Brigatinib is a cost-effective treatment in first-line anaplastic lymphoma kinase mutation-positive (ALK + ) advanced non-small cell lung cancer (NSCLC) with brain metastases

Introduction The aim of this paper was to assess the cost-effectiveness of alectinib and brigatinib in first-line for anaplastic lymphoma kinase mutation-positive (ALK+) advanced non-small cell lung cancer (NSCLC). Pivotal phase III RCTs were considered. Four hundred and eighty-two patients were included. Both trials, which compared alectinib and brigatinib versus (vs.) crizotinib (control group), respectively, showed a gain in pharmacological costs, compared to the control group, of 194.80 € for alectinib and 648.48 € for brigatinib for an entire treatment of a single patient. Brigatinib was the less expensive, with a cost of 269.78 € for each month of PFS for both intention-to-treat (ITT) population that patients with baseline brain metastases (BBM). In conclusion, combining pharmacological costs of drugs with the measure of efficacy represented by PFS, both alectinib and brigatinib are cost-effective treatments in first-line for ALK+ NSCLC. In the BBM population brigatinib seems to be the most cost-effectiveness.

FLT3-ITD Activates RSK1 to Enhance Proliferation and Survival of AML Cells by Activating mTORC1 and eIF4B Cooperatively with PIM or PI3K and by Inhibiting Bad and BIM

FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously found that FLT3-ITD activates the mTORC1/S6K/4EBP1 pathway cooperatively through the STAT5/PIM and PI3K/AKT pathways to promote proliferation and survival by enhancing the eIF4F complex formation required for cap-dependent translation. Here, we show that, in contrast to BCR/ABL causing Ph-positive leukemias, FLT3-ITD distinctively activates the serine/threonine kinases RSK1/2 through activation of the MEK/ERK pathway and PDK1 to transduce signals required for FLT3-ITD-dependent, but not BCR/ABL-dependent, proliferation and survival of various cells, including MV4-11. Activation of the MEK/ERK pathway by FLT3-ITD and its negative feedback regulation by RSK were mediated by Gab2/SHP2 interaction. RSK1 phosphorylated S6RP on S235/S236, TSC2 on S1798, and eIF4B on S422 and, in cooperation with PIM, on S406, thus activating the mTORC1/S6K/4EBP1 pathway and eIF4B cooperatively with PIM. RSK1 also phosphorylated Bad on S75 and downregulated BIM-EL in cooperation with ERK. Furthermore, inhibition of RSK1 increased sensitivities to BH3 mimetics inhibiting Mcl-1 or Bcl-2 and induced activation of Bax, leading to apoptosis, as well as inhibition of proliferation synergistically with inhibition of PIM or PI3K. Thus, RSK1 represents a promising target, particularly in combination with PIM or PI3K, as well as anti-apoptotic Bcl-2 family members, for novel therapeutic strategies against therapy-resistant FLT3-ITD-positive AML.