HEROEX-1 Trial Begins for HER2-Selective Inhibitor NVL-330 in NSCLC
The first pretreated patient with HER2-altered non–small cell lung cancer was dosed with NVL-330, a novel HER2-selective inhibitor, in the HEROEX-1 trial.
Illustration of lungs, medical concept: © yodiyim - stock.adobe.com
The phase 1a/1b HEROEX-1 trial has begun and the first pre-treated patient with HER2-altered non–small cell lung cancer (NSCLC) has been dosed with NVL-330, a novel HER2-selective inhibitor being evaluated in the study.1
The multicenter, open-label, dose-escalation and dose-expansion trial is assessing treatment with NVL-330 when given to pretreated patients with advanced HER2-altered NSCLC, including patients who harbor HER2 exon 20 mutations. End points being evaluated in the trial include overall safety, tolerability, pharmacokinetics, and antitumor activity. Experts will also look to establish the recommended phase 2 dose of NVL-330.
"HER2 alterations are an important category of oncogenic drivers within NSCLC that includes both HER2 amplification and HER2 mutations, the majority of which are exon 20 mutations. While HER2-targeted therapies have been developed, there are currently no approved [tyrosine kinase inhibitors (TKIs)] for the HER2-mutant NSCLC patient population," said Christopher Turner, MD, chief medical officer of Nuvalent, in a press release.
"At the outset of our program, physician-scientists outlined the need for a HER2 therapy that maintained activity against HER2 exon 20 mutations, was selective for HER2 vs wild-type EGFR to limit gastrointestinal and skin toxicities associated with EGFR inhibition and was brain penetrant to address and limit brain metastases. NVL-330's preclinical profile has demonstrated the potential to be differentiated through combining these desired characteristics and supports its initial clinical investigation in our HEROEX-1 trial for patients with HER2-altered NSCLC," continued Turner.
About NVL-330
NVL-330 is a novel brain-penetrant HER2-selective TKI being developed for the treatment of HER2-altered tumors, including patients with HER2 exon 20 insertion mutations. In preclinical studies, NVL-330 exhibited activity on HER2 oncogenic alterations.
Compared with zongertinib (BI 1810631), NVL-330 showed similar potency and selectivity over wild-type EGFR, as well as higher central nervous system (CNS) penetrance. When compared with fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd), NVL-330 also showed promise with a deeper response than the antibody-drug conjugate, higher CNS penetrance in an intracranial tumor model, and activity in cells that had acquired resistance to T-DXd.2
In addition to NVL-330, Nuvalent is also currently developing treatments for patients with ROS1-mutant NSCLC and ALK-driven NSCLC, known as zidesamtinib (NVL-520) and NVL-655.
"The initiation of this trial represents a significant milestone for Nuvalent, marking the third program from our novel pipeline to enter clinical development in under 3 years," said James Porter, PhD, chief executive officer at Nuvalent, in the press release.1 "This rapid execution serves as a testament to our team's dedication to rapid progress and growth across our pipeline, and our unwavering commitment to our goal of bringing precisely targeted therapies to patients with cancer."
