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11ms
Comprehensive review of ROS1 tyrosine kinase inhibitors (TKIs)-classified by structural designs and mutation spectrum [solvent front mutation (G2032R) and central β-sheet 6 (Cβ6) mutation (L2086F)]. (PubMed, J Thorac Oncol)
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.
Review • Journal
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FLT3 (Fms-related tyrosine kinase 3) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ROS1 fusion • ROS1 positive • ROS1 G2032R • ROS1 L2086F
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • Xospata (gilteritinib) • Cabometyx (cabozantinib tablet) • Augtyro (repotrectinib) • taletrectinib (AB-106) • zidesamtinib (NVL-520)
over1year
Enrollment change • Metastases
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ROS1 rearrangement
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zidesamtinib (NVL-520)
over2years
Preclinical activity of NVL-520 in ROS1-driven cancer models with diverse fusion partners and kinase-domain mutations (AACR 2022)
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).
Preclinical
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • CD74 (CD74 Molecule) • SLC34A2 (Solute carrier family 34 member 2) • SDC4 (Syndecan 4)
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ROS1 fusion • ROS1 positive • ROS1 G2032R • CD74 expression • GOPC-ROS1 fusion • ROS1 D2033N • SDC4-ROS1 fusion • ROS1 S1986F
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Xalkori (crizotinib) • Rozlytrek (entrectinib) • Lorbrena (lorlatinib) • zidesamtinib (NVL-520)
3years
New P1/2 trial
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ROS1 rearrangement
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zidesamtinib (NVL-520)
3years
Clinical • New P1/2 trial
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ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS)
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ROS1 rearrangement
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zidesamtinib (NVL-520)