zidesamtinib (NVL-520) / Nuvalent - LARVOL DELTA

Assessment of two new ROS1+ NSCLC patient-derived cell lines as in vitro models for TKI resistance studies (EACR 2025) - "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 – after being treated with lorlatinib+cis-platinum+pemetrexed, now currently successfully treated with lorlatinib mono-therapy... In this study we showed that PC1 cells generated from a crizotinib-resistant patient were resistant to all ROS1 inhibitors tested. The G2032R mutated PC2 cells generated from a crizotinib and lorlatinib resistant patient were sensitive to repotrectinib, but not to zidesamtinib. This PC2 cell line can be used to assess off-target resistance mechanism to zidesamtinib."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Respiratory Diseases • Solid Tumor • ARID1A • CD74 • PIK3CA • PIK3CG • ROS1

Nuvalent Announces Timing of Pivotal Data for TKI Pre-treated Patients with Advanced ROS1-positive NSCLC from ARROS-1 Clinical Trial of Zidesamtinib (PRNewswire) - "Nuvalent...announced that the company will host a webcast and conference call on Tuesday, June 24, 2025 at 8:00 a.m. ET, to discuss pivotal data for zidesamtinib, a novel ROS1-selective inhibitor, in TKI pre-treated patients with advanced ROS1-positive non-small cell lung cancer from the global ARROS-1 Phase 1/2 clinical trial."

P1/2 data • Non Small Cell Lung Cancer

Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations. (PubMed, Mol Cancer Ther) - "At clinically relevant concentrations, zidesamtinib robustly inhibited >1,500 pooled ROS1 mutants with virtually no resistance emerging (≤1%), outperforming comparators crizotinib, entrectinib, and repotrectinib. Zidesamtinib also induced more durable responses than repotrectinib and taletrectinib in an aggressive intracranial ROS1 G2032R xenograft model. A 2.2 Å co-crystal structure with ROS1 G2032R, the most frequently identified ROS1 resistance mutation, reveals that zidesamtinib uniquely accommodates the mutated residue while potentially clashing with TRK, consistent with its selective ROS1-targeting design and supported by computational modeling. Taken together, these data support zidesamtinib's potential as a novel best-in-class ROS1 inhibitor."

Journal • Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Nuvalent Announces Publication in Molecular Cancer Therapeutics Reinforcing Rational Molecular Design of Zidesamtinib as a Novel ROS1-Selective Inhibitor (PRNewswire) - "The manuscript explores the activity of zidesamtinib and other approved or investigational ROS1 TKIs at clinically relevant concentrations against ROS1 resistance mutations, including the most commonly occurring resistance mutation, ROS1 G2032R, in preclinical mutagenesis screens and an intracranial ROS1 G2032R xenograft model. Findings presented in the manuscript show that, at clinically relevant concentrations, zidesamtinib suppressed on-target resistance in ENU mutagenesis screens simulating first-line and later-line treatment and inhibited ROS1 G2032R brain tumors more effectively than the other ROS1 TKIs evaluated....The company expects to report pivotal clinical data for TKI pre-treated patients with advanced ROS1-positive NSCLC from the ARROS-1 Phase 1/2 trial in the first half of 2025 in support of an anticipated New Drug Application submission by mid-year 2025, with an initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC."

FDA filing • P1/2 data • Preclinical • Brain Cancer • CNS Tumor • Non Small Cell Lung Cancer

Crystal structure of drug-resistant ROS1 G2032R in complex with zidesamtinib, a clinical-stage ROS1 inhibitor with best-in-class potential (AACR 2025) - "Tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, and repotrectinib are FDA-approved for treatment of ROS1-positive NSCLC. 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."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NTRK2 • ROS1

ANS03, a novel, orally bioavailable small-molecule type II ROS1/NTRK inhibitor, effectively overcomes clinically relevant ROS1/NTRK resistance mutations and exhibits potent antitumor activity in preclinical tumor models (AACR 2025) - "ANS03 also had better activity against the ROS1 L2086F mutation when compared to both Repotrectinib and NVL-520. Non-clinical studies of ANS03 showed it is a potent, orally bioavailable Type II ROS1/NTRK inhibitor with remarkable activity against various pathogenetic ROS1/NTRK alterations and with favorable absorption, distribution, pharmacokinetics, efficacy, and tolerability profiles in vivo. The compound will enter Phase 1 clinical development in the US and China soon."

Preclinical • Oncology • NTRK • NTRK1

Targeting ROS1 rearrangements in non-small cell lung cancer: Current insights and future directions. (PubMed, Cancer) - "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."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Nuvalent to Present New Preclinical Data on ALK-Selective Inhibitor, Neladalkib, and ROS1-Selective Inhibitor, Zidesamtinib, at AACR Annual Meeting 2025 (PRNewswire) - "Nuvalent...announced upcoming poster presentations further characterizing the preclinical profiles of its novel ALK-selective inhibitor, neladalkib, and novel ROS1-selective inhibitor, zidesamtinib, at the American Association for Cancer Research (AACR) Annual Meeting 2025 from April 25-30, 2025, in Chicago."

Preclinical • Oncology

Novel strategies for rare oncogenic drivers in non-small-cell lung cancer: An update from the 2024 Annual ESMO meeting. (PubMed, Lung Cancer) - "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 % in patients pretreated with ≥ 2 ALK TKIs including lorlatinib and 57 % in patients pretreated with ≥ 1 ALK TKI, excluding lorlatinib...In addition, results of the first-line randomized phase III INSPIRE study were presented, in which iruplinalkib, an ALK and ROS1 selective TKI, is being evaluated versus crizotinib...Finally, results from ARROS-1, a single arm phase I/II study with zidesamtinib, a ROS1 selective and TRK-sparing TKI, were presented. An ORR of 73% was obtained in..."

Journal • Review • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • ROS1

Expanded Access Program of Zidesamtinib (NVL-520) for Patients with Advanced ROS1+ NSCLC (NVL-520-EAP) (clinicaltrials.gov) - P=N/A | N=0 | Available | Sponsor: Nuvalent Inc.

New trial • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Nuvalent Details Strategy to Seek First Potential Approval in 2026 and Outlines Key Anticipated 2025 Milestones (PRNewswire) - "As part of this plan, Nuvalent anticipates the following 2025 milestones: Report pivotal data for tyrosine kinase inhibitor (TKI) pre-treated patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) from its ARROS-1 Phase 1/2 trial of zidesamtinib in the first half of 2025; Submit a New Drug Application (NDA) for zidesamtinib with initial target indication of TKI pre-treated patients with advanced ROS1-positive NSCLC by mid-year 2025; Report pivotal data for TKI pre-treated patients with advanced ALK-positive NSCLC from its ALKOVE-1 Phase 1/2 trial of neladalkib (NVL-655) by year-end 2025; Initiate the ALKAZAR Phase 3 randomized, controlled trial of neladalkib for TKI-naïve patients with ALK-positive NSCLC in the first half of 2025; and Progress the HEROEX-1 Phase 1a/1b trial of NVL-330 for patients with advanced HER2-altered NSCLC."

FDA filing • P1/2 data • Trial status • Non Small Cell Lung Cancer

Profiling of zidesamtinib and other ROS1 inhibitors in an intracranial CD74-ROS1 G2032R preclinical model (ESMO 2024) - "Background: Tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, and repotrectinib (US only) are approved for the treatment of ROS1-positive non-small cell lung cancer. 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."

Preclinical • Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • NTRK2 • ROS1

Updates in Targeted Therapies for ALK+ and ROS1+ NSCLC from ESMO 2024 : Episode 3: Findings for Zidesamtinib in Advanced ROS1+ NSCLC and Other Solid Tumors (OncLive) - "Gregory J. Riely, MD, PhD...discuss data for zidesamtinib in ROS1-positive non-small cell lung cancer."

Video

ARROS-1 and ALKOVE-1: Dr. Gadgeel Shares Insights on ESMO Data (YouTube) - "Shirish M. Gadgeel, MD...discusses the ARROS-1 and ALKOVE-1 studies presented at the European Society of Medical Oncology (ESMO) 2024 Congress....'These data clearly demonstrate that this drug can be effective in patients who have had multiple prior TKIs, including lorlatinib, and it appears to be well tolerated,' he said. 'It doesn't appear to have the adverse events seen with lorlatinib related to the TRK inhibition. This drug is now going to be evaluated in other studies, including possibly in a frontline trial, to see if this drug provides better benefit than what we see with currently available ALK inhibitors.'"

Video

Phase I/II ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumours (ESMO 2024) - P1/2 | "Pts had a median of 3 (range: 1-11) prior anticancer therapies, including any ROS1 TKI (99%); lorlatinib (55%), repotrectinib (repo; 21%), or either (67%); ≥2 ROS1 TKIs (69%); and chemo (66%). Zidesamtinib demonstrated encouraging efficacy and durability in pts with pretreated ROS1+ NSCLC, including those who had exhausted available therapies, with ROS1 resistance mutations including G2032R, and/or with CNS mets. Safety was favorable and consistent with the highly ROS1-selective and TRK-sparing design. Ph 2 enrollment is ongoing with registrational intent in pts with TKI-naïve and pretreated ROS1+ NSCLC."

P1/2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ROS1

Updated ARROS-1 Phase 1 Data (PRNewswire) - P1/2 | N=359 | ARROS-1 (NCT05118789) |Sponsor: Nuvalent Inc. | "Updated Phase 1 data from...ARROS-1 clinical trial to be presented at the ESMO Congress 2024....As of the data cut-off date of March 12, 2024, 104 patients (99 NSCLC, 5 other) received zidesamtinib (25-150 mg orally QD) in Phase 1. Patients were heavily pre-treated with a median of 3 (range: 1-11) prior anticancer therapies including any ROS1 TKI (99%), and included: the most heavily pre-treated of patients, receiving two or more prior ROS1 TKIs (69%) and one or more prior lines of chemotherapy (66%); patients previously treated with lorlatinib (55%), repotrectinib (repo; 21%), or either (67%); and, patients with a history of treated/untreated CNS metastases (53%). 100 mg QD was selected as the RP2D with no observed dose relationships for safety or efficacy. "

P1 data • Non Small Cell Lung Cancer

Preclinical Intracranial Activity of Zidesamtinib (PRNewswire) - "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%....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."

Preclinical • Brain Cancer • CNS Tumor

Nuvalent Highlights Pipeline Progress, Reiterates Key Anticipated Milestones, and Reports Second Quarter 2024 Financial Results (PRNewswire) - "Enrollment is ongoing in the HEROEX-1 Phase 1a/1b clinical trial evaluating NVL-330 for pre-treated patients with HER2-altered NSCLC (NCT06521554)...2024: Execute on Global Registrational Strategies: Progress the Phase 2 portion of its ARROS-1 trial of zidesamtinib in patients with advanced ROS1-positive NSCLC with registrational intent; Initiate the Phase 2 portion of its ALKOVE-1 trial of NVL-655 in patients with advanced ALK-positive NSCLC with registrational intent; Launch the front-line development strategy for its ALK program; Initiate the Phase 1 trial for its HER2 program. Present interim data from its ongoing ARROS-1 and ALKOVE-1 clinical trials at medical meetings; and, 2025: First Pivotal Data: 2026: First Approved Product."

Clinical data • Enrollment status • New P1 trial • P1/2 data • Trial status • Non Small Cell Lung Cancer • HER-2

Nuvalent to Present Updated Data for ROS1-Selective Inhibitor, Zidesamtinib, and ALK-Selective Inhibitor, NVL-655, at the ESMO Congress 2024 - "Presenter: Alexander Drilon, M.D...Title: Phase 1/2 ARROS-1 study of zidesamtinib (NVL-520) in ROS1 fusion-positive solid tumors."

Nuvalent to Present Updated Data for ROS1-Selective Inhibitor, Zidesamtinib, and ALK-Selective Inhibitor, NVL-655, at the ESMO Congress 2024 (PRNewswire) - "Nuvalent...announced that updated data from the ARROS-1 Phase 1/2 clinical trial of zidesamtinib and ALKOVE-1 Phase 1/2 clinical trial of NVL-655, will be presented during two oral presentations at the European Society for Medical Oncology (ESMO) Congress 2024 taking place September 13-17, 2024, in Barcelona, Spain....Additionally, the company will present new preclinical data further characterizing the intracranial activity of zidesamtinib during a poster session."

P1/2 data • Preclinical • Non Small Cell Lung Cancer

ARROS-1 Trial of Zidesamtinib Aims to Address Current TKI Limitations in ROS1+ NSCLC (OncLive) - "'ROS1 fusions are rare but important events,' Stephen V. Liu, MD, explained in an interview with OncologyLive. 'These types of cancers don't respond particularly well to immunotherapy. They can respond to chemotherapy, but for years our standard of care has been targeted therapy.'"

Interview

Nuvalent Highlights Pipeline Progress, Reiterates Key Anticipated Milestones, and Reports First Quarter 2024 Financial Results (PRNewswire) - "Recent Pipeline Progress and Anticipated Milestones:...The company expects to share updated data from the ARROS-1 Phase 1/2 trial at a medical meeting in the second half of 2024. Enrollment is ongoing in the global Phase 2 portion of the study....Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 trial of NVL-655 for patients with advanced ALK-positive NSCLC and other solid tumors....The company expects to share updated data from the ALKOVE-1 trial at a medical meeting in the second half of 2024."

Enrollment status • P1 data • P1/2 data • Non Small Cell Lung Cancer

Dr Liu on the Ongoing Investigation of Zidesamtinib in ROS1+ Tumors (OncLive) - "Stephen V. Liu, MD...discusses the potential benefit of zidesamtinib (NVL-520) for patients with ROS1-positive tumors, expanding on the current investigation of the selective ROS1 inhibitor in the phase 1/2 ARROS-1 study (NCT05118789)."

Video

Mutagenesis screens support potential best-in-class profile for selective, brain-penetrant, and TRK-sparing ROS1 inhibitor zidesamtinib (NVL-520) (AACR 2024) - "Tyrosine kinase inhibitors (TKIs) crizotinib, entrectinib, and repotrectinib have been approved for the treatment of ROS1-positive NSCLC. The screens did not reveal any novel ROS1 mutations that could confer resistance to NVL-520 at the RP2D. The broad preclinical activity against ROS1 and diverse ROS1 mutations, together with its brain penetrance and TRK-sparing design, suggests NVL-520 as a potential best-in-class ROS1 therapy."

Late-breaking abstract • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CD74 • ROS1

👋 Connect with us at #AACR24, where we are presenting new data further characterizing the differentiated preclinical profiles of NVL-330 and zidesamtinib. View our posters: https://nuvalent.com/publications/?pag=1&filter=all Read more: ...