Dr Liu on the Ongoing Investigation of Zidesamtinib in ROS1+ Tumors

Stephen V. Liu, MD, associate professor, medicine, Georgetown University, director, Thoracic Oncology, head, Developmental Therapeutics, Georgetown Lombardi Comprehensive Cancer Center, discusses the potential benefit of zidesamtinib (NVL-520) for patients with ROS1-positive tumors, expanding on the current investigation of the selective ROS1 inhibitor in the phase 1/2 ARROS-1 study (NCT05118789).

The ongoing development of zidesamtinib represents an important advancement in precision oncology. Zidesamtinib was designed to address key limitations observed with currently available ROS1/TRK inhibitors, offering potential benefits such as increased potency, improved effectiveness, longer durability of response, enhanced activity in the brain, and an improved safety profile, Liu begins.

The first-in-human ARROS-1 study is looking to establish the optimal dosing, safety, tolerability, and efficacy of zidesamtinib for patients with ROS1 fusion–positive tumors, particularly those with lung cancer, he says. In the phase 1 dose-escalation portion, zidesamtinib was administered across 5 dose levels ranging from 25 mg to 125 mg once daily to identify the recommended phase 2 dose and any dose-limiting toxicities (DLTs). Patients enrolled in this phase of the study received a median of 3 prior lines of therapy (range, 1-11), with 77% having received 3 or more treatment lines, Liu reports.

Findings from the phase 1 dose-escalation portion were previously reported at the 34th EORTC-NCI-AACR (ENA) Symposium. Despite this population being heavily pretreated, zidesamtinib was found to be safe and well tolerated with no DLTs or severe treatment-related adverse effects (TRAEs), he explains. Moreover, AEs leading to dose reduction or dose discontinuation were not reported. The absence of DLTs or TRAEs underscores the potential for zidesamtinib to be a well-tolerated agent, even in patients who have received multiple lines of prior therapy, Liu adds.

The most common AEs observed with zidesamtinib, which included fatigue, nausea, and liver function test abnormalities, were predominantly grade 1. The absence of treatment-related dizziness is particularly notable given the central nervous system penetration challenges often encountered with targeted therapies.

In February 2024, the FDA granted breakthrough therapy designation to zidesamtinib for the treatment of patients with ROS1-positive metastatic non–small cell lung cancer who have been previously treated with 2 or more ROS1 TKIs. This designation reflects the potential of zidesamtinib to address an unmet medical need for heavily pretreated patients with ROS1-positive tumors, Liu concludes.