zidesamtinib (NVL-520) / Nuvalent 
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  • ||||||||||  Review, Journal, IO biomarker:  ROS1-positive non-small cell lung cancer: from genomics to treatment decisions. (Pubmed Central) -  Feb 18, 2026   
    Multiple ROS1 tyrosine kinase inhibitors (TKIs)-from crizotinib to newer agents such as entrectinib, lorlatinib, repotrectinib, taletrectinib, and the highly selective zidesamtinib-have improved systemic and intracranial outcomes, although resistance remains inevitable and biologically diverse, involving both on-target kinase mutations and off-target mechanisms...Pemetrexed-based chemotherapy remains an effective option, whereas immune checkpoint inhibitors provide limited benefit...Looking ahead, priorities include optimizing sequencing strategies, evaluating perioperative targeted approaches, and incorporating genomic monitoring to anticipate resistance. These advances are reshaping the natural history of ROS1-rearranged NSCLC and supporting a more durable, precision-driven treatment paradigm.
  • ||||||||||  Review, Journal:  Evolving Therapeutic Landscape of ROS1-Positive Non-Small Cell Lung Cancer: An Updated Review. (Pubmed Central) -  Nov 26, 2025   
    Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape.
  • ||||||||||  zidesamtinib (NVL-520) / Nuvalent
    Trial completion date, Trial primary completion date:  A Study of Zidesamtinib (NVL-520) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1) (clinicaltrials.gov) -  Oct 24, 2025   
    P1/2,  N=359, Recruiting, 
    This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape. Trial completion date: Oct 2026 --> Dec 2028 | Trial primary completion date: Oct 2025 --> Dec 2027
  • ||||||||||  Real-World Insights on Treatment Patterns and Outcomes in ROS1 NSCLC: An Australian Multicenter Study (AURORA) (Exhibit Hall) -  Jul 22, 2025 - Abstract #IASLCWCLC2025IASLC_WCLC_1076;    
    P
    First-line ROS1 therapy demonstrated a median survival of 56 months, comparable to PROFILE 1001 (51 months) and exceeding other real-world cohorts (24 months), likely due to reflex molecular testing, targeted therapy access, and trial prioritisation. This real-world data provides valuable insights into the longitudinal patient journey, outcomes with serial therapies, and the potential impact of treatment sequencing.
  • ||||||||||  Assessment of two new ROS1+ NSCLC patient-derived cell lines as in vitro models for TKI resistance studies (Poster and Exhibition Hall; Poster Board No EACR25-1298) -  Jun 29, 2025 - Abstract #EACR2025EACR_1005;    
    This real-world data provides valuable insights into the longitudinal patient journey, outcomes with serial therapies, and the potential impact of treatment sequencing. The IC50 values of unmutated ROS1+ Ba/F3 cells for crizotinib, entrectinib, lorlatinib, repotrectinib and zidesamtinib were 31.4; 44.6; 14.3; 14.9 and 29.9 nM, respectively...Interestingly, these cells were resistant to lorlatinib, while the patient is
  • ||||||||||  Review, Journal:  Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting. (Pubmed Central) -  Jun 5, 2025   
    For EGFR exon 20 insertion mutation positive NSCLC, results from REZILIENT-1, a single arm phase II study with zipalertinib, were presented, showing an objective response rate (ORR) of 50% in patients that were pretreated with amivantamab, and 25% in patients pretreated with amivantamab and an EGFR exon 20 insertion-directed TKI...For ALK, results from ALKOVE-1, a single arm phase I/II study with NVL-655, a next generation ALK TKI, were presented. The ORR was 35
  • ||||||||||  Review, Journal:  Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions. (Pubmed Central) -  Apr 2, 2025   
    First-generation inhibitors, such as crizotinib and entrectinib, have demonstrated impressive efficacy, with objective response rates exceeding 60%-70%...Next-generation TKIs, including lorlatinib, taletrectinib, and repotrectinib, have been developed to overcome these challenges...Zidesamtinib, a highly selective next-generation ROS1 inhibitor, further addresses TRK-mediated off-target neurological toxicities seen with prior agents, and is poised to offer improved tolerability...In addition, the development of novel diagnostic tools, including RNA-based next-generation sequencing, has enhanced the detection of functional ROS1 fusions by ensuring that patients with actionable mutations receive appropriate targeted therapies. These advances highlight the evolving landscape of treatment for ROS1-positive NSCLC, with the aim of maximizing long-term survival and quality of life.
  • ||||||||||  zidesamtinib (NVL-520) / Nuvalent
    Crystal structure of drug-resistant ROS1 G2032R in complex with zidesamtinib, a clinical-stage ROS1 inhibitor with best-in-class potential (Section 20; Poster Board No: 26) -  Mar 25, 2025 - Abstract #AACR2025AACR_8096;    
    Analysis of our ROS1 G2032R crystal structure and FEP modeling provide a structural explanation for how ROS1 G2032R impairs the binding of many ROS1 TKIs while maintaining high sensitivity to zidesamtinib. The data presented here, together with previously disclosed preclinical and clinical data, support our design of zidesamtinib as a differentiated ROS1 TKI with best-in-class potential for the treatment of ROS1-positive NSCLC.
  • ||||||||||  Review, Journal:  Comprehensive review of ROS1 tyrosine kinase inhibitors (TKIs)-classified by structural designs and mutation spectrum [solvent front mutation (G2032R) and central ?-sheet 6 (C?6) mutation (L2086F)]. (Pubmed Central) -  May 8, 2024   
    Despite ROS1 fusion-positive NSCLC accounting for approximately 1% to 2% of NSCLC, there is a long list of ROS1 tyrosine kinase inhibitors (TKIs) being developed in addition to three approved ROS1 TKIs, crizotinib, entrectinib and repotrectinib...Additionally, the less known central ?-sheet 6 (C?6) 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 C?6 mutation.
  • ||||||||||  Xospata (gilteritinib) / Astellas
    Activity of gilteritinib in resistant ROS1 rearranged non-small cell lung cancer (Wedgewood Ballroom) -  Jan 28, 2023 - Abstract #IASLCTTLC2023IASLC_TTLC_158;    
    N=247 --> 359 ROS1 G2032R kinase domain mutation is responsible for majority of crizotinib and lorlatinib resistance; however emerging next-generation inhibitors repotrectinib, taletrectinib and NVL-520 are active against ROS1 G2032R...METHODS Dose response cell viability and immunoblotting experiments to test activity of entrectinib, cabozantinib and taletrectinib were conducted in transformed Ba/F3 cells CD74-ROS1 and EZR-ROS1 fusions with wild type or mutant (F2004C, G2032R, L2086F) kinase domains...Gilteritinib seems to have fewer overlapping toxicities with type I inhibitors like crizotinib or lorlatinib as compared to cabozantinib, and overall may have better tolerability owing to its lack of VEGFR inhibitory activity which limits cabozantinib
  • ||||||||||  NVL-520 / Nuvalent, repotrectinib (TPX-0005) / BMS
    Journal:  TKIs for ROS1+ Cancers Get High Marks. (Pubmed Central) -  Nov 2, 2022   
    Phase I findings from two trials, TRIDENT-1 and ARROS-1, indicate high response rates with repotrectinib and NVL-520, respectively. The latter may be a potential best-in-class agent, with potent ROS1 selectivity that avoids off-target toxicity.