On December 13, 2022 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported the publication of a manuscript in Cancer Discovery, a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), which describes the design and characterization of NVL-520 and details Nuvalent’s approach to rationally targeting ROS1 (Press release, Nuvalent, DEC 13, 2022, View Source [SID1234625232]). NVL-520 is currently being studied in the ongoing ARROS-1 Phase 1/2 clinical trial for patients with advanced ROS1-positive non-small cell lung cancer (NSCLC) and other solid tumors.
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The paper, entitled "NVL-520 is a selective, TRK-sparing, and brain-penetrant inhibitor of ROS1 fusions and secondary resistance mutations," is published online and can be accessed here: View Source
"The ROS1 kinase is a clinically validated target for the treatment of NSCLC, and ROS1 tyrosine kinase inhibitors (TKIs) are established as an important treatment option for ROS1-driven lung cancers. However, limitations do exist with available ROS1 TKIs, including treatment-emergent drug resistance, off-target neurological adverse events, and inadequate control or prevention of brain metastases," said senior author Jessica J. Lin, M.D., Thoracic Oncologist at Mass General Cancer Center, Assistant Professor of Medicine at Harvard Medical School, and investigator in the ARROS-1 trial. "As described in this paper and earlier this year at the EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium, preclinical characterization and preliminary clinical data support the opportunity for NVL-520 to overcome these limitations as a potential best-in-class ROS1 kinase inhibitor and provide compelling rationale for its ongoing evaluation in patients with TKI-experienced ROS1 fusion-positive cancers and planned evaluation in treatment-naïve patients."
The paper details the design principles underlying the activity of NVL-520 against ROS1 and its most commonly occurring resistance mutation, ROS1 G2032R, and a molecular rationale for the selectivity of NVL-520 for ROS1 over the structurally-related TRK family. TRK inhibition in the CNS by approved or investigational ROS1 TKIs has been associated with neurological adverse events that can be dose limiting. Extensive preclinical characterization of the activity and selectivity of NVL-520 is presented, spanning biochemical and cellular assays, in vivo xenograft studies, and preclinical assessments of brain penetrance and intracranial activity.
In addition, the paper includes three case studies of patients with ROS1 fusion-positive lung cancers that had relapsed on or were refractory to a range of ROS1 TKIs, and includes patients with tumors that harbored ROS1 G2032R or had intracranial metastases. NVL-520 elicited tumor responses in the patients with no observed neurological toxicities. These findings support the potential for NVL-520 to treat these patient populations while also enhancing tolerability through improved selectivity for ROS1.
"At Nuvalent, we aim to solve for multiple, and at times competing, challenges in structure-based drug design with the goal to advance novel therapeutics with the potential for best-in-class activity against recalcitrant targets. This publication in Cancer Discovery provides insight into our focused approach to the discovery of NVL-520 and additional support for the potential achievement of our design goals through comprehensive biochemical and cellular profiling, evaluation across diverse ROS1-fusion driven preclinical models, and patient case studies, said Joshua Horan, Ph.D., Vice President, Chemistry at Nuvalent. "We are grateful to our collaborators for their contributions to this paper and to the continued advancement of NVL-520."
Initial data from the Phase 1 dose-escalation portion of the trial were presented during the "New Drugs on the Horizon" plenary session at the 2022 EORTC-NCI-AACR (Free EORTC-NCI-AACR Whitepaper) Symposium. The ARROS-1 trial is continuing to enroll patients in the Phase 1 portion of the study and is focused on further characterizing the safety profile of NVL-520, its pharmacokinetic profile, and determining the recommended Phase 2 dose.
About NVL-520
NVL-520 is a novel brain-penetrant ROS1-selective inhibitor designed to remain active in tumors that have developed resistance to currently available ROS1 inhibitors, including tumors with the prevalent G2032R resistance mutation and those with the S1986Y/F, L2026M, or D2033N resistance mutations. NVL-520 has been optimized for brain penetrance to potentially improve treatment options for patients with brain metastases. NVL-520 has been observed in preclinical studies to selectively inhibit wild-type ROS1 and its resistance variants over the structurally related tropomyosin receptor kinase (TRK) family to potentially avoid TRK-related CNS adverse events seen with dual TRK/ROS1 inhibitors and drive more durable responses for patients. NVL-520 is currently being investigated in the ARROS-1 study (NCT05118789), a first-in-human Phase 1/2 clinical trial for patients with advanced non-small cell lung cancer (NSCLC) and other solid tumors.