New Drug Application Submitted for Neladalkib in Advanced ALK+ NSCLC

A new drug application (NDA) to the FDA for neladalkib (NVL-655), an investigational, brain-penetrant, anaplastic lymphoma kinase (ALK)-selective tyrosine kinase inhibitor (TKI), has been submitted to the FDA. The application seeks approval for the treatment of patients with advanced ALK-positive non–small cell lung cancer (NSCLC) who have previously received treatment with at least 1 ALK TKI.¹

The submission is supported by data from the ALKOVE-1 clinical trial (NCT05384626), a global, registration-directed phase 1/2 study.² Neladalkib was designed to address the primary limitations of currently available ALK inhibitors, specifically the emergence of solvent-front resistance mutations, off-target central nervous system (CNS) toxicities associated with tropomyosin receptor kinase (TRK) inhibition, and the need for durable intracranial activity.

Clinical Efficacy and Resistance Management

Data from the ALKOVE-1 trial demonstrated that the next-generation TKI neladalkib achieved an objective response rate (ORR) of 31% (95% CI, 26%-37%) among 253 patients with heavily pretreated ALK-positive NSCLC.¹ In a subset of patients who were lorlatinib (Lorbrena)-naive, the ORR reached 46% (95% CI, 33%-59%). Notably, the drug showed significant activity against the G1202R mutation—a common mechanism of resistance to second-generation TKIs—yielding a 68% ORR in this specific population.

These results suggest that neladalkib may provide a viable therapeutic bridge for patients who have exhausted standard-of-care options. The estimated durability of response in the total TKI-pretreated population was 64% at 12 months and 53% at 18 months, indicating a sustained clinical benefit.

CNS Penetration and Safety Profile

Because CNS progression is a hallmark of ALK-positive disease, intracranial efficacy remains a critical end point for new agents.In patients with measurable brain metastases at baseline, neladalkib demonstrated an intracranial ORR of 32% in the total population and 63% in lorlatinib-naive patients.

The safety profile of neladalkib reflects its TRK-sparing design, intended to minimize CNS-related adverse events such as dizziness and cognitive impairment.In a cohort of 656 patients treated at the recommended phase 2 dose of 150 mg daily, the most frequent treatment-emergent adverse events (TEAEs) were laboratory abnormalities, including elevations in alanine aminotransferase (47%) and aspartate aminotransferase (44%). These elevations were generally low grade and manageable through dose modification. Other common TEAEs included constipation (28%), dysgeusia (23%), and peripheral edema (18%). Discontinuation due to adverse events occurred in only 5% of the study population.

Regulatory Context and Next Steps

The FDA previously granted neladalkib breakthrough therapy designation for patients with locally advanced or metastatic ALK-positive refractory NSCLC who have received 2 or more prior ALK TKIs.It has also received orphan drug designation.

"The advancement of neladalkib from first clinical trial initiation to NDA submission in less than 4 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, ALM, chief development officer at Nuvalent, in a news release.

If approved, neladalkib would enter a competitive landscape currently led by third-generation inhibitors, offering a differentiated option for patients with emergent ALK mutations or those intolerant to the off-target effects of multi-kinase inhibitors. The FDA will now review the filing to determine if it meets the criteria for formal acceptance and subsequent action.

REFERENCES

1. Nuvalent Announces Submission of New Drug Application to FDA for Neladalkib in TKI Pre-treated Advanced ALK-positive NSCLC. News release. Nuvalent Inc. April 7, 2026. Accessed April 7, 2026. https://tinyurl.com/mpemj6u4

2. A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1). ClinicalTrials.gov. Updated October 30, 2025. Accessed April 7, 2026. https://clinicaltrials.gov/study/NCT05384626