Nuvalent Announces Publication in Molecular Cancer Therapeutics Reinforcing Rational Molecular Design of Zidesamtinib as a Novel ROS1-Selective Inhibitor
Nuvalent announced the publication of research in Molecular Cancer Therapeutics supporting their novel cancer drug zidesamtinib. The drug is being tested in the ARROS-1 Phase 1/2 trial for patients with ROS1-positive non-small cell lung cancer and other solid tumors.
Key highlights:
- First-ever crystal structure of ROS1 G2032R mutation revealed
- Drug shows promising activity against resistance mutations
- Demonstrates effective inhibition of brain tumors compared to other treatments
- Designed to avoid TRK inhibition in the central nervous system
The company plans to report pivotal clinical data for TKI pre-treated patients in the first half of 2025, with a New Drug Application submission expected by mid-2025. The initial target indication focuses on TKI pre-treated patients with advanced ROS1-positive NSCLC.
Nuvalent ha annunciato la pubblicazione di uno studio su Molecular Cancer Therapeutics che supporta il loro nuovo farmaco antitumorale zidesamtinib. Il farmaco è attualmente in sperimentazione nel trial di fase 1/2 ARROS-1 per pazienti con carcinoma polmonare non a piccole cellule ROS1-positivo e altri tumori solidi.
Punti salienti:
- Prima struttura cristallina mai ottenuta della mutazione ROS1 G2032R
- Il farmaco mostra un'attività promettente contro le mutazioni di resistenza
- Dimostra un’efficace inibizione dei tumori cerebrali rispetto ad altri trattamenti
- Progettato per evitare l’inibizione di TRK nel sistema nervoso centrale
L’azienda prevede di presentare dati clinici fondamentali per pazienti già trattati con TKI nella prima metà del 2025, con l’invio della domanda di autorizzazione al nuovo farmaco previsto entro metà 2025. L’indicazione iniziale si concentra su pazienti con NSCLC avanzato ROS1-positivo già trattati con TKI.
Nuvalent anunció la publicación de una investigación en Molecular Cancer Therapeutics que respalda su nuevo fármaco contra el cáncer zidesamtinib. El medicamento se está evaluando en el ensayo de fase 1/2 ARROS-1 para pacientes con cáncer de pulmón no microcítico ROS1-positivo y otros tumores sólidos.
Puntos clave:
- Primera estructura cristalina revelada de la mutación ROS1 G2032R
- El fármaco muestra actividad prometedora contra mutaciones de resistencia
- Demuestra una inhibición efectiva de tumores cerebrales en comparación con otros tratamientos
- Diseñado para evitar la inhibición de TRK en el sistema nervioso central
La compañía planea presentar datos clínicos clave para pacientes pretratados con TKI en la primera mitad de 2025, con la presentación de la solicitud de nuevo fármaco esperada para mediados de 2025. La indicación inicial se centra en pacientes con NSCLC avanzado ROS1-positivo pretratados con TKI.
Nuvalent은 그들의 혁신적인 항암제 zidesamtinib를 지지하는 연구가 Molecular Cancer Therapeutics에 게재되었다고 발표했습니다. 이 약물은 ROS1 양성 비소세포폐암 및 기타 고형종양 환자를 대상으로 하는 ARROS-1 1/2상 임상시험에서 시험 중입니다.
주요 내용:
- ROS1 G2032R 돌연변이의 최초 결정 구조 공개
- 내성 돌연변이에 대해 유망한 활성을 보임
- 다른 치료제에 비해 뇌종양 억제 효과 입증
- 중추신경계에서 TRK 억제를 피하도록 설계됨
회사는 2025년 상반기에 TKI 전처리 환자 대상의 주요 임상 데이터를 보고할 계획이며, 2025년 중반까지 신약 허가 신청서를 제출할 예정입니다. 초기 목표 적응증은 TKI 전처리된 진행성 ROS1 양성 NSCLC 환자입니다.
Nuvalent a annoncé la publication d'une recherche dans Molecular Cancer Therapeutics soutenant leur nouveau médicament anticancéreux zidesamtinib. Ce médicament est testé dans l'essai de phase 1/2 ARROS-1 chez des patients atteints de cancer du poumon non à petites cellules ROS1-positif et d'autres tumeurs solides.
Points clés :
- Première structure cristalline jamais révélée de la mutation ROS1 G2032R
- Le médicament montre une activité prometteuse contre les mutations de résistance
- Démontre une inhibition efficace des tumeurs cérébrales comparée à d'autres traitements
- Conçu pour éviter l'inhibition de TRK dans le système nerveux central
L'entreprise prévoit de présenter des données cliniques majeures pour les patients prétraités par TKI au premier semestre 2025, avec une soumission de la demande d'autorisation de mise sur le marché prévue pour la mi-2025. L'indication initiale cible les patients atteints de NSCLC avancé ROS1-positif prétraités par TKI.
Nuvalent gab die Veröffentlichung einer Studie in Molecular Cancer Therapeutics bekannt, die ihr neuartiges Krebsmedikament zidesamtinib unterstützt. Das Medikament wird in der ARROS-1 Phase 1/2 Studie bei Patienten mit ROS1-positivem nicht-kleinzelligem Lungenkrebs und anderen soliden Tumoren getestet.
Wichtige Highlights:
- Erstmals wurde die Kristallstruktur der ROS1 G2032R Mutation enthüllt
- Das Medikament zeigt vielversprechende Aktivität gegen Resistenzmutationen
- Demonstriert wirksame Hemmung von Hirntumoren im Vergleich zu anderen Behandlungen
- Entwickelt, um eine TRK-Hemmung im zentralen Nervensystem zu vermeiden
Das Unternehmen plant, entscheidende klinische Daten für TKI-vorbehandelte Patienten in der ersten Hälfte des Jahres 2025 zu berichten, mit einer Einreichung des Zulassungsantrags für ein neues Medikament bis Mitte 2025. Die anfängliche Zielindikation konzentriert sich auf TKI-vorbehandelte Patienten mit fortgeschrittenem ROS1-positivem NSCLC.
- First-ever crystal structure of ROS1 G2032R mutation discovered, providing competitive advantage in drug development
- Zidesamtinib shows superior efficacy against brain tumors compared to other ROS1 TKIs in preclinical studies
- Pivotal clinical data expected in H1 2025 with NDA submission planned by mid-2025
- Drug designed to avoid TRK inhibition, potentially reducing dose-limiting side effects
- Preclinical data suggests potential to delay both peripheral and intracranial tumor progression
- Clinical efficacy in humans still pending - current data only preclinical
- Drug still in Phase 1/2 trial stage - no approved products yet
- Potential competition from other ROS1 inhibitors in development
Insights
Nuvalent's publication reveals first ROS1 G2032R crystal structure, strengthening scientific foundation for zidesamtinib ahead of H1 2025 pivotal data.
Nuvalent's publication in Molecular Cancer Therapeutics represents a significant scientific milestone for their ROS1 inhibitor zidesamtinib. The manuscript reveals what appears to be the first-ever crystal structure of ROS1 G2032R, the most common resistance mutation in ROS1-positive cancers. This structural insight provides crucial mechanistic understanding of how resistance develops and how zidesamtinib was designed to overcome it.
The preclinical data demonstrates that zidesamtinib effectively suppressed resistance in mutagenesis screens and showed superior efficacy against intracranial ROS1 G2032R tumors compared to other ROS1 inhibitors. Particularly noteworthy is the drug's selective ROS1 targeting while avoiding TRK inhibition, potentially reducing neurological adverse events that have limited other therapies.
For investors, the publication establishes stronger scientific validation for zidesamtinib's differentiated profile. The company has outlined clear development milestones with pivotal clinical data expected in H1 2025 and NDA submission targeted by mid-year 2025. The initial indication focuses on TKI pre-treated ROS1-positive NSCLC patients, addressing an important treatment gap where resistance to first-line therapies develops.
This structural biology achievement reinforces confidence in Nuvalent's rational drug design approach while the established regulatory timeline provides transparency for the path to market. The publication represents important scientific validation amid the ongoing registrational ARROS-1 trial.
The publication, entitled "Zidesamtinib Selective Targeting of Diverse ROS1 Drug-Resistant Mutations," is published online and can be accessed here: http://doi.org/10.1158/1535-7163.MCT-25-0025
"Zidesamtinib was specifically designed with the goal of addressing the combined medical needs of treating tumors that have developed resistance, treating brain metastases and avoiding off-target adverse events. Structural studies play a critical role in the development and optimization of novel therapeutics, particularly when aiming to solve for multiple, and at times competing, challenges. To date, structural studies for ROS1-positive cancers have been hindered by a lack of ROS1 G2032R crystal structures, despite G2032R being the most commonly occurring ROS1 resistance mutation," said first author Anupong Tangpeerachaikul, Ph.D., Director, Biology at Nuvalent. "With this publication in Molecular Cancer Therapeutics, we are pleased to have shared what is, to our knowledge, the first structure of ROS1 G2032R, or any ROS1 mutation, offering a framework for understanding ROS1 TKI activity against these important drivers of disease progression. This structure further illustrates the intentional design of zidesamtinib and adds to the growing body of preclinical data supporting its ROS1-selective and TRK-sparing design."
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. This favorable preclinical activity suggests the potential for zidesamtinib to delay tumor progression, both peripherally and intracranially.
In addition, the manuscript details the first crystal structure of ROS1 G2032R in complex with zidesamtinib, which further supports zidesamtinib's molecular design and provides structural insights into how the ROS1 G2032R mutation affects TKI binding. Zidesamtinib was designed with the goal of being active against ROS1 and ROS1 resistance mutations while avoiding the inhibition of the structurally related tropomyosin receptor kinase (TRK) family in the central nervous system (CNS), which has been associated with neurological adverse events that can be dose limiting. The crystal structure elucidates zidesamtinib's preclinical affinity for ROS1 G2032R and selectivity for ROS1 over TRK.
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.
About Zidesamtinib
Zidesamtinib is a novel brain-penetrant ROS1-selective inhibitor created with the aim to overcome limitations observed with currently available ROS1 inhibitors. Zidesamtinib is designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with treatment-emergent ROS1 mutations such as G2032R. In addition, zidesamtinib is designed for central nervous system (CNS) penetrance to improve treatment options for patients with brain metastases, and to avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Together, these characteristics have the potential to avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and to drive deep, durable responses for patients across all lines of therapy. Zidesamtinib has received breakthrough therapy designation for the treatment of patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) who have been previously treated with 2 or more ROS1 tyrosine kinase inhibitors and orphan drug designation for ROS1-positive NSCLC.
About Nuvalent
Nuvalent, Inc. (Nasdaq: NUVL) is a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for patients with cancer, designed to overcome the limitations of existing therapies for clinically proven kinase targets. Leveraging deep expertise in chemistry and structure-based drug design, we develop innovative small molecules that have the potential to overcome resistance, minimize adverse events, address brain metastases, and drive more durable responses. Nuvalent is advancing a robust pipeline with investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer, and multiple discovery-stage research programs.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements regarding Nuvalent's strategy, business plans, and focus; the expected timing of data announcements and FDA submissions; the clinical development program for and potential effects of zidesamtinib; the potential of Nuvalent's pipeline programs, including zidesamtinib; the implications of data readouts and presentations; Nuvalent's research and development programs for the treatment of cancer; and risks and uncertainties associated with drug development. The words "may," "might," "will," "could," "would," "should," "expect," "plan," "anticipate," "aim," "goal," "intend," "believe," "expect," "estimate," "seek," "predict," "future," "project," "potential," "continue," "target" or the negative of these terms and similar words or expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Drug development and commercialization involve a high degree of risk, and only a small number of research and development programs result in commercialization of a product. You should not place undue reliance on these statements or the scientific data presented.
Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties, and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation: risks that Nuvalent may not fully enroll its clinical trials or that enrollment will take longer than expected; unexpected concerns that may arise from additional data, analysis, or results obtained during preclinical studies and clinical trials; the risk that results of earlier clinical trials may not be predictive of the results of later-stage clinical trials; the risk that data from our clinical trials may not be sufficient to support registration and that Nuvalent may be required to conduct one or more additional studies or trials prior to seeking registration of our product candidates; the occurrence of adverse safety events; risks that the FDA may not approve our potential products on the timelines we expect, or at all; risks of unexpected costs, delays, or other unexpected hurdles; risks that Nuvalent may not be able to nominate drug candidates from its discovery programs; the direct or indirect impact of public health emergencies or global geopolitical circumstances on the timing and anticipated timing and results of Nuvalent's clinical trials, strategy, and future operations, including the ARROS-1trial; the timing and outcome of Nuvalent's planned interactions with regulatory authorities; and risks related to obtaining, maintaining, and protecting Nuvalent's intellectual property. These and other risks and uncertainties are described in greater detail in the section entitled "Risk Factors" in Nuvalent's Annual Report on Form 10-K for the fiscal year ended December 31, 2024, as well as any prior and subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Nuvalent's views only as of today and should not be relied upon as representing its views as of any subsequent date. Nuvalent explicitly disclaims any obligation to update any forward-looking statements.
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