Exploring the potential of vamotinib in Ph+ leukemias: is it indeed a 3rd generation tyrosine kinase-inhibitor?

The development of tyrosine kinase inhibitors (TKIs) has markedly improved outcomes in Philadelphia chromosome-positive leukemias; however, resistance mediated by BCR::ABL1 kinase domain (KD) mutations remains a major challenge. While the third-generation TKIs ponatinib and asciminib can suppress many resistant mutations including the gatekeeper mutation T315I, their use may be limited by vascular toxicity and emerging resistance, respectively. Compound mutations (CMs), particularly those involving T315I, are frequent in advanced chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia and are largely refractory to approved TKIs when used as monotherapy. Vamotinib (formerly PF-114), a structural analogue of ponatinib with a narrower kinase inhibition profile avoiding vascular endothelial growth factor receptor-2 (VEGFR-2) inhibition, was developed to retain broad anti-BCR::ABL1 activity while reducing toxicity. Here, we evaluated the in vitro activity of vamotinib against a comprehensive panel of BCR::ABL1 KD mutants using drug concentrations corresponding to clinically relevant dosing regimens and compared the results with available clinical data from a phase-1 trial. Our findings indicate that, even at effective average plasma concentrations corresponding to the maximum tolerated dose, vamotinib exhibits a resistance profile comparable to that of a well-performing second-generation TKI. Notably, high-level resistance persisted for T315I and several P-loop mutations. Clinical responses in mutation-positive patients were largely concordant with these observations. Collectively, these data suggest that vamotinib may not meet the criteria for classification as a third-generation TKI but could have utility in selected patient populations or in rational combination strategies.