ROS-1 TKI for the treatment of concurrent sarcomatoid transformation and acquired ROS-1 F2004C mutation in a lung adenocarcinoma patient

Ko, How-Wen; Hsu, Chia-Lin; Yeh, Yi‐Chen; Huang, Hui‐Chun

doi:10.1016/j.pulmoe.2021.08.009

Cited by 4 publications

(1 citation statement)

References 7 publications

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“…The G2032R “solvent-front” substitution, identified in 30% to 40% of patients after crizotinib or lorlatinib progression ( 20 ), is particularly recalcitrant. Other clinically observed ROS1 resistance mutations include S1986F ( 22 ), S1986Y ( 22 ), F2004C ( 23 ), F2004I ( 21 ), F2004V ( 24 ), L2026M ( 25 ), D2033N ( 26 ), and G2101A ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance Mutations

et al. 2022

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ROS1 tyrosine kinase inhibitors (TKIs) have been approved (crizotinib and entrectinib) or explored (lorlatinib, taletrectinib, and repotrectinib) for the treatment of ROS1 fusion-positive cancers, although none simultaneously address the need for broad resistance coverage, avoidance of clinically dose-limiting TRK inhibition, and brain penetration. NVL-520 is a rationally designed macrocycle with >50-fold ROS1 selectivity over 98% of the kinome tested. It is active in vitro against diverse ROS1 fusions and resistance mutations and exhibits 10-to-1,000-fold improved potency for the ROS1 G2032R solvent-front mutation over crizotinib, entrectinib, lorlatinib, taletrectinib, and repotrectinib. In vivo, it induces tumor regression in G2032R-inclusive intracranial and patient-derived xenograft models. Importantly, NVL-520 has a ~100-fold increased potency for ROS1 and ROS1 G2032R over TRK. As clinical proof-of-concept, NVL-520 elicited objective tumor responses in three patients with TKI-refractory ROS1 fusion-positive lung cancers, including two with ROS1 G2032R and one with intracranial metastases, with no observed neurological toxicities.

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