Anti-programmed death 1 (anti–PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors have been an exciting advance in oncology treatment. However, immune-related adverse effects (irAEs) of these therapies can be long-lasting and life-altering in some patients. Grade 2 or higher irAEs occur in 25% to 30% of patients treated with single-agent checkpoint therapy and in up to 55% for combination therapies, with increased severity.
In a recent publication, Dr Joanne Weidhaas and colleagues evaluated microRNA (miRNA) pathways for association with immune-related toxicity and identified a germline miRNA-based biomarker panel that predicts toxicity in patients receiving checkpoint inhibitors, regardless of tumor type. The study included 161 patients treated with single-agent anti–PD-1 or anti–PD-L1 therapy. Patients with melanoma had the longest time before developing toxicity (median 14 cycles), and patients with prostate cancer had the shortest time before developing toxicity (median 4 cycles). Toxicity increased more than 9-fold with increasing cycles of treatment in patients with the toxicity biomarker signature. The biomarker panel consists of inherited, germline mutations primarily in regions disrupting miRNAs, called miRNA single-nucleotide polymorphisms (miRSNPs). The most significant biomarker in predicting toxicity across cancers was a 3’UTR germline mutation in RAC1. Additional research is ongoing to determine if this germline signature of toxicity to single-agent therapy is predictive of increased toxicity risk with immunotherapy combinations.
Another study using data from the SWOG Cancer Research Network, by Dr Joseph M. Unger and colleagues, revealed that the risk of severe symptomatic AEs is greater among women than men, particularly severe hematologic AEs. Symptomatic and hematologic AEs occurred in 33.7% of women receiving immunotherapy compared with 25.4% of men. Their risk of severe toxicity and risk of sleep-related AEs were also higher. Within subsets, the risk of symptomatic AEs was 66% greater for women (vs men) receiving immune checkpoint inhibitors and immune system modulators compared with those receiving other types of therapy, but this association was not observed for nonsymptomatic AEs.
Dr Weidhaas et al stated that dysregulation of the RAC1 protein could be reasonably expected to predict irAEs to anti–PD-1/PD-L1 therapy. Another biomarker identified as having high variable importance is the interleukin-10 receptor 2 SNP rs2834167. Application of germline variant panels may improve the ability to offer truly personalized cancer therapy by considering toxicity along with patient response. With increasing rates of long-term cancer control with new therapies, cure without harm will become an increasingly important endpoint for clinical trials. Dr Unger et al suggest that studying AEs from immunotherapy agents should continue to be a priority.
The ability to predict toxicity to anti–PD-1/PD-L1 therapy has broad clinical utility, as the primary goal of cancer therapy is to maximize treatment efficacy while limiting toxicity. Application of germline variant panels may improve clinicians’ ability to offer truly personalized cancer therapy by considering toxicity along with patient response. As use of checkpoint inhibitors broadens, the likelihood of serious toxicity could prove critical in deciding whether to implement therapy in other settings, such as adjuvant and palliative care. This could also inform altered management through cycle reductions or closer surveillance if potential benefits outweigh the risks of treatment.