Immunotherapy-related AEs reviewed, underlying mechanism postulated
medwireNews: Researchers have comprehensively analyzed the incidence of adverse events (AEs) in trials of PD-1 and PD-L1 inhibitors, while another team has provided insight into the potential pathophysiologic process underlying these effects.
Michael Wang (The University of Texas MD Anderson Cancer Center, Houston, USA) and co-authors conducted a meta-analysis of data from 125 trials – comprising 20,218 participants – that reported on AEs associated with the use of the PD-1 inhibitors nivolumab and pembrolizumab or the PD-L1 inhibitors atezolizumab, avelumab, and durvalumab, in all cases given as monotherapy. Lung cancer trials were the most common (n=26), followed by trials in patients with genitourinary tumors (n=22), melanoma (n=16), and gastrointestinal tumors (n=14).
In all, any-grade AEs occurred in 66% of 18,610 patients from 106 trials with available data, with the most frequent being fatigue (18.26%), pruritus (10.61%), and diarrhea (9.47%). And AEs of grade 3 or worse were observed in 14% of 18,715 participants of 110 trials – fatigue was still the most common event (0.89%), with anemia (0.78%) and elevations in aspartate aminotransferase (AST; 0.75%) the next most frequent AEs.
With regard to immune-related (ir)AEs, hypothyroidism (6.07%) and hyperthyroidism (2.82%) were the most common of the endocrine dysfunctions of any grade, with lower incidences of hyperglycemia, thyroiditis, adrenal insufficiency, hypophysitis, type 1 diabetes, and hypopituitarism (incidence, 0.69–1.20%).
The study authors point out, however, that these latter effects were much more likely to be severe, with, for instance, a 42% likelihood that type 1 diabetes would manifest as grade 3 or worse versus an approximately 2% probability for hypo- and hyperthyroidism.
“Close monitoring and early recognition of pertinent symptoms and signs may help enable their proper management, such as prompt initiation of steroids,” they write.
One hundred and twelve studies reported on treatment-related mortality, with a total of 82 deaths, giving an incidence rate of 0.45%. Over a quarter (28.0%) of the treatment-related deaths were due to pneumonitis.
There were no significant differences in the mean incidence of any-grade and grade 3 or worse AEs across tumor types. But PD-1 inhibitors were associated with a higher mean incidence of grade 3–5 AEs than PD-L1 inhibitors (odds ratio [OR]=1.58), with higher rates for nivolumab than pembrolizumab (OR=1.30).
“This global overview of the adverse events of PD-1 and PD-L1 inhibitors can be used as a reference by clinicians and may guide clinical practice,” conclude the researchers.
The authors of the second study aimed to gain insight into the mechanism underlying the development of checkpoint inhibitor-mediated skin AEs by analyzing matched biopsies of tumor and skin tissue from 73 individuals with non-small-cell lung cancer who received nivolumab or pembrolizumab at one of four Swiss centers.
Overall, autoimmune skin AEs developed in 34.2% of patients, but were significantly more common among patients who had achieved complete or partial remission than those with stable or progressive disease, at rates of 68.2% and 19.6%, respectively.
Individuals with autoimmune skin effects had a significant 71% reduced risk for death relative to their counterparts without these AEs, and the risk for progression or death was also a significant 78% lower.
T-cell receptor clonotype analysis of biopsy specimens showed that the tumor tissue and autoimmune skin lesions shared certain T-cell antigens, with in silico analysis identifying nine potential candidates, such as keratin 6 and 14, desmocollin 3, and maspin.
“This study suggests that, during checkpoint inhibitor therapy, T cells recognizing shared lung tumor and skin antigens simultaneously target both organs,” say Lukas Flatz, from Kantonsspital St Gallen in Switzerland, and co-researchers.
“This process is associated with the development of autoimmune skin toxic effects and likely with tumor regression as well.”
Flatz et al conclude: “If this hypothesis can be proven in larger prospective cohorts, relevant antigen-specific T cells may be useful as potential biomarkers of response to treatment. Combined with appropriate patient selection, this knowledge may help improve the efficacy of immunotherapy and anticipate its associated autoimmune toxic effects, thereby fostering its clinical application.”
Both studies appear in JAMA Oncology.
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