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Nuvalent Granted FDA Breakthrough Therapy Designation for Non–Small Cell Lung Cancer Drug


NVL-520 is a novel, brain-penetrant, ROS1-selective tyrosine kinase inhibitor under evaluation for patients with metastatic ROS1-positive non–small cell lung cancer.

Image credit: Vector Market | stock.adobe.com. Male lung cancer biopsy respiratory system in x-ray. 3d render

Image credit: Vector Market | stock.adobe.com

Nuvalent, Inc’s novel, brain-penetrant, ROS1-selective tyrosine kinase inhibitor (TKI) NVL-520 has been granted Breakthrough Therapy Designation by the FDA to treat patients with metastatic ROS1-positive non–small cell lung cancer (NSCLC) who received prior therapy with at least two ROS1 TKIs.1 NVL-520 was developed with the intention of addressing treatment challenges that limit the use of current ROS1 TKIs, including treatment resistance, brain metastases, and off-target central nervous system (CNS) adverse events (AEs) that have been linked to inhibiting the structurally-related tropomyosin receptor kinase family.1

"In line with our commitment to bringing new potential best-in-class medicines to patients with cancer as quickly as possible, we are always looking for opportunities to further accelerate our programs," James Porter, PhD, CEO of Nuvalent, said in a press release. "We're very encouraged by today's announcement of FDA breakthrough therapy designation for NVL-520, as it recognizes the continued need for innovation for patients with ROS1-positive NSCLC who have exhausted available therapies. We look forward to providing an update from the ARROS-1 trial of NVL-520 at a medical meeting later this year."1

Investigators are currently evaluating NVL-520 in the open-label, nonrandomized, Phase I/II ARROS-1 trial (NCT05118789) among patients with advanced NSCLC and other ROS1-positive solid tumors. Findings from the dose-escalation Phase I trial showed no dose-limiting toxicities, serious treatment-related AEs, dizziness associated with treatment, or AEs causing treatment reductions or discontinuations in all evaluable patients (n = 35). The partial response rate was 48% among those with heavily pretreated NSCLC who were evaluable for efficacy (n = 21).2

ARROS-1 enrolled mostly adult patients, other than a cohort subgroup that enrolled patients at least 12 years of age weighing more than 40 kg. In the trial’s dose-escalation portion, enrollment criteria included having histologically or cytologically confirmed locally advanced or metastatic solid tumors with ROS1 rearrangements. Cohorts in Phase II enrolled patients with histologically or cytologically confirmed locally advanced or metastatic NSCLC harboring a ROS1 rearrangement.

Patients were required to have previously received anticancer treatment, other than the cohort of younger patients, and all patients were required to have adequate baseline organ function and bone marrow reserve. Patients were excluded if they had an oncogenic driver alteration other than ROS1 or if they underwent major surgery within four weeks of the first dose of NVL-520.3

For the Phase I portion, patients were administered once-daily doses of NVL-520 that ranged from 25 mg to 150 mg, with the recommended Phase II dose established at 100 mg once per day. The majority of the overall Phase I patient population were previously administered at least three prior lines of anti-cancer therapy (77%); two or more ROS1 TKIs and one or more lines of chemotherapy (71%); and a ROS1 TKI other than Xalkori (crizotinib) or Rozlytrek (entrectinib).2

Investigators observed activity with the study drug across subgroups of patients with NSCLC. Those diagnosed with ROS1 G2032R mutations (n = 9) achieved an ORR of 78%, whereas patients with a prior history of CNS metastases (n = 11) achieved an ORR of 73%. ORR among those previously administered two or more ROS1 TKIs and one or more lines of chemotherapy (n = 17) was 53%, whereas patients previously administered lorlatinib or repotrectinib (n = 18) achieved an ORR of 50%.


1. Nuvalent receives U.S. FDA breakthrough therapy designation for NVL-520. News release. Nuvalent. February 27, 2024. Accessed February 28, 2024. https://investors.nuvalent.com/2024-02-27-Nuvalent-Receives-U-S-FDA-Breakthrough-Therapy-Designation-for-NVL-520

2. Nuvalent reports preliminary phase 1 clinical data from ARROS-1 trial that support best-in-class potential of NVL-520 for patients with ROS1-positive NSCLC. News release. Nuvalent. October 28, 2022. Accessed February 28, 2024. https://investors.nuvalent.com/2022-10-28-Nuvalent-Reports-Preliminary-Phase-1-Clinical-Data-from-ARROS-1-Trial-that-Support-Best-In-Class-Potential-of-NVL-520-for-Patients-withROS1-Positive-NSCLC

3. Nuvalent initiates the phase 2 portion of ARROS-1 clinical trial for patients with ROS1-positive NSCLC and other solid tumors. News release. September 5, 2023. Accessed February 28, 2024. https://investors.nuvalent.com/2023-09-05-Nuvalent-Initiates-the-Phase-2-Portion-of-ARROS-1-Clinical-Trial-for-Patients-with-ROS1-Positive-NSCLC-and-other-Solid-Tumors

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