A Phase 3 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 Compared to Alectinib in First-Line Treatment of Patients With ALK-Positive Advanced Non-Small Cell Lung Cancer (ALKAZAR)

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Investigational drug late phase More information Active drug More information Moderate burden on patient More information

Trial Details

Sponsor: Nuvalent Inc. (industry)

Phase: 3

Start date: Jan. 9, 2025

Planned enrollment: 450

Trial ID: NCT06765109
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More trial details at ClinicalTrials.gov More info

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Investigational Drug AI Analysis

chevron Show for: neladalkib (NVL-655, NUV-655)

TrialFetch AI Analysis

Goal: Demonstrate superiority of the selective ALK inhibitor neladalkib (NVL-655) over alectinib in prolonging progression-free survival in treatment-naïve patients with advanced ALK-positive NSCLC.

Patients: Adults with histologically or cytologically confirmed locally advanced (not amenable to multimodality therapy) or metastatic ALK-rearranged NSCLC, no prior systemic therapy for advanced disease (adjuvant/neoadjuvant allowed if completed ≥12 months before randomization), at least one RECIST 1.1 measurable lesion, ECOG 0–2, and available pretreatment tumor tissue. Excludes tumors with alternative oncogenic drivers, significant uncontrolled comorbidities or infections, clinically unstable CNS disease, significant QTc prolongation or cardiovascular disease, and recent major surgery or radiotherapy per protocol windows.

Design: Multicenter, randomized, controlled, open-label Phase 3 trial with 1:1 allocation to neladalkib or alectinib, approximately 450 patients total. Blinded independent central review is used for primary PFS assessment. Follow-up for efficacy, safety, and patient-reported outcomes is up to 5 years after first patient dosed.

Treatments: Neladalkib (NVL-655) 150 mg orally once daily. NVL-655 is a brain-penetrant, ALK-selective tyrosine kinase inhibitor engineered to retain activity across diverse ALK fusions and resistance mutations, including lorlatinib-refractory compound mutations such as G1202R/L1196M and G1202R/G1269A, while sparing TRKB to mitigate neurologic adverse events. In the Phase 1 ALKOVE-1 study of heavily pretreated ALK+ NSCLC, NVL-655 showed an objective response rate of about 39% overall, with higher responses in patients with CNS metastases and ALK resistance mutations, and a favorable tolerability profile with low rates of dose reductions and discontinuations; the recommended Phase 2 dose is 150 mg QD. Alectinib 600 mg orally twice daily is an established second-generation ALK TKI and a current first-line standard of care with proven systemic and CNS activity.

Outcomes: Primary: PFS by blinded independent central review. Secondary: overall survival; PFS by investigator; time to intracranial progression by BICR; intracranial ORR and intracranial duration of response; systemic ORR and duration of response; time to intracranial progression by investigator; safety including TEAEs and laboratory parameters; patient-reported outcomes using EORTC QLQ-C30, EORTC QLQ-LC29, and EQ-5D-5L. Assessments continue for up to 5 years after first patient dosed.

Burden on patient: Moderate to low. Both study arms use oral TKIs with outpatient administration and monitoring that largely mirrors standard ALK+ NSCLC care, including periodic imaging (systemic and CNS) and routine laboratory tests. Requirements include baseline and possibly on-treatment tumor tissue (archival or fresh biopsy), regular clinic visits for safety assessments and PRO questionnaires, and imaging at protocol-defined intervals, which may be slightly more structured than routine practice. No intensive pharmacokinetic sampling is noted, and no infusion visits are required, minimizing visit complexity and travel beyond standard-of-care expectations for first-line ALK TKI therapy.

Last updated: Oct 2025

Eligibility More information

Caution: ClinicalTrials.gov appears to have newer eligibility criteria than the version saved here. Review the current criteria in ClinicalTrials.gov.

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Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

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