Douglas B. Johnson, MD
Findings from recent studies have begun to answer a question that oncologists have been asking since the FDA approved the first immune checkpoint inhibitor, ipilimumab (Yervoy), in 2011: Which patients will tolerate a particular immunotherapy and which patients will suffer serious toxicities?
Investigators have identified several biomarkers that are significantly associated with immune-related adverse events (irAEs) in clinical trial data, both for patients with melanoma who use certain checkpoint inhibitors and in patients with leukemia who receive T cells modified with chimeric antigen receptors (CARs).
The biomarkers found to date are far from perfect prediction tools, even among patients in the studies in which they were analyzed. Additional studies are needed to identify more predictive biomarkers and to validate those found to date, experts say. As immunotherapy becomes more widely used and information from hundreds of ongoing trials accumulates, far more data will be available for analysis.
“There is a great deal of interest right now in finding out why only certain people experience [adverse] effects [AEs] and the related question of why only certain people respond to immunotherapies. The National Cancer Institute is investing considerable money in research, and a number of groups are investigating,” said Douglas B. Johnson, MD, clinical director of the melanoma research program at Vanderbilt University Medical Center in Nashville, Tennessee.
“Ideally, we’d like to find biomarkers that accurately predict which patients will experience serious [adverse] effects, and even if we find no predictive biomarkers, the work we’re doing should help us understand the pathways through which [adverse] effects develop, and that could give us better ways to prevent or treat those effects…But we’re a long way from that. We’re just beginning to get a little peek into what has been a black box.”
Grade 3 or higher irAEs are observed in up to 43% of all patients who take ipilimumab, the only approved CTLA-4 inhibitor. Drugs that target PD-1 and PD-L1 are better tolerated, producing grade 3 or higher irAEs in up to 20% of patients.1 Combination therapy results in more frequent irAEs than either type of checkpoint inhibitor on its own.2
Although predictive biomarkers for these effects have not been established, the Society for Immunotherapy of Cancer has recommended a list of tests for oncology specialists to consider before prescribing immune checkpoint inhibitor therapy (Table 1
Search for Answers Starts With Autoimmunity
The most common irAEs associated with checkpoint inhibitors are autoimmune attacks on healthy cells, so researchers hypothesized that preexisting autoimmune disease would be among the best predictors of new irAEs; these patients have routinely been excluded from immunotherapy trials. However, investigators recently found that although an underlying autoimmune disorder can flare during ipilimumab therapy or can result in irAEs, a preexisting condition does not negatively affect response, and the resulting irAEs are manageable.3,4
Studies focused on less-intuitive baseline predictors initially did not prove much more fruitful. In a 2011 study of ipilimumab therapy, investigators made pairwise comparisons of serum interleukin-17 (IL-17) levels in patients with colitis (n = 13) versus those with no irAEs (n = 16). Serum IL-17 levels were significantly higher in patients with colitis at weeks 7 (P = .007) and 12 (P = .02). However, although IL-17 levels correlated with the development and resolution of colitis, pretreatment IL-17 levels were similar between patients with or without colitis, invalidating IL-17 as a credible predictive factor.5
A 2013 study performed gene expression profiling on 162 patients who took ipilimumab for advanced melanoma. Baseline samples showed 27 probe sets—most of them related to patient immune system, cell cycle, and intracellular trafficking—with differential mean expression (≥1.5-fold; P
≤.05) in patients who did and did not experience gastrointestinal irAEs. However, the investigators concluded that the low sensitivity of the biomarkers they found would prevent them from being used on their own to predict irAEs.6