NTRK1 G595R

These results indicate that resistant mutations, such as NTRK1-G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib-resistant tumors, thereby causing resistance to second-generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.

P1, P2 | "ctDNA next-generation sequencing represents a promising technology but its optimal integration into testing NTRK gene fusions or resistance mutations still remains to be determined. Known resistance mutations in NTRK may cause progression, but further studies are warranted."

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.

A BaF3 xenograft model encoding the LMNA-NTRK1 gene fusion and G595R solvent front mutation showed superior efficacy with PBI-200 relative to first-generation compounds larotrectinib and entrectinib, and equivalent efficacy to the second-generation compound selitrectinib, in terms of tumor growth inhibition. Together, these data suggest that PBI-200 has potential as a best-in-class, highly CNS-penetrant next generation TRKi. A Phase 1/2 clinical trial evaluating PBI-200 in NTRK fusion-positive patients, including patients with PBT, is ongoing (NCT04901806).

Background: NTRK rearrangements, though rare in common cancers, are clinically actionable targets with two FDA-approved drugs for pan-cancer indications, larotrectinib and entrectinib. NTRK1 fusions were detected in cfDNA at a similar prevalence to tissue NGS, demonstrating high sensitivity of plasma-based assays to detect these fusions. NTRK1 fusion partners were diverse, with the majority of partner genes observed only once across the cohort. Both clonal and subclonal NTRK1 rearrangements were detected, affirming that this biomarker can emerge as an oncogenic driver or as a mechanism of resistance.

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.

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