NVL-655 Is a Selective and Brain-Penetrant Inhibitor of Diverse ALK-Mutant Oncoproteins, Including...

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Three generations of tyrosine kinase inhibitors (TKIs) are approved for anaplastic lymphoma kinase (ALK) fusion-positive non-small cell lung cancer (NSCLC).
• Current ALK TKIs have limitations including insufficient resistance coverage, limited brain activity, and dose-limiting TRK inhibition.

Purpose of the Study:

• To evaluate NVL-655, a novel TKI designed for broad ALK inhibition with high selectivity.
• To assess NVL-655's efficacy against diverse ALK alterations, including resistance mutations and in models with brain metastases.

Main Methods:

• NVL-655's selectivity and potency against various ALK fusions, activating alterations, and resistance mutations were assessed in vitro.
• In vivo efficacy was evaluated in 12 tumor models, including intracranial and patient-derived xenografts.
• NVL-655's selectivity over TRK inhibition was determined.

Main Results:

• NVL-655 demonstrated >50-fold selectivity for ALK over 96% of the kinome.
• It potently inhibited diverse ALK alterations, including ALKG1202R mutations, with ≥100-fold improved potency over approved ALK TKIs.
• NVL-655 induced tumor regression in vivo and showed significant selectivity over TRK inhibition (22-fold to >874-fold).
• Phase I/II trial data indicated preliminary clinical activity in heavily pretreated NSCLC patients with brain metastases and resistance mutations.

Conclusions:

• NVL-655 exhibits broad activity against ALK resistance mutations and penetrates the brain.
• Its high selectivity addresses limitations of current ALK inhibitors, positioning it as a potential fourth-generation treatment for ALK-driven cancers.