ARROS-1 Study Finds ROS1 Tyrosine Kinase Inhibitor Has Promise as a Tumor Agnostic Therapy
BARCELONA, Spain—Findings from a study of a new investigational therapy targeting the ROS-1 receptor tyrosine kinase—mutated in some cancers—were reported at the 2022 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics conference held in Barcelona.
First author Medical Oncologist Alex Drilon MD, Chief of the Early Drug Development Service at Memorial Sloan-Kettering Cancer Center in New York, gave the Audio Journal of Oncology his take on the safety and preliminary clinical activity of NVL-520: described as a “highly selective ROS1 inhibitor” in patients with solid tumors—mainly non-small cell lung cancer (NSCLC).
Patients selected for the study had gene rearrangements in the ROS-1 receptor tyrosine kinase. The aim was to test whether targeting gene fusions which are molecular driver of cancer could be more valid than individualising therapy to tumors of a specific organ.
Text from symposium ABSTRACT 8:
TITLE:Â Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors
AUTHORS:Â A. Drilon1, B. Besse2, D.R. Camidge3, S.H.I. Ou4, S.M. Gadgeel5, M.L. Johnson6, A. Calles7, M.J. de Miguel8, A.I. Spira9, E. Felip10, G. Lopes11, A.J. van der Wekken12, Y.Y. Elamin13, J. Green14, Y. Sun15, J. Soglia16, V.W. Zhu14, J.J. Lin17
INSTITUTIONS: Memorial Sloan Kettering Cancer Center, Early Drug Development Service, New York, US, Institut Gustave Roussy, Cancer Medicine, Villejuif, France, University of Colorado Cancer Center- Anschutz Medical Campus, Thoracic Oncology, Aurora, USA, University of California Irvine Medical Center, Medicine, Orange, USA, Henry Ford Cancer Institute, Internal Medicine, Detroit, USA, Sarah Cannon Research Institute, Oncology, Nashville, USA, Hospital Universitario Gregorio Marañón, Medical Oncology, Madrid, Spain, START Madrid- HM CIOCC, Medical Oncology, Madrid, Spain, NEXT Oncology – Virginia Cancer Specialists, Thoracic and Phase I Program, Fairfax, USA, Hospital Vall d’Hebron, Oncology, Barcelona, USA, Sylvester Comprehensive Cancer Center- University of Miami Miller School of Medicine, Medical Oncology- Thoracic Medical Oncology, Miami, USA, University of Groningen and University Medical Centre Groningen, Pulmonary Oncology, Groningen, Netherlands, MD Anderson Cancer Center, Thoracic Head & Neck Medical Oncology, Houston, USA, Nuvalent Inc., Clinical Development, Cambridge, USA, Nuvalent Inc., Biology, Cambridge, USA, Nuvalent Inc., Translational Development, Cambridge, USA, Massachusetts General Hospital, Medicine, Boston, USA
BACKGROUND:Â Oncogenic ROS1 fusions drive various malignancies, including 1-3% of non-small cell lung cancers (NSCLC). Rationally designed ROS1 tyrosine kinase inhibitors (TKIs) that surpass the limitations of FDA/EMA-approved (crizotinib/entrectinib) or other investigational agents are a medical need. The novel ROS1 TKI NVL-520 is highly selective and designed to avoid the neurologic toxicities associated with ROS1 TKIs that concurrently inhibit TRK (entrectinib/repotrectinib/taletrectinib). Furthermore, NVL-520 is brain-penetrant and targets a diverse array of ROS1 fusions and recalcitrant resistance mutations, including the ROS1 G2032R solvent-front mutation.
MATERIALS AND METHODS: ARROS-1 (NCT05118789) is a global, tumor-agnostic, phase 1/2 trial of NVL-520. In the ongoing phase 1 dose escalation, patients are required to have a previously treated ROS1 fusion-positive solid tumor, including NSCLC treated with ≥1 prior ROS1 TKI. Primary objectives are to determine the recommended phase 2 dose (RP2D) and, if applicable, the maximum tolerated dose. Additional objectives include safety, pharmacokinetics (PK), pharmacodynamics, and preliminary activity. Response (RECIST v1.1) was investigator assessed. Data cut: June 13, 2022.
RESULTS: Twenty patients (19 NSCLC, 1 pancreatic cancer) have received NVL-520 orally at dose levels of 25-100 mg once daily. Patients received a median of 3 (range: 1-9) prior anticancer therapies, including any ROS1 TKI (100%); investigational ROS1 TKI (85%, including lorlatinib in 55%, repotrectinib in 40%); ≥2 ROS1 TKIs (75%); any chemotherapy (80%); ≥2 lines of chemotherapy (50%). At baseline, 55% had CNS metastases and 45% had ROS1 G2032R. No dose-limiting toxicities (DLTs), dose reductions, or drug-related treatment discontinuations have been reported. All treatment-related adverse events (TRAEs) were grade 1. The only TRAE in >1 patient was nausea (n=2). NVL-520 PK analyses demonstrated dose-dependent exposure. Among 12 efficacy-evaluable patients with ROS1+ NSCLC treated at 25-75 mg QD, 6 confirmed partial responses (PRs) were achieved. Shrinkage or resolution of intracranial metastases were observed; no patients had intracranial progression. A PR was achieved in most (n=5/7) ROS1 G2032R-mutant cancers, including lorlatinib or repotrectinib pretreated tumors. Circulating tumor DNA analyses showed reductions of ROS1 variant allele frequency. The RP2D has not been identified and dose escalation continues.
CONCLUSIONS: NVL-520 has been well-tolerated up to 100 mg daily with favorable pharmacokinetics. Activity has been demonstrated in heavily pretreated patients (of whom 70% received ≥2 prior ROS1 TKIs plus chemotherapy), including those with brain metastases and the G2032R mutation.
