On June 21, 2022 Nuvalent, Inc. (Nasdaq: NUVL), a clinical-stage biopharmaceutical company focused on creating precisely targeted therapies for clinically proven kinase targets in cancer, reported progress on its parallel lead clinical programs NVL-520, a novel ROS1-selective inhibitor, and NVL-655, a novel ALK-selective inhibitor (Press release, Nuvalent, JUN 21, 2022, View Source [SID1234616147]). Nuvalent announced that it plans to share preliminary data from the dose-escalation portion of its ongoing ARROS-1 Phase 1/2 clinical trial for NVL-520 in patients with advanced ROS1-positive NSCLC and other solid tumors in the second half of 2022. In addition, Nuvalent announced that the first patient has been dosed in ALKOVE-1, its Phase 1/2 clinical trial evaluating NVL-655 in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors. NVL-520 and NVL-655 have been designed to address the clinical challenges of emergent treatment resistance, off-target CNS adverse events, and brain metastases that may limit the use of currently available ROS1 and ALK kinase inhibitors.

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"Advancing two novel candidates into clinical development in a little over six months is a significant achievement that we believe demonstrates our ability to scale as a clinical stage company with our growing portfolio, and the value of continued collaboration with leading physician-scientists in the advancement of investigational opportunities for patients in need of new therapies," said Christopher Turner, M.D., Chief Medical Officer of Nuvalent. "We remain committed to the efficient and data-driven development of NVL-520 and NVL-655 through our ARROS-1 and ALKOVE-1 studies and look forward to the opportunity to share preliminary data from the dose-escalation portion of the ARROS-1 trial later this year."

ARROS-1 is a Phase 1/2, multicenter, open-label, dose-escalation and expansion trial evaluating NVL-520 in patients with advanced ROS1-positive NSCLC and other solid tumors. ARROS-1 is actively enrolling patients with previously treated ROS1-positive solid tumors in the Phase 1 portion of the study. Additional information on the ARROS-1 trial is available on www.ClinicalTrials.gov (NCT05118789).

ALKOVE-1 is a Phase 1/2, multicenter, open-label, dose-escalation and expansion trial evaluating NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors. The Phase 1 dose-escalation portion of the study is open and enrolling patients with previously treated ALK-positive solid tumors and will evaluate the overall safety and tolerability of NVL-655. Additional objectives include determination of the recommended Phase 2 dose (RP2D), characterization of the pharmacokinetic profile, and evaluation of preliminary anti-tumor activity.

Once a safe and tolerable dose is determined as the RP2D, the ALKOVE-1 trial is designed to transition directly into the Phase 2 multiple cohort expansion portion, which will evaluate the overall activity of NVL-655 in patients with advanced ALK-positive NSCLC and other solid tumors. The Phase 2 portion will examine several cohorts of patients based on the number and type of prior anti-cancer therapies they have received. The Phase 2 cohorts are designed with the intent to expand in size, as data emerge and in collaboration with the U.S. Food and Drug Administration (FDA), into potential registrational cohorts for the treatment of previously treated patients with ALK-positive NSCLC. Additional information on the ALKOVE-1 trial is available on www.ClinicalTrials.gov (NCT05384626).

"The ALKOVE-1 study has been designed with the goal of seamlessly accelerating from first-in-human dose-exploration of NVL-655 into Phase 2 cohorts evaluating a range of ALK-positive patient populations," said Darlene Noci, A.L.M., Senior Vice President of Product Development & Regulatory Affairs for Nuvalent. "We believe the growing body of preclinical data generated to date for NVL-655 continue to demonstrate its promise as a differentiated ALK-selective inhibitor with the potential to overcome the limitations of currently available therapies, and are supportive of its development throughout the treatment paradigm for patients with ALK-positive cancers."

In addition to NVL-520 and NVL-655, Nuvalent continues to advance its pipeline expansion efforts with multiple discovery-stage research programs.

About NVL-520
NVL-520 is a 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.

About NVL-655
NVL-655 is a novel brain-penetrant ALK-selective inhibitor created to overcome limitations observed with currently available ALK inhibitors. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with the solvent front G1202R mutation or compound mutations G1202R / L1196M ("GRLM"), G1202R / G1269A ("GRGA"), or G1202R/L1198F ("GRLF"). NVL-655 has been optimized for CNS penetrance to improve treatment options for patients with brain metastases. NVL-655 has been observed in preclinical studies to selectively inhibit wild-type ALK 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/ALK inhibitors and drive more durable responses for patients. NVL-655 is currently being investigated in the ALKOVE-1 study (NCT05384626), a first-in-human Phase 1/2 clinical trial for patients with advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors.