Clinical characterization of colitis arising from anti-PD-1 based therapy

Abstract

Colitis is a frequent, clinically-significant immune-related adverse event caused by anti-programmed death-1 (PD-1). The clinical features, timing, and management of colitis with anti-PD-1-based regimens are not wellcharacterized. Patients with advanced melanoma that received either anti-PD-1 monotherapy ("monotherapy") or combined with ipilimumab ("combination therapy") were screened from 8 academic medical centers, to identify those with clinically-relevant colitis (colitis requiring systemic steroids). Of 1261 patients who received anti-PD-1-based therapy, 109 experienced colitis. The incidence was 3.2% (30/937) and 24.4% (79/324) in the monotherapy and combination therapy cohorts, respectively. Patients with colitis from combination therapy had significantly earlier symptom onset (7.2 weeks vs 25.4 weeks, p < 0.0001), received higher steroid doses (median prednisone equivalent 1.5 mg/kg vs 1.0 mg/kg, p = 0.0015) and experienced longer steroid tapers (median 6.0 vs 4.0 weeks, p = 0.0065) compared to monotherapy. Infliximab use and steroid-dose escalation occurred more frequently in the combination therapy cohort compared to monotherapy. Nearly all patients had resolution of their symptoms although one patient died from complications. Anti-PD-1 associated colitis has a variable clinical presentation, and is more frequent and severe when associated with combination therapy. This variability in checkpoint-inhibitor associated colitis suggests that further optimization of treatment algorithms is needed.

Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors

“…12,13 Although there is not a clear relation between the type of checkpoint inhibitor and the induction of irAEs, some toxicities, such as hypophysitis and colitis, are found with a higher prevalence among patients receiving anti-CTLA-4 mAb agents, either as single agents or in combination with anti PD1/PDL1 inhibitors. 14,15 As described in the literature, diarrhea associated with anti-CTLA-4 therapy usually appears after 7-8 weeks from the first infusion, while anti-PD1 associated diarrhea usually onsets as late as 12-24 weeks following treatment initiation. 14,15 These diarrheas have been linked to macroscopic and microscopic alterations similar to the ones found on immune-mediated colitis.…”

“…14,15 As described in the literature, diarrhea associated with anti-CTLA-4 therapy usually appears after 7-8 weeks from the first infusion, while anti-PD1 associated diarrhea usually onsets as late as 12-24 weeks following treatment initiation. 14,15 These diarrheas have been linked to macroscopic and microscopic alterations similar to the ones found on immune-mediated colitis. 16 In general terms, drug-induced microscopic colitis (MC) can be grouped into two main categories, known as microscopic colitis: collagenous and lymphocytic colitis, both of which have a grossly normal endoscopic appearance and are differentiated by histology.…”

Systematic review with meta‐analysis: effectiveness of anti‐inflammatory therapy in immune checkpoint inhibitor‐induced enterocolitis

“…Notably, we observed a significant degree of heterogeneity between studies, which may be partly explained by differences in their inclusion criteria. For example, many studies included patients with any gastrointestinal symptom, 14,22,25,27,35,37,41,[60][61][62] while others were more stringent and only included patients exhibiting at least CTCAE grade 2 40,63,64 or 3 23,34 diarrhoea, endoscopic and/or histological evidence of inflammation, 16,33,42,44,[65][66][67] patients requiring corticosteroids 24,30 or having some response to immunosuppressive therapy. 68 Moreover, there was marked variation between studies Finally, in the subgroup analysis we included some studies where not all the study group belonged to the covariate being analysed.…”

“…This study was a retrospective analysis, and so it could be argued that patients requiring corticosteroids at baseline might have had an increased burden of comorbidity and reduced performance status as a potentially important confounding issue for survival. In addition to their potential impact on checkpoint inhibitor efficacy, it is also important to consider other potential side effects of immunosuppressive therapy in cancer patients treated with checkpoint inhibitors.Five studies reported safety outcomes in corticosteroid monotherapy, including no 'major adverse events' in 16 corticosteroid-treated patients,40 corticosteroid-induced diabetes mellitus in a cohort of 12 treated patients,60 adrenal insufficiency (n = 5), hyperglycaemia (n = 4), musculoskeletal issues (n = 3), volume overload (n = 2), hypertension, psychosis, insomnia and clostridium difficile colitis of 109 treated patients,23 hyperglycaemia, labile mood and vaginal candidiasis,40 and one study reporting infectious colitis in 2 patients alongside the other commonly documented corticosteroid complications in 23 corticosteroid-treated patients 30.…”

Recognition and management of the gastrointestinal and hepatic immune‐related adverse events

“…Anti‐CTLA‐4 antibody‐related gastrointestinal irAEs can occur throughout the treatment course, and can develop even more than 1 month after the completion of therapy . The median time of onset is 6.14 weeks (range 3.71‐8.14 weeks), whereas resolution time is 6.86 weeks (range 4.14‐8.43 weeks), compared to resolution time 25.4 weeks of anti‐PD‐1 . Combination therapy of anti‐CTLA‐4 and anti‐PD‐1 predictably leads to an earlier development of gastrointestinal toxicity (7.2 vs 25.4 weeks, P < .0001) compared to anti‐PD‐1 monotherapy …”