Neladalkib Reaches FDA Review for TKI-Pretreated ALK-Positive Non-Small Cell Lung Cancer

Neladalkib has been submitted for FDA review in TKI pre-treated advanced ALK-positive NSCLC, based on data from the global ALKOVE-1 Phase 1/2 trial. The brain-penetrant, ALK-selective inhibitor showed encouraging overall and intracranial activity, with a generally well-tolerated safety profile. Neladalkib has already received FDA breakthrough therapy designation and orphan drug designation in ALK-positive NSCLC.

Nuvalent announced the submission of a new drug application to the U.S. Food and Drug Administration (FDA) for neladalkib, an investigational ALK-selective inhibitor, for patients with tyrosine kinase inhibitor, TKI, pre-treated advanced ALK-positive non-small cell lung cancer, NSCLC. The filing is based on results from the global, registration-directed ALKOVE-1 Phase 1/2 trial.

If accepted and ultimately approved, neladalkib could add a new option for patients whose disease has progressed after prior ALK-directed therapy, a setting where resistance mutations, central nervous system involvement, and treatment tolerability remain major clinical challenges.

"The advancement of neladalkib from first clinical trial initiation to NDA submission in less than four years represents a remarkable pace in oncology drug development, underscoring the vigor and urgency our team brought to this program and our deep commitment to the ALK-positive NSCLC community," said Darlene Noci, A.L.M., Chief Development Officer at Nuvalent.

According to the company, the application is supported by data from TKI pre-treated patients with advanced ALK-positive NSCLC enrolled in ALKOVE-1. In that population, neladalkib showed encouraging overall antitumor activity, including intracranial responses, and appeared capable of targeting key drivers of disease progression. Nuvalent also said the drug demonstrated a generally well-tolerated safety profile, consistent with its

ALK-selective, TRK-sparing design. Detailed efficacy and safety findings are expected to be presented at a future medical meeting.

Neladalkib is a brain-penetrant ALK inhibitor designed to address several limitations of currently available ALK-targeted therapies. The agent was developed to retain activity against tumors that have acquired resistance to first-, second-, and third-generation ALK inhibitors, including tumors harboring single or compound treatment-emergent ALK mutations such as G1202R. Its central nervous system penetration may be particularly relevant for patients with brain metastases, a frequent and clinically significant problem in ALK-positive NSCLC.

Another distinguishing feature is its avoidance of tropomyosin receptor kinase, TRK, inhibition. This TRK-sparing approach could reduce the risk of TRK-related CNS adverse effects that have been associated with dual TRK/ALK inhibitors, while preserving potent ALK inhibition.

The FDA has already granted neladalkib breakthrough therapy designation for patients with locally advanced or metastatic ALK-positive NSCLC previously treated with two or more ALK TKIs. The drug has also received orphan drug designation for ALK-positive NSCLC.

ALKOVE-1, NCT05384626, is a first-in-human Phase 1/2 study in patients with advanced ALK-positive NSCLC and other ALK-positive solid tumors. The completed Phase 1 portion evaluated safety, tolerability, pharmacokinetics, preliminary antitumor activity, and the recommended Phase 2 dose. The ongoing global Phase 2 portion is a single-arm, open-label study designed with registrational intent for TKI pre-treated advanced ALK-positive NSCLC. Enrollment also continues for adult and adolescent patients with ALK-positive solid tumors outside NSCLC, as well as adolescent patients with ALK-positive NSCLC.