Dose EScalation Induction of EvERolimus

The BOLERO-2 study demonstrated an enormous benefit for patients who received everolimus in addition to exemestane in patients who progressed during/after a non steroidal (NSAI), which led to approval of everolimus in this indication. However, experience from routine use report a high rate of intolerability of this innovative treatment approach especially during the first 12 weeks of treatment. Most common side effect is mucositis/Mucositis which is considered the leading cause for treatment discontinuation not related to tumor progression. This outside clinical trial experience is contrary to findings from BOLERO-2, where the number of patients still taking full-dose (10mg) of everolimus at 4, 8, and 12 weeks is 77.8%, 75.6%, and 75.6%, respectively. These findings are in concordance with non-interventional studies. However, findings might be biased by positive pre-selection. In the non-responder part (setting III) of the neoadjuvant GeparQuinto study, everolimus was given as salvage treatment in combination with paclitaxel for patients without response to 4 cycles epirubicin/cyclophosphamide +/- bevacizumab. A dose-escalation schema was successfully used to improve tolerability of everolimus together with the cytotoxic agent. In fact the addition of everolimus to paclitaxel led only to increases of grades 1-4 leukopenia, grades 1-2 thrombocytopenia, leukopenia, skin changes and hyperlipidemia. Grades 3-4 hematological and nonhematological toxic effects were infrequent with no differences between treatment arms. Moreover, Ravaud et al performed a metaanalysis of clinical trials in order to evaluate the potential relationship between everolimus exposure, safety and efficacy. Previous studies have shown that maximum everolimus concentrations are reached 1-2 hours after administering 5-70 mg oral doses, maximum everolimus concentrations increase in a dose-proportional manner between 5 mg and 10 mg and that continuous 5-10 mg once-daily dosing enables steady state to be achieved within 1 week. The metaanalysis shows that a two-fold increase in the minimum concentration of everolimus increased the probability of tumor size reduction (odds ratio 1.4), which was associated with a trend for reduced risk of PFS events (risk ratio \[RR\] 0.9), but with an increased risk of grade 3 pulmonary toxicity (RR1.93), Mucositis (RR 1.49), and metabolic toxicity (RR 1.3). Taking together these results suggest a dose-dependent antitumor effect of everolimus that have to be balanced against the correlated increased toxicities. For this reason the optimal dose and schedule need to be explored within randomized prospective clinical trial, in order to increase compliance and tolerability, maximizing efficacy.