PIK3CA and Hyperinsulinemia: Another issue that cannot be overlooked about PI3K inhibitors is their on-target, off-tumor toxicity, particularly hyperglycemia and hyperinsulinemia which are observed as major dose-limiting toxicities.98,108,109 Despite the benefits of PFS shown in several randomized clinical trials, the increased toxicities of PI3K inhibitors have raised concerns about the potential detriments of OS in the PI3K inhibitor arm.34,105,110–113 In blood cancers, future approvals of PI3K inhibitors by FDA should be supported by randomized data.114