Pipeline

ALK fusions are an oncogenic driver alteration found in up to 5% of patients with non-small cell lung cancer (NSCLC). The clinical utility of approved therapies for ALK-driven NSCLC is limited by emergent resistance mutations as well as central nervous system (CNS) disease.

NVL-655

NVL-655 is a novel brain-penetrant ALK-selective inhibitor created to overcome several limitations observed with currently available therapies. NVL-655 is designed to remain active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with the solvent front G1202R mutation or compound mutations G1202R / L1196M (“GRLM”), G1202R / G1269A (“GRGA”), or G1202R/L1198F (“GRLF”).

NVL-655 has been optimized for brain penetrance to improve treatment options for patients with brain metastases. ALK-selectivity is emphasized to minimize CNS adverse events related to off-target inhibition of the structurally-related tropomyosin receptor kinase (TRK) family and potentially drive more durable responses for patients with ALK-mutant variants.

The ALKOVE-1 Phase 1/2 clinical trial of NVL-655 for patients with advanced ALK-positive NSCLC and other solid tumors is now enrolling. To learn more, please visit www.clinicaltrials.gov (NCT05384626).

ALK IXDN

The ALK I1171X (X = N, S, or T) / D1203N (“IXDN”) compound mutations are emerging mutations that confer resistance to all available ALK inhibitor therapies for NSCLC. There are no approved therapies for the treatment of NSCLC with IXDN compound mutations.

We are advancing toward a novel, selective, brain-penetrant ALK inhibitor designed to remain active in tumors harboring IXDN compound resistance mutations.

Mutations in human epidermal growth factor receptor 2 (“HER2” or “ERBB2”) occur in up to 4% of metastatic non-small cell lung cancer (NSCLC), with in-frame deletions, insertions, or duplications in exon 20 accounting for 90% of cases (collectively “HER2ex20”). Approximately 20% of patients with HER2 mutant NSCLC present with brain metastases, with the percentage increasing upon treatment. There are limited therapeutic options targeting these mutations.

NVL-330

NVL-330 is a novel, brain-penetrant HER2-selective tyrosine kinase inhibitor designed with the aim to address the combined medical needs of:

• Treating tumors driven by HER2ex20,
• Avoiding treatment-limiting adverse events due to off-target inhibition of wild-type EGFR, and
• Treating brain metastases.

HER2-selectivity is emphasized to minimize potentially dose-limiting adverse events associated with inhibition of the structurally related wild-type EGFR kinases such as skin rash and gastrointestinal toxicity. In addition, NVL-330 has been optimized for brain penetrance to potentially improve treatment options for patients with brain metastases.