Preliminary Results From ARROS-1 Phase I Clinical Trial Suggest That NVL-520 May Be Well Tolerated and Active in NSCLC

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Preliminary data from a phase I clinical trial of the ROS1 inhibitor NVL-520 to treat patients with non–small cell lung cancer (NSCLC) and other solid tumors suggested that it may have the potential to both halt tumor growth by inhibiting a cancer-causing gene change and reach cancer cells within the brain, with very few side effects, according to a study by Drilon et al in the European Journal of Cancer.

Although the primary goal of the phase I part of the trial was to evaluate safety and tolerability of NVL-520, the findings—presented at the 34th European Organisation for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics (Abstract 8)—revealed early signs of activity, and there were no dose-limiting toxicities or side effects that led to dose reductions or treatment discontinuations.

“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,” said first study author Alexander Drilon, MD, a medical oncologist and Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center.

Alexander Drilon, MD

Alexander Drilon, MD

Study Background

The fusion of ROS1 with part of another gene activates the ROS1 gene in a way that causes uncontrolled cancer cell growth. These fusions occur in 1% to 3% of NSCLCs, as well as some other cancers, such as pancreatic cancer. Tumors that are driven by a ROS1 fusion can be treated with targeted therapies known as ROS1 tyrosine kinase inhibitors.

At present, there are only two ROS1 tyrosine kinase inhibitors approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency: crizotinib and entrectinib. However, in some cases, the cancers eventually become resistant to these therapies and start to grow again. Other ROS1 tyrosine kinase inhibitors are being investigated, but they are limited by factors such as treatment resistance (particularly when new ROS1 mutations such as G2032R emerge), an inability to cross the blood–brain barrier to target brain metastases, or adverse neurologic side effects.

ARROS-1 Methods and Results

The patients in the ARROS-1 phase I clinical trial all had previously treated solid tumors driven by ROS1 fusions, and all patients with NSCLC had been previously treated with one or more courses of ROS1 tyrosine kinase inhibitors. The median number of prior lines of anticancer treatment was three, ranging from 1 to 11 courses of therapy. Of the 35 patients with NSCLC treated with NVL-520, all of them had received other ROS1 tyrosine kinase inhibitors; 77% had received three or more prior lines of anticancer therapy, 80% had received two or more ROS1 tyrosine kinase inhibitors, and 80% had received other ROS1 tyrosine kinase inhibitors in development. At enrollment in the trial, 51% of patients had a history of brain metastases.

The primary objective of the phase I portion of the trial was to establish the recommended phase II dose for the phase II part of the trial. Thirty-five patients—34 with NSCLC and one with pancreatic cancer—received NVL-520 orally at dose levels ranging from 25 to 125 mg once daily. A maximum tolerated dose has not been reached, and the recommended phase II dose has not yet been selected.

The ARROS-1 trial involved the tumor response data of 21 patients with NSCLC. Of these patients, 48% achieved partial responses—in which their cancer shrank by at least 30%—following treatment with NVL-520. Responses were seen across all dose levels tested. In addition, responses were seen in the most heavily pretreated patients enrolled in the trial. These included 53% of patients who had received two or more prior ROS1 tyrosine kinase inhibitors and one or more prior lines of chemotherapy, and 50% of patients previously treated with lorlatinib or repotrectinib, which are also ROS1 tyrosine kinase inhibitors in development. Additionally, responses were seen in 78% of patients whose tumors also had a ROS1 G2032R point mutation that enables resistance to currently available ROS1 inhibitors.

NVL-520 has now been studied in 35 patients at five increasing dose levels with no dose-limiting toxicities and no adverse events leading to dose reductions or treatment discontinuations. Most treatment-related side effects were mild, with the most frequent being fatigue in 11% of patients. There was no reported treatment-related dizziness, a common neurologic side effect that has been observed with other ROS1 tyrosine kinase inhibitors in development.

In many patients with ROS1-positive NSCLC, cancer cells can metastasize to the brain from the site of the primary tumor. Following treatment with NVL-520, measurable brain metastases either shrank or became undetectable in all three patients who had them. In addition to these patients, some had a prior history of brain metastases or tumors in the brain that were not measurable. For these patients, the response rate to NVL-520 was 73%. None of the 35 patients treated showed any emergence of or increase in metastases in the brain.

“Because therapies that enter the brain are needed to treat brain metastases, there is the added challenge of avoiding inhibition of the TRK protein. Several [ROS1 tyrosine kinase inhibitors] inhibit TRK because ROS1 and TRK are similar in structure. TRK inhibition can cause neurologic side effects such as dizziness, burning or tingling, weight gain, and pain when the drug is temporarily or permanently stopped,” said Dr. Drilon. “NVL-520 was designed with the goal to both enter the brain well and avoid TRK inhibition. These characteristics were observed in patients treated on ARROS-1. Brain metastases responded to treatment and substantial neurologic side effects have not been observed thus far,” he continued.


“These preliminary data show that NVL-520 had encouraging activity against ROS1 resistance mutations, including a commonly occurring resistance mutation, ROS1 G2032R,” said Dr. Drilon.

The phase I part of the trial is continuing to enroll previously treated patients with advanced NSCLC or other solid tumors that have a ROS1 fusion. Once a recommended dose has been identified for the phase II part of the trial in discussion with the FDA, more patients will be enrolled, including patients who have not received any previous treatment, to evaluate efficacy and safety of the drug.

“These are the first clinical results to be reported for NVL-520 in [NSCLC] and it is encouraging that the drug appears to be safe and is showing some activity against this disease. Advanced NSCLC is a cancer that is in urgent need of more effective treatments. Existing drugs, such as crizotinib and entrectinib … are important treatment options, but eventually patients will relapse as their tumors become resistant to them. At present, there are no targeted therapies approved for use after this happens. We look forward to seeing further results from this trial,” said Ruth Plummer, MD, PhD, Professor of Experimental Cancer Medicine at Newcastle University and Chair of the 34th EORTC–NCI–AACR Symposium on Molecular Targets and Cancer Therapeutics, who was not involved in the study.

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