NVL-520 Is a Selective, TRK-Sparing, and Brain-Penetrant Inhibitor of ROS1 Fusions and Secondary Resistance
Alexander Drilon1, Joshua C Horan2, Anupong Tangpeerachaikul2
1Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.
Cancer Discovery
|December 13, 2022
Summary
NVL-520 shows promise as a novel tyrosine kinase inhibitor (TKI) for ROS1-positive cancers. It effectively targets ROS1 mutations and penetrates the brain, potentially overcoming limitations of current treatments.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- ROS1 fusion-positive cancers represent a significant therapeutic challenge.
- Earlier-generation tyrosine kinase inhibitors (TKIs) face limitations including resistance mutations and poor brain penetration.
Purpose of the Study:
- To evaluate the preclinical profile of NVL-520, a novel ROS1 TKI.
- To assess NVL-520's potential to overcome resistance and improve outcomes in ROS1 fusion-positive patients.
Main Methods:
- Preclinical evaluation of NVL-520's potency and selectivity.
- Assessment of NVL-520's activity against diverse ROS1 resistance mutations.
- In vivo studies to determine brain penetration capabilities.
Main Results:
- NVL-520 demonstrates potent targeting of ROS1, including key resistance mutations.
- High selectivity for the ROS1 G2032R mutation over TRK was observed.
- NVL-520 exhibits significant brain penetration in preclinical models.
Conclusions:
- NVL-520 possesses distinct preclinical features suggesting it may surpass earlier-generation TKIs.
- This novel TKI holds potential for improved efficacy in ROS1 fusion-positive patients, including those with brain metastases.
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