zidesamtinib (NVL-520)

Despite ROS1 fusion positive (ROS1+) NSCLC accounting approximately 1-2% of NSCLC, there is a dizzying list of ROS1 tyrosine kinase inhibitor (TKIs) being developed in addition to two approved ROS1 TKIs, crizotinib and entrectinib...Additionally, the less known central β-sheet 6 (Cβ6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target Cβ6 mutation.

P1/2, N=359, Recruiting, Nuvalent Inc. | N=247 --> 359

Crizotinib and entrectinib are FDA-approved ROS1 tyrosine kinase inhibitors (TKIs), but clinical emergence of ROS1 resistance mutations S1986F/Y, F2004C/I/V, L2026M, G2032R, and D2033N restricts their therapeutic utility...TRKB inhibition in the central nervous system has been implicated in adverse events observed with FDA-approved dual TRK/ROS1 inhibitor entrectinib and FDA-approved ALK inhibitor lorlatinib...In conclusion, the preclinical profile of NVL-520 supports its potential to address a medical need for patients with a diverse array of ROS1 fusion partners and kinase-domain mutations, both in NSCLC and in other cancers such as glioblastoma. NVL-520 is being evaluated in a Phase 1/2 clinical trial for patients with advanced ROS1-positive NSCLC or other solid tumors (NCT05118789).

P1/2, N=246, Recruiting, Nuvalent Inc.

P1/2, N=246, Nuvalent, Inc.