8P - Profiling of zidesamtinib and other ROS1 inhibitors in an intracranial CD74-ROS1 G2032R preclinical model

Background

Tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, and repotrectinib (US only) are approved for the treatment of ROS1-positive non-small cell lung cancer. Depth and durability of responses can be limited by the ROS1 G2032R resistance mutation and brain metastases, identified in ∼40% and ∼50% of patients, respectively, after progression on crizotinib. ROS1-selective TKI zidesamtinib and dual-TRK/ROS1 TKIs repotrectinib and taletrectinib have reported clinical activity against ROS1 G2032R and intracranial activity, with different adverse event profiles. In this study, we compared these three TKIs in a preclinical ROS1 G2032R brain tumor model.

Methods

Ba/F3 CD74-ROS1 G2032R luciferase cells were implanted in the brain of Balb/c nude mice. Mice were orally treated with TKIs for 25 days once (QD) or twice (BID) daily. Brain tumors were monitored 1 – 2 times per week by bioluminescence imaging (BLI). At the endpoint, plasma and brain samples were collected for pharmacokinetics (PK) analyses.

Results

Zidesamtinib (3 mg/kg BID) suppressed CD74-ROS1 G2032R brain tumors to <5% of initial BLI signal through day 25. Brain tumors were suppressed by repotrectinib (15 or 75 mg/kg BID) and taletrectinib (100 mg/kg QD) up to day 8 but regrew and eventually exceeded the initial BLI signal by 300 – 3,000%. Switching from repotrectinib (15 mg/kg BID) to zidesamtinib (3 mg/kg BID) on day 8 kept brain tumors to <15% of initial BLI signal. In this study, all TKIs achieved plasma exposures near or above their reported clinical plasma exposures. Zidesamtinib brain exposure exceeded its in vitro ROS1 G2032R IC₅₀ but not TRKB IC₅₀; by contrast, repotrectinib brain exposure exceeded its TRKB IC₅₀ but not ROS1 G2032R IC₅₀.

Conclusions

In this preclinical model, zidesamtinib demonstrated more durable intracranial activity than repotrectinib and taletrectinib at clinically relevant plasma concentrations. Switching treatment from repotrectinib to zidesamtinib resulted in improved preclinical intracranial activity. Preclinical activity against ROS1 G2032R, including in the brain, together with a TRK-sparing design supports zidesamtinib as a potential best-in-class ROS1-selective therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Nuvalent, Inc.

Funding

Nuvalent, Inc.

Disclosure

A. Tangpeerachaikul: Financial Interests, Institutional, Full or part-time Employment: Nuvalent, Inc.; Financial Interests, Institutional, Ownership Interest: Nuvalent, Inc.; Financial Interests, Institutional, Stocks/Shares: Nuvalent, Inc. H.E. Pelish: Financial Interests, Institutional, Full or part-time Employment: Nuvalent, Inc.; Financial Interests, Institutional, Leadership Role: Nuvalent, Inc.; Financial Interests, Institutional, Ownership Interest: Nuvalent, Inc.; Financial Interests, Institutional, Stocks/Shares: Nuvalent, Inc.