About the Trial
Trial Name: Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC (ALKAZAR)
ClinicalTrials.gov ID: NCT06765109
Sponsor: Nuvalent Inc.
Completion Date (Estimated): December 2029
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Nuvalent Initiates Phase 3 ALKAZAR Trial of Neladalkib in NSCLC
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Key Takeaways
- Neladalkib is a brain-penetrant ALK-selective inhibitor designed to overcome resistance and improve CNS treatment options in ALK-positive NSCLC.
- The phase 3 ALKAZAR trial compares neladalkib to alectinib in TKI-naïve patients, focusing on progression-free survival and other key endpoints.
Neladalkib enters phase 3 trials, targeting advanced ALK-positive NSCLC, promising improved outcomes for TKI-naïve patients with brain metastases.
The first patient in the phase 3 ALKAZAR clinical trial (NCT06765109) assessing neladalkib (NVL-655; Nuvalent) in tyrosine kinase inhibitor (TKI)–naïve patients with advanced ALK-positive non-small cell lung cancer (NSCLC) has received their first dose of treatment, according to a news release from the manufacturer.1,2 Currently, neladalkib is also being evaluated in the phase 2 portion of the ALKOVE-1 phase 1/2 clinical trial (NCT05384626).1,3
Image credit: Dr_Microbe | stock.adobe.com
Neladalkib is a novel brain-penetrant ALK-selective inhibitor that was designed to overcome the limitations observed with currently available ALK inhibitors. It remains active in tumors that have developed resistance to first-, second-, and third-generation ALK inhibitors, including tumors with single or compound treatment-emergent ALK mutations. Additionally, neladalkib is designed for central nervous system (CNS) penetrance to improve treatment options for patients who have brain metastases, as well as avoid inhibition of the structurally related tropomyosin receptor kinase (TRK) family. Previously, neladalkib received breakthrough therapy designation for the treatment of patients with locally advanced or metastatic ALK-positive NSCLC who were previously treated with 2 or more ALK TKIs and an orphan drug designation for ALK-positive NSCLC.1
"Neladalkib is rationally designed with the goal of addressing the combined medical needs of treating key drivers of disease progression such as brain metastases and treatment-emergent resistance mutations, while also offering a generally safe and well-tolerated safety profile supportive of long-term treatment," Darlene Noci, ALM, chief development officer at Nuvalent, said in a news release. "We have been encouraged by neladalkib's clinical profile to date…The initiation of the registration-directed ALKAZAR study enables us to explore this potential by comparing neladalkib to a front-line standard of care in a randomized, controlled clinical trial setting, and advances us towards our ultimate goal of bringing neladalkib to all patients with advanced ALK-positive NSCLC."1
ALKAZAR is a global, randomized, controlled, open-label phase 3 trial studying neladalkib in TKI-naïve patients with advanced ALK-positive NSCLC. About 450 patients will be enrolled and randomly assigned to receive either 150 mg of neladalkib orally once per day or 600 mg of alectinib (Alecensa; Genentech) orally twice per day. Additionally, patients will be stratified by brain metastases, ethnicity, and Eastern Cooperative Oncology Group performance status score.2,4
The trial’s primary end point is progression-free survival, and secondary end points include objective response rate, intracranial activity, duration of response, overall survival, safety and tolerability, and patient-reported outcomes. Further, the investigators noted that there will be additional analyses conducted to investigate candidate biomarkers and molecular mechanisms of response and resistance to the 2 study drugs.2,4
Results from the phase 1 portion of the ALKOVE-1 trial showed that patients treated with neladalkib achieved durable clinical responses, which were observed in response-evaluable patients treated at the recommended phase 2 dose as well as across all dose levels. Overall, neladalkib was well-tolerated with a preliminary safety profile that was favorable and consistent with its ALK-selective, TRK-sparing design. Among the 133 patients treated at all doses, the most frequent treatment-related adverse events (AEs) were alanine aminotransferase (ALT) increase (34%), aspartate aminotransferase (AST) increase (30%), constipation (16%), dysgeusia (13%), and nausea (12%).5
Among these most frequent treatment-related AEs, approximately 13% of patients experienced grade 3 ALT increase, 1 patient experienced grade 4 ALT increase, and about 9% of patients experienced grade 3 AST increase. Transaminase elevations were generally transient and reversible, noted the investigators. Discontinuations because of treatment-related AEs occurred in 2% of patients, and dose reductions occurred in 15% of patients. In this phase 1 portion, a maximum tolerated dose was not identified.5
"The currently available therapies represent important scientific advancements that provide hope for patients with ALK-positive NSCLC. However, these therapies have limitations that can lead to challenging treatment decisions for newly diagnosed patients and their health care providers," Kirk Smith, president of the Board of ALK Positive Inc., said in the news release. "We encourage continued innovation and the investigation of new treatment opportunities for all patients with ALK-positive NSCLC and look forward to following the progress of the ALKAZAR study."1
REFERENCES
Nuvalent Investors. Nuvalent Announces Initiation of ALKAZAR Phase 3 Randomized, Controlled Trial Evaluating Neladalkib for Patients with TKI-naïve ALK-positive NSCLC. News release. July 21, 2025. Accessed July 21, 2025. https://investors.nuvalent.com/2025-07-21-Nuvalent-Announces-Initiation-of-ALKAZAR-Phase-3-Randomized,-Controlled-Trial-Evaluating-Neladalkib-for-Patients-with-TKI-naive-ALK-positive-NSCLC
Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC (ALKAZAR). ClinicalTrials.gov identifier: NCT06765109. Updated March 12, 2025. Accessed July 21, 2025. https://clinicaltrials.gov/study/NCT06765109
A Study of NVL-655 in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1). ClinicalTrials.gov identifier: NCT05384626. Updated December 13, 2024. Accessed July 21, 2025. https://clinicaltrials.gov/study/NCT05384626
Neladalkib (NVL-655), a highly selective anaplastic lymphoma kinase (ALK) inhibitor, compared to alectinib in first-line treatment of patients with ALK-positive advanced non-small cell lung cancer: The phase 3 ALKAZAR study. J Clin Oncol. 2025;43(Number 16_suppl). doi:10.1200/JCO.2025.43.16_suppl.TPS8666
Nuvalent Investors. Nuvalent Highlights Presentation of Clinical Data at ESMO 2024 for Parallel Lead Programs for ROS1 and ALK-positive NSCLC and Accelerated Development Timelines. News release. September 14, 2024. Accessed July 21, 2025. https://investors.nuvalent.com/2024-09-14-Nuvalent-Highlights-Presentation-of-Clinical-Data-at-ESMO-2024-for-Parallel-Lead-Programs-for-ROS1-and-ALK-positive-NSCLC-and-Accelerated-Development-Timelines
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