NVL-330

NVL-330 is a novel, brain-penetrant, HER2-selective tyrosine kinase inhibitor (TKI) developed by Nuvalent for the treatment of tumors with HER2 alterations. It is specifically designed to target HER2 mutations—including exon 20 insertion mutations—and amplifications in cancers such as non-small cell lung cancer (NSCLC). The drug aims to address key clinical needs by maintaining activity against HER2 exon 20 mutations, minimizing off-target inhibition of wild-type EGFR (to reduce gastrointestinal and skin toxicities), and achieving high central nervous system penetrance to treat or prevent brain metastases. Preclinical studies have shown that NVL-330 has broad activity against various oncogenic HER2 alterations and demonstrates higher CNS penetrance compared to other agents like zongertinib and fam-trastuzumab deruxtecan-nxki. As of mid-2025, it is being evaluated in the phase 1a/1b HEROEX-1 clinical trial for pretreated patients with advanced or metastatic HER2-altered NSCLC[1][3][4][5][7].