FDA Grants Breakthrough Therapy Designation to NVL-520 for ROS1-Positive NSCLC


NVL-520 is a novel brain-penetrant ROS1-selective TKI being investigated for ROS1-positive metastatic non–small cell lung cancer in patients who have previously been treated with 2 or more ROS1 TKIs.

The FDA granted breakthrough therapy designation to NVL-520 (Nuvalent Inc) for the treatment of individuals with ROS1-positive metastatic non­–small cell lung cancer (NSCLC) who have previously been treated with 2 or more ROS1 tyrosine kinase inhibitors (TKIs), according to a press release from the company.1

NVL-520 is a novel brain-penetrant ROS1-selective TKI, according to the press release. The aim of the drug is to help with the clinical challenges that emerge with treatment resistance, brain metastases, and off-target central nervous system adverse events associated with inhibition of tropomyosin receptor kinases, which can limit the use of ROS1 TKIs.1

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"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,” James Porter, PhD, CEO at Nuvalent, said in the press release.1

According to a review published in Current Oncology, lung cancer accounted for approximately 1.8 million deaths worldwide in 2020. Approximately 85% ore NSCLC, with ROS1 rearrangement present in 0.9% to 2.6% of NSCLC cases. The gene plays a major role in the “activation of several signaling pathways associated with differentiation, proliferation, cell growth, and survival,” according to the study. Rearrangement of the gene can deregulate proteins and produce abnormal activation of signaling pathways, according to the study authors.2

The designation is based on preliminary safety and activity of the phase 1 portion of the phase 1/2 ARROS-1 (NCT05118789) clinical trial, which included heavily pretreated individuals with advanced ROS1-positive NSCLC, according to the press release.1 The phase 1/2 study is a dose escalation and expansion study aimed at evaluating the safety and tolerability in the drug and determine a recommended phase 2 dose.3 Further, the study investigators will also evaluate antitumor activity, according to the clinical trial information.

About The ARROS-1 Trial

Trial Name: A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement

ClinicalTrials.gov ID: NCT05118789

Sponsor: Nuvalent Inc

Completion Date (Estimated): October 2026

Enrollment is currently ongoing for the phase 2 potion of the trial and the company expects to share updated data at a medical meeting in 2024.1

The phase 2 portion will have 5 cohorts including: cohort 2a with patients who have ROS1-positive NSCLC naïve to TKI therapy and up to 1 prior chemotherapy and/or immunotherapy; cohort 2b, with ROS1-positive NSCLC treated with 1 prior ROS1 TKI and no prior chemotherapy or immunotherapy; cohort 2c, with ROS1-positive NSCLC with 1 prior ROS1 TKI and 1 prior platinum-based chemotherapy with or without immunotherapy; cohort 2d, with ROS1-positive NSCLC with 2 or more prior ROS1 TKIs and up to 1 prior chemotherapy and/or immunotherapy; and cohort 2e, with ROS1-positive tumors and progression on any prior therapy.3

Investigators are including individuals aged 18 years and older who meet the disease criteria for each cohort and adequate baseline organ function and bone marrow reserve, according to the trial information. Individuals will be excluded if their cancer has a known oncogenic driver alteration other than ROS1, known allergy or hypersensitivity to NVL-520, major surgery within 4 weeks prior to the first dose, ongoing anticancer therapy, and/or are actively receiving systemic treatment or direct medical interventions on another clinical study.3

  1. Nuvalent Receives U.S. FDA Breakthrough Therapy Designation for NVL-520. News release. Nuvalent. February 27, 2024. Accessed February 28, 2024. https://prnmedia.prnewswire.com/news-releases/nuvalent-receives-us-fda-breakthrough-therapy-designation-for-nvl-520-302071947.html
  2. Gendarme S, Bylicki O, Chouaid C, Guisier F. ROS-1 Fusions in Non-Small-Cell Lung Cancer: Evidence to Date. Curr Oncol. 2022;29(2):641-658. doi:10.3390/curroncol29020057
  3. A Study of NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ROS1 Rearrangement (ARROS-1). ClinicalTrials.gov. Updated January 23, 2024. Accessed February 28, 2024. https://clinicaltrials.gov/study/NCT05118789
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