ticilimumab’, ‘diarrhea’, ‘colitis’, and ‘clinical trial’. All clinical trials were analyzed for patient recruitment, intervention, and outcomes. Incidence and risk ratio (RR) were calculated with 95% confidence intervals.
Results:
13 single or double arm, phase II/III clinical trials involving 4,383 patients treated with ipilimumab or tremelimumab were identified. The incidence of CTLA-4 blockade associated severe (grade 3-4) diarrhea was 9.5% (95% CI [5.4-16.2]; p<0.0001) and severe colitis was 6.3% (95% CI [4.9-8.0]; p<0.001) among 1,464 patients in 9 clinical trials in which CTLA-4 blockade monotherapy was used in a single arm trial or RCT. Among 4,383 ipilimumab or tremelimumab treated patients in 10 RCTs, the risk of severe diarrhea in the treatment group was 9% compared to 1.5% in control (RR 4.18, 95% CI [1.44-12.15]; p=0.009) while severe colitis in the treatment group was 5.3% compared to 0.2% in the control (RR 11.53, 95% CI [3.65-36.44]; p=<0.001). The incidence and risk of severe CTLA-4 blockade-associated GI adverse events were not significantly different between melanoma and solid tumor, between 3mg and 10mg dosage regimens, or when monotherapy and/or concomitant chemotherapy were used. Significant heterogeneity was found among identified trials with regards to underlying malignancies, the dosage of the treatment, and duration of the treatment.
Conclusion:
CTLA-4 blockade is associated with a significantly increased risk of all- and high-grade diarrhea and colitis. Altering in dosing regimens or combinational chemotherapy utilizing CTLA-4 blockade did not significantly reduce the risk of GI adverse events. Although adequately powered large studies are needed to further investigate contributing risk factors for the GI adverse events, GI adverse events should be carefully monitored in patients treated with CTLA-4 blockade.