The immune-related adverse effects of inhibitors of programmed cell death protein 1 (PD-1) and its ligand varied by tumor type in a large systematic review and meta-analysis.

Patients with melanoma were significantly more likely to develop colitis (odds ratio, 4.2; 95% confidence interval, 1.3 to 14.0), diarrhea (OR, 1.9), pruritus (OR, 2.4), and rash (OR, 1.8) compared with patients with non–small cell lung cancer, who were significantly more likely to develop pneumonitis, reported Leila Khoja, MBChB, PhD, of AstraZeneca UK, Melbourn, England, and associates. Patients with melanoma also were significantly more likely to develop arthralgia, hypothyroidism, rash, pruritus, and diarrhea compared with patients with renal cell carcinoma, who were more likely to develop pneumonitis and dyspnea.

“In light of this study, we should be mindful that different tumor types may have different immune-related adverse effect patterns when treated with the same immune checkpoint inhibitor,” the reviewers noted (Ann Oncol. 2017 Aug 8. doi: 10.1093/annonc/mdx286 ).

The review included 48 trials of nearly 7,000 patients with solid tumors who received CTLA-4 inhibitors (26 studies), PD-1 inhibitors (17 studies), PD-1 ligand (PD-L1) inhibitors (two trials), or both CTLA-4 and PD-1 inhibitors (three trials). The reviewers identified the studies by searching the Medline, EMBASE, and COCHRANE databases for prospective trials published from 2003 through November 2015.

Severe or life-threatening immune-related adverse effects developed in 31% of patients who received CTLA-4 inhibitors and 10% of patients who received PD-1 inhibitors. Inhibitors of CTLA-4 were significantly more likely to cause all grades of colitis (OR, 8.7), hypophysitis (OR, 6.5), and rash (OR, 2.0), while PD-1 inhibitors were more strongly linked with pneumonitis (OR 6.4), hypothyroidism (OR 4.3), arthralgia (OR, 3.5), and vitiligo (OR, 3.5).

The reviewers also looked for significant predictors of immune-related colitis and pneumonitis, because these are potentially fatal. They found that pneumonitis was significantly linked to PD-1/PD-L1 inhibitor therapy (P less than .001) and colitis to CTLA-4 treatment (P = .04), even after accounting for therapeutic dose and tumor type. No other factors reached significance in this multivariable model.

“Clearly, a more thorough understanding of the mechanisms of immune-related adverse effects is needed, which may lead to the identification of biomarkers to predict the occurrence of toxicity in patients or predict those who have immune-related adverse effects that are unlikely to respond to corticosteroids,” the reviewers concluded. Researchers should also study whether clinical factors such as treatment history or comorbidities affect the risk of immune-related adverse effects from immune checkpoint inhibitors, they said.

The reviewers reported having no funding sources and no relevant conflicts of interest.


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