Neladalkib (NVL-655) is a potent, selective and brain-penetrant fourth-generation inhibitor of diverse ALK-mutant oncoproteins with IC50 of 0.9 nM and 1.8 nM for WT ALK and ALK G1202R/L1196M mutant respectively.
Neladalkib (NVL-655) potently inhibits cell lines expressing WT ALK fusions with average IC50 < 1.1 nM.
Neladalkib (NVL-655) exhibits an IC50 of 0.3 to 1.6 nM against MGH048-1, MGH064-1, and MGH026-1 cell lines, which were established from TKI-naïve patients with NSCLC harboring EML4–ALK v1, v2, and v3 fusions, respectively, and IC50 of 2 nM against the anaplastic large cell lymphoma cell line Karpas299 harboring the NPM1–ALK fusion.
Neladalkib (NVL-655) potently inhibits the growth of cell lines harboring ALKG1202R fusions (IC50 = 0.1–0.8 nmol/L, average
< 0.3 nM), including three PDCs established after progressive disease on alectinib (MGH953-4 and YU1077) or brigatinib (MGH9037-2).
Neladalkib (NVL-655) is >14-fold more potent than zotizalkib, >100 fold more potent than lorlatinib, and >280-fold more potent
than 1G and 2G ALK TKIs on average.
Neladalkib (NVL-655) inhibits ALK over TRK with 22-fold to >874-fold selectivity.
Neladalkib (NVL-655) demonstrates preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion-positive non-small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations.