NTRK1 G667C

The capability of AZD4547 to inhibit TRKA, TRKB and clinically relevant mutants (TRKA G595R, G667S, G667C and G667A) was also evaluated using Ba/F3 cells harboring the ETV6-NTRKs fusion gene. The combined observations demonstrate the potential application of AZD4547 for treatment of NTRK fusion driven cancers.

While the 1st generation TKIs larotrectinib (LOXO101, LAR), entrectinib (ENT) and crizotinib (CRI) have provided effective initial treatment for patients with cancers harboring these mutations, acquired resistance including secondary kinase domain mutations invariably arise. Kinase and cell proliferation inhibition and in vivo antitumor activity were determined using recombinant kinases and engineered NIH3T3 or Ba/F3 cells expressing WT or mutated TRKs and ROS1, respectively...Against the resistant solvent-front (G595R) mutant AGX87 was >1000-fold more potent (IC50=0.2 nM) than LAR and ENT and 20-fold more potent than LOXO195... AGX87 demonstrated best-in-class activity against WT and mutated TRKs and ROS1 and exhibited excellent drug-like properties. IND enabling studies are in progress.

Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

Currently in clinic, first generation TRK inhibitors, such as larotrectinib and entrectinib, have demonstrated marked efficacy in patients with cancers carrying TRK fusions, however, like most kinase inhibitors, acquired resistance mediated by kinase domain mutations has occurred. To overcome the acquired resistances, second-generation TRK inhibitors, TPX-0005 and LOXO-195, targeting both wild-type and mutant TRK fusions are currently in clinical development...XZP-5955 is currently undergoing further characterizations in IND enabling studies. IND submission is expected by the end of 2020.

Drugs targeting tyrosine kinases TrkA/B/C and ROS1, such as larotrectinib and entrectinib, are proven highly efficacious in diverse adult and pediatric tumor types (ORR > 75%)...The use of second generation of TKI, such as repotrectinib to against these acquired resistance mutations, has been explored in clinical trials and reported unsatisfied efficacy in patients under acceptable dosages, which might due to its broader inhibition of multiple kinases... Collectively, these studies have shown SIM1803-1A is a potent Trk/ROS1 dual inhibitor with better safety potentially from improved kinase selectivity. SIM1803-1A is currently at IND submission stage and represents a promising clinical candidate for the treatment-naïve and acquired-resistance NTRK/ROS1 fusion-positive malignancies. Research Funding: None