As determined by phase 1 of the ARROS-1 study, patients with ROS1-positive non–small cell lung cancer and other solid tumors will be further assessed with the recommended phase 2 dose of NVL-520 in phase 2 of the trial.
Trial Name: A Phase 1/2 Study of the Highly Selective ROS1 Inhibitor NVL-520 in Patients With Advanced NSCLC and Other Solid Tumors (ARROS-1)
ClinicalTrials.gov Identifier: NCT05118789
Sponsor: Nuvalent Inc.
Recruitment Contact: Nuvalent, 857-357-7000, clinicaltrials@nuvalent.com
Completion Date: October 31, 2026
Following alignment with the FDA on a recommended phase 2 dose (RP2D) of NVL-520 given at 100 mg daily for patients with ROS1-positive non–small cell lung cancer (NSCLC) and other solid tumors, the phase 2 portion of the phase 1/2 ARROS-1 trial has been initiated.1
Phase 1 of the ARROS-1 study assessed NVL-520 at 6 dose levels ranging from 25 mg to 150 mg daily. Patients who were heavily pre-treated with ROS1-positive solid tumors, including NSCLC, were included in the study.
Findings did not reveal a maximum tolerated dose (MTD) to be reached, and no clinically significant exposure-response relationships for safety and efficacy were seen across the dose levels. As a result, 100 mg daily as the RP2D maintained steady state plasma levels above all target efficacy thresholds.
"The ARROS-1 trial was designed to support a seamless transition from first-in-human dose-exploration in a heavily pre-treated population to a phase 2 portion designed with the potential to support registration. We are thrilled to achieve this milestone towards our goal of bringing a potential best-in-class therapy to patients with ROS1-positive NSCLC as efficiently as possible," said Darlene Noci, asset and liability management, chief development officer at Nuvalent, in a press release.
NVL-520 is a novel brain-penetrant ROS1-selective tyrosine kinase inhibitor (TKI). The agent simultaneously combats emergent treatment resistance, off-target central nervous system (CNS) adverse events (AEs) associated with TRK inhibition, and brain metastases.
Now, phase 2 of the ARROS-1 trial plans to enroll approximately 225 patients with ROS1-positive NSCLC and other solid tumors who are naïve and who have been pre-treated with TKI. The cohorts being assessed in the single arm, open-label phase 2 portion of the study will evaluate NVL-520 globally across North America, Europe, Asia, and Australia.
The potential pivotal cohorts of the study consist of patients with advanced/metastatic ROS1-positive NSCLC naïve to TKI therapy who may have received up to 1 prior line of chemotherapy and/or immunotherapy (cohort 2a), patients with advanced/metastatic ROS1-positive NSCLC treated with 1 prior ROS1 TKI who have not received prior chemotherapy or immunotherapy (cohort 2c), patients with advanced/metastatic ROS1-positive NSCLC treated with 1 prior ROS1 TKI and 1 prior line of platinum-based chemotherapy with or without immunotherapy (cohort 2c), and patients with advanced/metastatic ROS1-positive NSCLC treated with at least 2 prior ROS1 TKIs and up to 1 line of chemotherapy and/or immunotherapy (cohort 2d). Then, an exploratory cohort will also be evaluated and include patients with any advanced/metastatic ROS1-positive solid tumor who have progressed on any prior therapy.
"The phase 2 portion of the ARROS-1 trial includes multiple cohorts which enable the parallel investigation of NVL-520 for patients with ROS1-positive NSCLC who are either TKI naïve or pre-treated with a ROS1 TKI," Noci said. "Support for the phase 2 cohort design includes the demonstrated nonclinical activity of NVL-520 in the periphery and in the CNS, and its selective inhibition of ROS1 and ROS1 drug-resistance mutant G2032R over the structurally-related TRK kinases. Combined with the broad clinical activity and favorable tolerability observed to date in heavily pre-treated patients in the phase 1 portion of ARROS-1, we believe there is the potential for NVL-520 to provide durable responses while minimizing adverse events and dose limiting toxicities for patients with ROS1-positive cancers throughout the treatment paradigm."
In the study, investigators aim to assess MTD, RP2D, and objective response rate (ORR) as primary end points, and AEs, pharmacokinetics, duration of response, clinical benefit rate, time to response, progression-free survival, overall survival, rate of CNS progression, intracranial ORR, and quality of life as secondary end points.2
Prior to the estimated study completion date of October 31, 2026, investigators plan to report findings from the ARROS-1 study at an upcoming medical meeting in 2024.
"With the advancement of the first of our parallel lead programs into a phase 2 trial with registrational intent, the Nuvalent team demonstrates its continued ability to scale while maintaining ambitious timelines towards our goal of delivering precisely targeted therapies to patients with cancer," said James Porter, PhD, chief executive officer at Nuvalent, in the press release.1 "We look forward to providing an update from the ARROS-1 trial at a medical meeting in 2024."
