NVL-520 May Stop Tumor Growth, Garner CNS Response in ROS1+ NSCLC and Solid Tumors

Results from the phase 1 ARROS-1 trial showed NVL-520 may stop tumor growth and yielded response in brain metastases in patients with ROS1-positive non–small cell lung cancer and other solid tumors.

Early data for NVL-520 in patients with ROS1-positive non–small cell lung cancer (NSCLC) and other solid tumors showed the potential to halt tumor growth and penetrate the blood brain barrier, in addition to demonstrating few adverse effects (AEs), according to results from the phase 1/2 ARROS-1 trial (NCT05118789).

The data were presented at the 2022 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium. In the phase 1 portion of the study, investigators aimed to evaluate NVL-520’s safety and tolerability. A partial response was achieved in 48% of patients (n = 10/21), with cancer shrinking by 30% after treatment in responders. Of note, responses were observed across all dose levels and in patients who were most heavily pretreated. In 78% of patients who had a G2032R ROS1 mutation had an observed response (n = 7/9). In addition to observing early signs of activity, no dose-limiting toxicities or AEs leading to dose reduction or discontinuation were reported.

“These preliminary data from the phase I part of the ARROS-1 study are very encouraging and I believe support further clinical investigation of NVL-520 as a potential best-in-class ROS1 inhibitor,” Alexander Drilon, MD, who is the chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, said in the press release.

A total of 35 patients were evaluated in the trial, of whom 34 had NSCLC and 1 had pancreatic cancer. Patients received orally NVL-520 at one of several dose levels—from 25 mg to 125 mg—once a day. At the time of the presentation, the maximum tolerated dose had not yet been reached, nor has the recommended phase 2 dose.

A total of 21 patients with NSCLC had available tumor response prior to the presentation. A total of 53% of patients previously had 2 or more ROS1 tyrosine kinase inhibitors (TKIs) with 1 or more lines of chemotherapy. Moreover, 50% of patients were previously pretreated with ROS1 TKIs such as lorlatinib (Lorbrena) or repotrectinib.

Patients who enrolled on the trial had previously treated solid tumors driven by ROS1 fusions, and all patients with NSCLC were treated with 1 or more lines of ROS1 TKIs. Patients received a median of 3 lines of prior therapy. Of those who received NVL-520 and had prior ROS1 TKIs, 77% had received 3 or more prior lines of therapy, 80% had received 2 or more ROS1 TKIs, and 80% had received other ROS1 TKIs in development.

Investigators reported that of a total of 35 patients who have received NVL-520 at 5 increasing different dose levels, no dose-limiting toxicities have been observed. The most common treatment-related AE was mild fatigue in 11% of patients. Of note, there was no dizziness related to treatment, which is often a common AE that occurs following treatment with ROS1 TKIs.

Brain metastases are common in patients with ROS1-positive NSCLC. After patients were treated with NVL-520, brain metastases were noted to have decreased in size or become undetectable in 3 of 3 patients who had a prior history of unmeasurable brain metastases or tumors. The response rate was 73% in this population. No emergence of or increase in brain metastases were observed in the overall patient population.

At the time of this data readout, patients continue to be enrolled in the phase 1 portion of the trial to determine the recommended phase 2 dose. As part of a discussion with the FDA, additional patients will be enrolled in the phase 2 portion, some of whom have not yet received previous treatment. This will help to further evaluate efficacy and safety.


Preliminary data suggest that ROS1 inhibitor, NVL-520, is well-tolerated and active in non-small cell lung cancer: first results from ARROS-1 phase I clinical trial. News release. ENA 2022. Accessed November 2, 2022. https://bit.ly/3zBwyYR