Incidence of Cutaneous Adverse Events With Phosphoinositide 3-Kinase Inhibitors as Adjuvant Therapy in Patients With Cancer

Abstract

ImportanceThe phosphoinositide 3-kinase (PI3K) pathway is among the most frequently activated pathways in human cancers. As the use of PI3K inhibitors for cancer treatment grows, there is increasing need for understanding the cutaneous effects associated with these therapies.ObjectiveTo systematically review the published literature reporting incidence of cutaneous adverse events with PI3K inhibitors and to provide pooled incidence estimates using meta-analysis.Data SourcesThis systematic review and meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The literature search concerned entries through September 2021 in the following sources: PubMed, Cochrane registry, ClinicalTrials.gov, and evidence from the NHS UK and Trip medical database. To analyze PI3K inhibitors’ cutaneous adverse events incidence, only randomized clinical trials (RCTs) were considered. The search strategy used the following keywords: (prevalence OR incidence OR epidemiology) and (phosphoinositide 3 kinase inhibitors OR PI3K inhibitors). No language restriction was applied. Analysis was conducted on July 1, 2022.Study SelectionStudies included phase 2 and phase 3 RCTs that reported incidence of cutaneous adverse events associated with use of PI3K inhibitors.Data Extraction and MeasuresData extracted included sex, medication name and class, sample size, rash incidence, and grade. The bias risk was assessed by the Cochrane tool for risk of bias assessment in RCTs.Main Outcomes and MeasuresThe primary outcome was incidence of PI3K inhibitor cutaneous adverse events (with 95% CIs) among the overall population and among subgroups. Between-study heterogeneity was assessed using the I2 statistic.ResultsThe analysis found the incidence of PI3K inhibitor cutaneous events of any grade to be 29.30% in the intervention group, translating to a pooled odds ratio (OR) for incidence of cutaneous adverse events of any grades of 2.55 (95% CI, 1.74-3.75). Incidence of severe grade (grade ≥3) of rash in the intervention group was estimated to be 6.95%, yielding a pooled Peto OR of 4.64 (95% CI, 2.70-7.97). Subgroup analyses revealed that the incidence of severe cutaneous adverse events (grade ≥3) was higher with the use of Pan-class-1 PI3K inhibitors (OR, 6.67; 95% CI, 4.28-10.38) than isoform-selective PI3K inhibitors (OR, 6.37; 95% CI, 3.25-12.48).Conclusions and RelevanceThis systematic review and meta-analysis identified an overall incidence of PI3K inhibitor cutaneous adverse events of any grade to be 29.30% with a pooled OR of 2.55; (95% CI, 1.74-3.75). These findings clarify the risk of cutaneous adverse events associated with this important class of anticancer therapies.

Validity of Meta-Analytical Data on Cutaneous Adverse Events with Phosphoinositide 3-Kinase Inhibitors—Reply

“…In addition, we originally reported that subgroup analyses found an inconclusively higher incidence of severe rashes with the use of Pan-class compared with isoform-selective PI3K inhibitors; corrected subgroup analyses revealed that the incidence of severe rashes did not differ significantly between classes of PI3K inhibitors. These corrections do not change the overall results and conclusions of our study, 1 which continues to find an increased risk of all-grade and severe-grade (3-5) eruptions associated with PI3K inhibitors.…”

“…We defined rashes according to the Common Terminology Criteria for Adverse Events (CTCAE v 5.0). We appreciate Wu and colleagues' attention to detail and have added severe-grade rash data from the studies by Zelenetz et al study, Vuylsteke et al, and Bowles et al 1 In addition, we have corrected data for severe grade rash reported in the study by Powles et al 1 These corrections to the data on severe grade rash resulted in an increase to 17 trials comprising 4429 participants vs the originally reported 14 trials and 3750 participants; a change to no evidence of statistical heterogeneity (I 2 = 0%, Q = 7.16) from our previously reported significant statistical heterogeneity (I 2 = 43.62%, Q = 23.06); and a change in the pooled Peto odds ratio (OR) to 6.36 (95% CI, 4.58-8.83) and incidence of 3.41% from the originally reported pooled Peto OR of 4.64 (95% CI, 2.70-7.97) and incidence of 6.95%. In addition, we originally reported that subgroup analyses found an inconclusively higher incidence of severe rashes with the use of Pan-class compared with isoform-selective PI3K inhibitors; corrected subgroup analyses revealed that the incidence of severe rashes did not differ significantly between classes of PI3K inhibitors.…”

“…For our review, 1 we dichotomized results for the frequency of rashes into 2 groups according to their severityeither any grade or severe grade (3)(4)(5). We defined rashes according to the Common Terminology Criteria for Adverse Events (CTCAE v 5.0).…”

“…Exceptions have been made, using continuity corrections. With reference to the studies by Levy et al and Jimeno et al, 1 we included these studies with zero events in our severe rash analyses because a continuity correction of 0.5 was applied in both of those studies. This was specifically referenced in our study's Methods section.…”

“…This was specifically referenced in our study's Methods section. The forest plot mentioned zero frequency as 1 for Levy et al, 1 and for the study by Jimeno et al the software rounded off 0.5 (continuity correction) to 1. This is also intuitive because a frequency of 0.5 would not make sense to the readers.…”