Combining targeted agents and ET improves outcomes in pts with HR+ MBC but increases the risk of AEs. However, the specific additional toxicity burden caused by these agents remains unknown. Our meta-analysis aims to better estimate the comparative risk of AEs with the combination of ET and CDK4/6 inhibitors, PI3K inhibitors, mTOR inhibitors and anti-HER2 agents in pts with HR+ MBC.
A systematic literature search of MEDLINE, EMBASE, Cochrane Library and proceedings from major conferences up to March 31st 2017 was conducted to identify randomized controlled trials investigating ET plus CDK4/6, PI3K, mTOR inhibitors and anti-HER2 agents as compared to ET alone in pts with HR+ MBC. For each class of targeted agents, two groups were considered: ET plus targeted agent vs. ET alone. Summary risk estimates (odds ratio, OR) and 95% confidence intervals (CI) were calculated for each side effect within each class of targeted agents for each trial. Pooled analysis was conducted using the random and fixed effects models.
A total of 7865 pts from 15 studies were included in our meta-analysis. Overall, the addition of targeted agents to ET was associated with significant higher risk of grade 3-4 AEs: OR 2.95 (95% CI 2.47-3.53) for CDK4/6 inhibitors, 2.05 (95% CI 1.63-2.58) for PI3K inhibitors, 1.89 (95% CI 1.40-2.56) for mTOR inhibitors, and 2.33 (95% CI 1.17-4.63) for anti-HER2 agents. Anti-HER2 agents, CDK4/6 and PI3K inhibitors significantly increased the risk of grade 3-4 fatigue, but not mTOR inhibitors (OR 1.48; 95% CI 0.64-3.43). Anti-HER2 agents, PI3K and mTOR inhibitors significantly increased the risk of grade 3-4 diarrhea, but not CDK4/6 inhibitors (OR 1.15; 95% CI 0.46-2.87). Other AEs and class specific toxicities will be reported at the conference.
In pts with HR+ MBC, the combination of targeted agents and ET is associated with significant increased risk of AEs. The risk of developing different AEs varies largely according to the type of agent used. Potential specific toxicities should be taken into account and discussed with patients when deciding to opt for combination regimens.
Clinical trial identification
PROSPERO registration number: CRD42017058278
Legal entity responsible for the study
E. De Azambuja: Honoraria from Roche and travel grants from Roche and GlaxoSmithKline outside the submitted work. All other authors have declared no conflicts of interest.