Incidence of cutaneous adverse events with PI3K-Akt-mTOR pathway inhibitors: 

A Systematic Review and Network Meta-analysis

Abdulhadi Jfri1,2, Rachel Meltzer1,2, Lauren Guggina1,2

Background

Phosphoinositide 3-kinase/Akt mammalian target of
rapamycin (PI3K-Akt-mTOR) pathway is an intracellular
signaling pathway that plays a pivotal role in the cell cycle
control. It is an important target in malignancies that include
PI3K inhibitors that contain three classes (Pan-class I,
Isoform-selective and Dual PI3K/mTOR inhibitors), Akt
inhibitors and mTOR inhibitors. Immune-mediated side effects
are common with inhibitors of this pathway, but incidence of
cutaneous adverse events is lacking.

Objective

To investigate the incidence of cutaneous adverse events with 
PI3K-Akt-mTOR pathway inhibitors from randomized clinical 
trials. 

Methods

We performed a systematic review of the PubMed, Cochrane
Central Register, Embase and clinical trial registries on
September 9, 2021 on phase 2 or 3 randomized control trials
(RCTs) studying PI3K/Akt/mTOR inhibitors. Data were
extracted based on the Preferred Reporting Items for
Systematic Review and Meta-analysis guidelines. Network
meta-analysis in frequentist framework using Mantel-Haenszel
method (for sparse event data) was performed with R package
“netmeta.”

1Brigham and Women’s hospital, Harvard Medical School, Boston, USA. 2Dana Farber Cancer Institute, Boston, USA. 

Results

A total of 134 publications were initially identified and 58 registered trials. There
were a total of 43 relevant RCTs examining 7 PI3K inhibitors, 4 Akt inhibitors, 3
mTOR inhibitors, conventional and placebo, with a cumulative sample size of
13,029 participants. Test of inconsistency yielded statistical non-significance (Q=
11.12, df= 6, p =0.08). Compared with placebo and conventional treatments, PI3K
inhibitors, mTOR inhibitors and AKT inhibitors were more likely to develop rashes
among the intervention group (Figure 1). Largest effect sizes were seen for PI3K
inhibitors (OR = 4.46, 95% CI: 3.32 to 5.99), followed by AKT inhibitors (OR =
3.53, 95% CI: 2.08 to 5.98) and mTOR inhibitors (OR = 3.47, 95% CI= 2.79 to
4.32).

Conclusion

This study provides incidence of cutaneous adverse events with PI3K inhibitors, Akt
inhibitors and mTOR inhibitors. Further studies to explore the predictive value of
cutaneous adverse events on response to therapy and survival outcomes are
warranted.

References

Figure 1. Pairwise comparisons presenting likelihood of 

development of cutaneous adverse events with PI3K-Akt-mTOR 

pathway inhibitors