Oncogenic TRKA/B/C fusions are identified in multiple cancer types in adults and children. TRK inhibitors (TRKis) have demonstrated marked efficacy in patients with these cancers, however, acquired on-target resistance mediated by kinase domain mutations can occur. Next-generation TRKis targeting both wildtype and mutant TRK fusions can address this unmet need. Repotrectinib was designed to potently inhibit wildtype (WT) TRKs and overcome resistance mutations. The anti-proliferative activity of 1st generation (larotrectinib/entrectinib) and next-generation (repotrectinib/LOXO-195) TRKis were compared using engineered Ba/F3 cells expressing WT or mutated TRKs (Table). Repotrectinib was over 10-fold more potent than LOXO-195 against WT TRK fusions and solvent front mutations (SFMs), and more than 100-fold more potent against the gatekeeper mutations TRKA F589L and TRKC F617I. Furthermore, repotrectinib was the only TRKi active against the compound mutation TRKA G595R/F589L in cis in preclinical Ba/F3 cells. In xenograft tumor models, repotrectinib led to significant tumor regression in tumors carrying WT or mutated TRK fusions. In the ongoing TRIDENT-1 phase 1 clinical trial of repotrectinib (NCT03093116), the SFMs TRKA G595R, TRKC G623R and TRKC G623E and the gatekeeper mutation TRKA F589L were detected in plasma cfDNA samples at baseline from three TRKi-resistant patients. Repotrectinib was active against ETV6-TRKC G623E in an entrectinib-resistant patient with a salivary gland tumor (-82%, confirmed partial response, RECIST v1.1). Tumor regression (-33%) was achieved in a larotrectinib-resistant cholangiocarcinoma patient with LMNA-TRKA G595R and F589L mutations in trans. TRIDENT-1 is currently enrolling NTRK fusion-positive patients with advanced solid tumors.

 Ba/F3 Cell Proliferation Assay IC50 (nM) 
 LMNA-TRKA ETV6-TRKB ETV6-TRKC 
TRK Inhibitor WT G595R G667C F589L G595R/F589L WT G639R WT G623R G623E F617I 
Repotrectinib <0.1 0.1 9.2 <0.1 17.4 <0.1 3.2 <0.1 0.4 0.9 <0.2 
LOXO-195 8.6 13.1 94.9 31.6 531.1 1.0 28.4 1.7 24.6 49.1 53 
Larotrectinib 15.9 1898 1863 625.3 10000 13.1 3000 23.2 6999 2162 5000 
Entrectinib 0.3 614 186.7 <0.2 2000 0.2 2000 0.4 1340 1712 61.7 
 Ba/F3 Cell Proliferation Assay IC50 (nM) 
 LMNA-TRKA ETV6-TRKB ETV6-TRKC 
TRK Inhibitor WT G595R G667C F589L G595R/F589L WT G639R WT G623R G623E F617I 
Repotrectinib <0.1 0.1 9.2 <0.1 17.4 <0.1 3.2 <0.1 0.4 0.9 <0.2 
LOXO-195 8.6 13.1 94.9 31.6 531.1 1.0 28.4 1.7 24.6 49.1 53 
Larotrectinib 15.9 1898 1863 625.3 10000 13.1 3000 23.2 6999 2162 5000 
Entrectinib 0.3 614 186.7 <0.2 2000 0.2 2000 0.4 1340 1712 61.7 

Citation Format: Alexander Drilon, Dayong Zhai, Wei Deng, Xin Zhang, Dong Lee, Evan Rogers, Jeffrey Whitten, Zhongdong Huang, Armin Graber, Juliet Liu, Shanna Stopatschinskaja, J. Jean Cui, Dong-Wan Kim, Byoung Chul Cho, Robert C. Doebele, Sai-Hong Ignatius Ou, Jeeyun Lee, Alice T. Shaw. Repotrectinib, a next generation TRK inhibitor, overcomes TRK resistance mutations including solvent front, gatekeeper and compound mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 442.