(A-116) Efficacy and Safety of PI3K/Akt/mTOR Inhibitors Combined with Taxane Therapy for Treatment of Breast Cancer: A Systematic Review and Meta-Analysis

Background: Drug resistance in breast cancer is caused by activation of the PI3K/AKT/mTOR pathway. This resistance can be overcome by PI3K/AKT/mTOR inhibitors that synergizes the activity of taxanes to enhance its apoptotic activity.

Objectives: To evaluate the efficacy and safety of PI3K/AKT/mTOR inhibitors in combination with taxane therapy for the treatment of breast cancer.

Methods: We searched ‘PubMed’, ‘Embase’, ‘Cochrane’, ‘Scopus’ platforms till 15th October 2024 for randomized controlled trials (RCTs) of PI3K/AKT/mTOR inhibitors (Pictilisib, Buparlisib, Capivasertib, Ipatasertib, Everolimus) with taxanes (Paclitaxel, Docetaxel) therapy. The protocol was registered with PROSPERO (CRD42024619455). Screening was done using Rayyan software and meta-analysis was conducted using ‘meta’ package in R (version 4.4.2).

Results: The analysis included 11 RCTs with 2,730 patients and showed that the combination of PI3K/AKT/mTOR inhibitors with taxane therapy significantly improved Progression Free Survival (PFS) compared to taxane therapy alone (HR: 0.79; 95% CI: 0.69-0.91). However, the PFS improvements in both PI3K-mutated (HR: 0.71: 95% CI: 0.47-1.07) and non-mutated populations (HR: 0.91; 95% CI: 0.70-1.17) were not statistically significant. Overall Survival (OS) did not show a significant benefit in the overall population (HR: 0.83; 95% CI: 0.61-1.14) or in mutated subgroup (HR: 0.66; 95% CI: 0.37-1.17). The Overall Response Rate (RR: 0.97; 95% CI: 0.83-1.14), Pathological Complete Response (RR: 1.02; 95% CI: 0.63-1.67), and Clinical Benefit Rate (RR: 1.07; 95% CI: 0.97-1.17) were comparable between groups. With significant increase in grade 3/4 (RR: 1.67; 95% CI: 1.25-2.24), grade ≥3 (RR: 1.51; 95% CI: 1.10-2.07), and serious adverse events (AEs) (RR: 1.43; 95% CI: 1.13-1.83), the combination group observed a greater incidence of AEs.

Conclusions: The combination of taxane and PI3K/AKT/mTOR inhibitors significantly improved PFS but not OS, while increasing the risk of AEs. To optimize this combination therapy for breast cancer, more studies are required to weigh the PFS advantage versus toxicity.