Reference Detail

Ref Type

Abstract

PMID

Authors

A. Drilon B. Besse D.R. Camidge S.H.I. Ou S.M. Gadgeel M.L. Johnson A. Calles M.J. de Miguel A.I. Spira E. Felip G. Lopes A.J. van der Wekken Y.Y. Elamin J. Green Y. Sun J. Soglia V.W. Zhu J.J. Lin

Title

Safety and preliminary clinical activity of NVL-520, a highly selective ROS1 inhibitor, in patients with advanced ROS1 fusion-positive solid tumors

Journal	Vol	Issue	Date	Pages	Journal Short Title
European Journal of Cancer	174	Supplement 1	Oct 1, 2022

URL

https://www.ejcancer.com/article/S0959-8049(22)00821-8/fulltext

Abstract Text

Background: 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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ROS1 fusion	lung non-small cell carcinoma	predicted - sensitive	NUV-520	Phase I	Actionable	In a Phase I trial (ARROS-1), NUV-520 treatment resulted in 6 partial responses among 12 patients with non-small cell lung cancer harboring a ROS1 fusion including a partial response in 5 of 7 patients harboring a ROS1 fusion with ROS1 G2032R (Eu J Cancer 2022 Vol 174, Supp 1:S6-S7; NCT05118789).	detail...
ROS1 fusion ROS1 G2032R	lung non-small cell carcinoma	predicted - sensitive	NUV-520	Phase I	Actionable	In a Phase I trial (ARROS-1), NUV-520 treatment resulted in 6 partial responses among 12 patients with non-small cell lung cancer harboring a ROS1 fusion including a partial response in 5 of 7 patients harboring a ROS1 fusion with ROS1 G2032R (Eu J Cancer 2022 Vol 174, Supp 1:S6-S7; NCT05118789).	detail...