The 1.5, 2.5, and 6.0/3.0 mg doses in Schedules A, B, and C, respectively, were declared as maximum tolerated dose. Based on the strength of these data, BI 894999 was further evaluated in a Phase Ib trial.
Our study suggests that pre-existing heterogeneous subclones with epigenetic plasticity contribute to escaping direct KRAS inhibition in pancreatic cancer and provides a new avenue to overcome such resistance by combining KRAS inhibitors with BET inhibitors.