Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations

Abstract

The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA-C can result in significant clinical benefit in patients with diverse tumors harboring , or rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALK, ROS1 or ROS1, TRKA, and TRKC are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA-C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions and As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with or fusion-positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance. Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving , and Repotrectinib may represent an effective therapeutic option for patients with -rearranged malignancies who have progressed on earlier-generation TKIs. .

Emerging therapies for non-small cell lung cancer

“…For patients with brain metastasis, a significant clinical challenge, this next-generation TKI showed superior efficacy compared to crizotinib in patients with CNS metastasis. This may be partly due to its smaller molecule structure compared to previous TKI drugs [144]. The current phase I/II clinical trial investigating the efficacy and safety of repotrectinib is still ongoing (NCT03093116), and further results should be expected.…”

Revisiting NTRKs as an emerging oncogene in hematological malignancies

“…As such, second generation NTRK inhibitors that overcome this acquired resistance are currently in development. These inhibitors include LOXO-195 [115] and repotrectinib (TPX-0005) [116]. Advancements in molecular profiling and the occurrence of NTRK mutations in liquid tumors, calls for the validation of these inhibitors in hematologic malignancies.…”

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK ‐rearranged lung cancer

“…% change in tumor volume was calculated according to the following formula: ( V t − V 0 )/ V 0 × 100. TGI was calculated using the method of Drilon et al (): 100% × [1 − (TV t − TV 0 )/(CV t − CV 0 )] where V 0 was the tumor volume at the beginning of the study, V t was the tumor volume at the end of the study, TV 0 was the V 0 in the treatment group, TV t was the V t in the treatment, CV 0 was the V 0 in the control group, and CV t was the V t in the control group.…”