Preliminary data show that the ROS1 inhibitor, NVL-520, is well tolerated and active in non-small cell lung cancer

Preliminary data from a phase I clinical trial of a new drug called NVL-520 in patients with non-small cell lung cancer (NSCLC) and other solid tumors suggests it may have the potential to stop tumor growth by inhibiting the cancer. causing the genes to change and reaching the cancer cells in the brain, with very few side effects.

Presenting preliminary data from the ARROS-1 phase I/II trial on Friday at the 34th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapy in Barcelona, ​​Spain, Dr. Alexandre Drilon said that while the primary objective of the phase I part of the trial was to evaluate the safety and tolerability of NVL-520, early signs of activity were also seen and there were no dose-limiting toxicities (DLTs) or adverse effects that led to dose reductions or discontinuation of treatment.

“These preliminary data from the phase I portion of the ARROS-1 trial are very encouraging and I believe they support further clinical investigation of NVL-520 as a potentially best-in-class ROS1 inhibitor,” said Dr. Drilan, who is chief of the Early drug development Memorial Sloan Kettering Cancer Center (MSK), New York, USA.

ROS1 is a gene that can join (or fuse) with part of another gene. The fusion activates the ROS1 gene in a way that causes cancer cells to grow out of control. The gene change is called a ROS1 fusion. These adhesions occur in 1-3% of NSCLC cases, as well as in some other cancers, such as pancreatic cancer. Tumors caused by ROS1 fusions can be treated with targeted therapies known as ROS1 tyrosine kinase inhibitors (TKIs).

There were 21 in the ARROS-1 process patients from NSCLC for which tumor response data were available through September 13, 2022. Of these patients, 48% (10/21) achieved a partial response, in which the cancer shrank by at least 30% in size after treatment with NVL-520. Responses were observed at all dose levels tested. In addition, responses were seen in patients who had undergone the most intensive pretreatment participating in the trial. This included 53% (9/17) of patients previously treated with two or more ROS1 TKIs and one or more prior lines of chemotherapy, and 50% (9/18) of patients previously treated with lorlatinib or repotrectinib, which are ROS1 TKIs . also in development. In addition, responses were seen in 78% (7/9) of patients whose tumors also had a ROS1 mutation called G2032R, which confers resistance to currently available ROS1 inhibitors.

To date, NVL-520 has been studied in 35 patients at five escalating doses with no DLTs or adverse events leading to dose reduction or treatment discontinuation. Most treatment-related adverse events were mild, with the most common being mild fatigue, which occurred in 11% (4/35) of patients. No treatment-related dizziness, a common neurological side effect seen with other ROS1 TKIs in development, was reported.

In many patients with ROS1-positive NSCLC, cancer cells can spread (metastasize) to the brain from the site of the primary tumor. After treatment with NVL-520, measurable brain metastases were reduced or undetectable in three of three patients. In addition to these patients, some had previously had brain metastases or brain tumors that were not measurable. For these patients, the response rate was 73% (8/11). None of the 35 treated patients developed or increased the number of brain metastases.

Dr. Drilan said, “Since brain-directed therapy is needed to treat brain metastases, there is an additional challenge to avoid inhibiting a protein called TRK. Several ROS1 TKIs inhibit TRK because ROS1 and TRK are structurally similar. Inhibiting TRK can cause neurological side effects such as dizziness, burning or tingling, weight gain, and pain when the drug is stopped temporarily or permanently.

“NVL-520 was designed to have good brain penetration and avoid TRK inhibition. These characteristics were observed in patients treated with ARROS-1. Brain metastases have responded to treatment, and no significant neurological side effects have been observed so far. “

Currently, there are only two TKIs approved by the US Food and Drug Administration (FDA) and the European Medicines Agency: crizotinib and entrectinib. However, in some cases, the cancer eventually becomes resistant to these treatments and starts growing again. There are no approved targeted therapies available for use after this. Other ROS1 TKIs are being investigated but are limited by factors such as resistance to treatment, especially when new ROS1 mutations such as the G2032R mutation appear, inability to cross the blood-brain barrier to target brain metastases, or adverse neurologic outcomes. side effects.

“These preliminary data show that NVL-520 had promising activity against ROS1 resistance mutations, including the common ROS1 resistance mutation G2032R,” said Dr. Drilan.

All patients in the ARROS-1 phase I clinical trial were previously treated solid tumors driven by ROS1 fusions, and all NSCLC patients were previously treated with one or more courses of ROS1 TKIs. The median (median) number of prior lines of anticancer treatment was three, ranging from one to 11 courses of therapy. Of the 35 patients receiving NVL-520, all were receiving other ROS1 TKIs; 77% had received three or more prior lines of anticancer therapy, 80% had received two or more ROS1 TKI therapies, and 80% had received other ROS1 TKIs in development. At the time of inclusion in the study, 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 trial. Patient data through September 13, 2022 were analyzed for presentation at the EORTC-NCI-AACR Symposium. Thirty-five patients, 34 with NSCLC and one with pancreatic cancer, received oral NVL-520 at doses ranging from 25 to 125 mg once daily. The maximum tolerated dose has not been reached and the recommended phase II dose has not yet been selected.

Part of the phase I trial continues to enroll patients with previously treated advanced NSCLC or other solid tumors harboring a ROS1 fusion. Once the recommended dose has been determined for phase The second part of the trial in discussion with the FDA, more patients will be registered, including patients who have not received any previous treatment, to evaluate the effectiveness and safety of the drug.

Advanced NSCLC is difficult to treat successfully, and the proportion of patients who are still alive five years after diagnosis is approximately less than 8%.

Professor Ruth Plummer of the University of Newcastle, UK, is Chair of the 34th EORTC-NCI-AACR Symposium and was not involved in the study. She said: “These are the first clinical results for NVL-520 in non-small cell lung cancer and it is encouraging that the drug appears to be safe and has some activity against this disease. Advanced NSCLC is a cancer that needs more effective treatments. Existing drugs such as crizotinib and entrectinib, which have been approved by the FDA and EMA for the treatment of ROS1-positive NSCLC, are important treatment options, but patients will eventually relapse if their tumors become resistant to them. There is currently no targeted therapy approved for use after this. We look forward to the further outcome of this litigation.”

Additional information:
Abstract #8, “Safety and preclinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced stage ROS1 solid tumors,” by Alex Drilon, presented at the New Medicines on the Horizon session, 11:30-13:00 CEST, Friday 28 October

Courtesy of the European Organization for Research and Treatment of Cancer