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

Presentation of preliminary data from the phase I of the phase I/II ARROS-1 trial on Friday at the 34th EORTC-NCI-AACR [1] Symposium on Molecular Targets and Cancer Therapeutics in Barcelona, ​​Spain, Dr. Alexander Drilon said that while the primary goal of the Phase I trial was to assess the safety and tolerability of NVL-520 , early signs of activity were also observed and there were no dose limiting toxicities (DLT) or side effects that led to dose reductions or discontinuation of treatment.

“These preliminary data from the Phase I portion of the ARROS-1 study are very encouraging and I believe support further clinical study of NVL-520 as a potential best ROS1 inhibitor,” said Dr. Drilon, who is the head of the Early Drug Development Service at 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 ROS1 fusion. These fusions occur in 1-3% of NSCLCs, as well as in some other cancers, such as pancreatic cancer. Tumors induced by ROS1 fusion can be treated with targeted therapies called ROS1 tyrosine kinase inhibitors (TKIs).

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

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

In many patients with ROS1-positive NSCLC, cancer cells can spread (metastasize) to the brain from the site of the primary tumor. Following treatment with NVL-520, measurable brain metastases decreased or became undetectable in three out of three patients. In addition to these patients, some had a history of brain metastases or unmeasurable brain tumors. For these patients, the response rate was 73% (8/11). None of the 35 patients treated showed emergence or increase in brain metastases.

Dr Drilon said: “Because therapies that enter the brain are needed to treat brain metastases, there is the added challenge of avoiding inhibition of a protein called TRK. Several ROS1 TKIs inhibit TRK because ROS1 and TRK have a similar structure. TRK inhibition can cause neurological side effects such as dizziness, burning or tingling, weight gain, and pain when the drug is temporarily or permanently stopped.

“NVL-520 was designed with the aim of both penetrating well into the brain and avoiding TRK inhibition. These characteristics were observed in patients treated with ARROS-1. Brain metastases responded to the treatment and significant neurological side effects have not been observed so far.

Currently, only two TKIs are approved by the US Food and Drug Administration (FDA) and the European Medicines Agency: crizotinib and entrectinib. However, in some cases, the cancers eventually become resistant to these therapies and begin to grow again. There are no approved targeted therapies available after that. Other ROS1 TKIs are under investigation but are limited by factors such as drug resistance, especially when new ROS1 mutations emerge such as the G2032R mutation, the inability to cross the blood-brain barrier to target brain metastases or adverse neurological side effects.

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

Patients in the ARROS-1 phase I clinical trial had all previously treated solid tumors induced by ROS1 fusions, and all patients with NSCLC had previously been treated with one or more courses of TKI ROS1. The median (mean) number of prior lines of cancer treatment was three, ranging from one to 11 treatment cycles. Of the 35 patients treated with NVL-520, all had received other ROS1 TKIs; 77% had received at least three prior lines of cancer therapy, 80% had received two or more ROS1 TKI therapies, and 80% had received other ROS1 TKIs in development. At the time of trial enrollment, 51% of patients had a history of brain metastases.

The main objective of the phase I trial was to establish the recommended phase II dose for the phase II trial. Patient data through September 13, 2022 was analyzed for presentation at the EORTC-NCI-AACR symposium. Thirty-five patients, 34 with NSCLC and one with pancreatic cancer, received NVL-520 orally at doses ranging from 25 to 125 mg once daily. A maximum tolerated dose has not been reached and the recommended dose for phase II has not yet been chosen.

The Phase I trial continues to enroll previously treated patients with advanced NSCLC or other solid tumors with ROS1 fusion. Once a recommended dose is identified for the Phase II trial in discussion with the FDA, more patients will be recruited, including patients who have not received any prior treatment, to assess efficacy 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 less than about 8%.

Professor Ruth Plummer, University of Newcastle, UK, chairs the 34th EORTC-NCI-AACR Symposium and was not involved in the research. She said: “These are the first clinical results to be reported for NVL-520 in non-small cell lung cancer and it is encouraging that the drug appears to be safe and shows some activity against this disease. Advanced NSCLC is a cancer that urgently 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 as their tumors will become resistant to it. Currently, there are no targeted therapies approved for use after this. We look forward to seeing more results from this trial.

(ends)

Abstract No.: 8“Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibit, in patients with advanced ROS1 fusion-positive solid tumors”, by Alex Drilon, presented in the session “New drugs on the horizon”, 11:30-13:00 CEST , Friday, October 28

[1] EORTC [European Organisation for Research and Treatment of Cancer, NCI [National Cancer Institute]AACR [American Association for Cancer Research]. The Symposium will take place in Barcelona from October 26 to 28, 2022.