Sponsor: Nuvalent Inc. (industry)
Phase: 3
Start date: Jan. 9, 2025
Planned enrollment: 450
Neladalkib (NVL-655; NUV-655) is an investigational, brain-penetrant, ALK-selective tyrosine kinase inhibitor (TKI) being developed for ALK-rearranged non–small cell lung cancer (NSCLC) and other ALK-driven solid tumors. It is designed to retain activity against treatment-emergent ALK resistance mutations, including solvent-front G1202R and G1202R-based compound mutations, while sparing TRK to potentially reduce TRK-related central nervous system (CNS) adverse effects. Neladalkib has received U.S. FDA Breakthrough Therapy and Orphan Drug designations for previously treated ALK-positive NSCLC. Phase 1/2 clinical development (ALKOVE-1; NCT05384626) is ongoing. (aacrjournals.org)
Neladalkib is a small-molecule ALK inhibitor with high selectivity: >50-fold selectivity for ALK versus 96% of kinases tested and 22- to >874-fold selectivity for ALK over TRK in biochemical assays. Preclinically, it shows broad potency across diverse ALK fusions and activating alterations, with ≥100-fold improved potency against ALK G1202R single and compound mutations compared with approved ALK TKIs, and intracranial antitumor activity in ALK-driven brain tumor models. (aacrjournals.org)
Early clinical activity has been reported from the Phase 1 portion of ALKOVE-1 (data cutoff March 23, 2024; presented at ESMO 2024). Among 103 response-evaluable ALK+ NSCLC patients (heavily pretreated; 79% had received ≥1 second-generation ALK TKI and lorlatinib; 56% had a history of CNS metastases), the ORR was 38% with a median duration of response (DOR) of 9.2 months (95% CI, 6.9–NE). Activity was enriched in key molecular subsets: ORR 55% in patients with detectable ALK resistance mutations, 76% in those with G1202R, and 58% in those with compound (≥2) ALK mutations; median DOR in mutation-positive subsets was 14.4 months (95% CI, 6.9–NE). In lorlatinib-experienced patients, ORR was 49%. CNS responses, including complete resolution of brain metastases in lorlatinib-experienced patients, were observed. At the selected RP2D (150 mg once daily), ORR was 39% overall and 83% in the G1202R subset. (oncologypro.esmo.org)
Case reports included in a 2024 peer‑reviewed preclinical/clinical translational study also describe radiographic responses (including intracranial activity) in heavily pretreated ALK+ NSCLC patients harboring single or compound ALK resistance mutations, supporting proof-of-concept. (aacrjournals.org)
Planned next steps include an expansion with “registrational intent” in previously treated ALK+ NSCLC and a Phase 3 study (ALKAZAR) in TKI‑naïve patients (announced January 13, 2025). (investors.nuvalent.com)
Across 133 patients treated in Phase 1 (dose range 15–200 mg once daily), the maximum tolerated dose was not reached; 150 mg once daily was selected as the RP2D. The most common treatment-related adverse events (TRAEs) were increased ALT (33%), increased AST (29%), constipation (15%), nausea (12%), and dysgeusia (11%); 2% discontinued due to TRAEs. Reported safety was consistent with the ALK‑selective, TRK‑sparing design. (oncologypro.esmo.org)
ALKOVE-1 is a first‑in‑human, multicenter Phase 1/2 study enrolling adults (and a limited adolescent cohort in Phase 2) with ALK‑positive NSCLC or other ALK‑driven solid tumors. Phase 1 evaluates safety, PK/PD, and RP2D; Phase 2 assesses objective response by blinded independent central review across multiple cohorts (including post‑TKI and TKI‑naïve NSCLC, and other ALK‑driven tumors). Estimated primary completion is in the mid‑to‑late 2020s; multiple U.S. centers remain recruiting. An expanded access protocol for advanced ALK+ NSCLC is also available at select sites. (jto.org)
Notes: Efficacy and safety data above reflect the most recent peer‑reviewed or conference‑presented results identified (ESMO 2024; data cutoff March 23, 2024). Phase 2 cohorts and additional updates are ongoing; see trial resources for the latest enrollment and outcomes. (oncologypro.esmo.org)
Last updated: Oct 2025
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
Caution: ClinicalTrials.gov appears to have newer eligibility criteria than the version saved here. Review the current criteria in ClinicalTrials.gov.
Inclusion Criteria:
1. Histologically or cytologically confirmed locally advanced (not amenable for multimodality treatment) or metastatic Non-small Cell Lung Cancer (NSCLC)
2. Documented Anaplastic Lymphoma Kinase (ALK) rearrangement via testing of tissue or blood
3. No prior systemic anticancer treatment for NSCLC (adjuvant/neoadjuvant chemotherapy allowed if 12 months prior to randomization; prior ALK tyrosine kinase inhibitor \[TKI\] such as alectinib is not allowed in any setting)
4. Measurable disease (1 or more target lesions per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1)
5. Pretreatment tumor tissue (archived or a fresh biopsy)
6. Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2
Exclusion Criteria:
1. Patient's cancer has a known oncogenic driver alteration other than ALK.
2. Known allergy/hypersensitivity to excipients of neladalkib or alectinib.
3. Ongoing or recent radiotherapy as per protocol-specified timeframes prior to randomization
4. Major surgery within 4 weeks prior to randomization
5. Uncontrolled clinically relevant infection requiring systemic therapy
6. Known active tuberculosis, or active Hepatitis B or C
7. QT corrected for heart rate by Fridericia's formula (QTcF) \> 470 msec on repeated assessments
8. Clinically significant cardiovascular disease
9. Brain metastases associated with progressive neurological symptoms or requiring increasing doses of corticosteroids to control CNS disease
10. Active malignancy requiring therapy within 2 years prior to randomization
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