AP26113- Pharmacodynamics

Brigatinib (AP26113) is a tyrosine kinase inhibitor with in vitro activity against a number of kinases, including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), FLT-3, and also epidermal growth factor receptor (EGFR) deletion and point mutations. Autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signalling proteins STAT3, AKT, ERK1/2, and S6 is inhibited by Brigatinib in vitro and in vivo [1].

In in vitro kinase assays, Brigatinib had potent activity against ALK (IC50 0.6 nmol/L), including the mutant variants C1156Y (0.6 nmol/L), F1174L (1.4 nmol/L), L1196M (1.7 nmol/L), G1202R (4.9 nmol/L) and R1275Q (6.6 nmol/L). The drug also demonstrated activity against ROS1, FLT3, mutant variants of FLT3 (D835Y) and EGFR (L858R; IC50 1.5–2.1 nmol/L) and to a lesser extent EGFR with a T790M resistance mutation (L858R/T790M), native EGFR, IGF-R1, and INSR (IC50 values 29–160 nmol/L) [2].

Brigatinib inhibited growth of various anaplastic large cell lymphoma (ALCL) and NSCLC cell lines expressing NPM-ALK or EML4-ALK fusions [growth inhibition of 50% of cells (GI50) 4–31 nmol/L]; the ALK phosphorylation IC50 of the drug in these cell lines was 1.5–12 nmol/L. GI50 values for Brigatinib ranged between 503 and 2387 nmol/L in 3 ALK-negative ALCL and NSCLC cell lines [2].

Brigatinib had substantial in vitro activity against a panel of 17 ALK mutants that confer resistance to Crizotinib, Ceritinib, And Alectinib (IC50 of Brigatinib 9–184 nmol/L). Brigatinib had 2.2- to 77-fold more potency than Crizotinib (IC50 170–1109 nmol/L) against all but the L1198F mutant, was C3-fold more potent than Ceritinib against L1152R/P, C1156Y, L1198F, and G1269A and C3-fold more potent than Alectinib against L1152R, I1171N, V1180L, L1196M, G1202R, and G1269A [2].

Oral Brigatinib 10, 25 or 50 mg/kg administered once daily inhibited tumour growth dose dependently in ALK positive Karpas-299 (ALCL) and H2228 (NSCLC) xenograft mouse models [3].

In a murine orthotopic brain tumour model in which ALK-positive H2228 (NSCLC) cells were injected intracranially to form tumours in the brain, daily oral administration of Brigatinib 25 and 50 mg/kg prolonged median survival to 62 and [64 days, respectively, compared to crizotinib 100 mg/kg/day (median survival 47.5 days) and vehicle (median survival 28 days) [3].

On the 28th of April 2017, Brigatinib (AP26113) received its first global approval in the USA for the treatment of patients with metastatic ALK-positive NSCLC.

References

1.Anthony M. Brigatinib: First Global Approval[J]. Drugs, 2017, 77:1131–1135
2.Zhang S, Anjum R, Squillace R. The potent ALK inhibitor Brigatinib (AP26113) overcomes mechanisms of resistance to first- and second-generation ALK inhibitors in preclinical models[J]. Clin Cancer Res. 2016, 22(22):5527–38.
3.Gettinger SN, Bazhenova LA, Langer CJ. Activity and safety of Brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial[J]. Lancet Oncol. 2016, 17(12):1683–96.

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