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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Overview

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)

Mechanism of action

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)

Efficacy

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)

Safety

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)

Trial status and design

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)

Further reading

• NVL‑655 preclinical profile and case reports (Cancer Discovery, 2024). (aacrjournals.org)
• ESMO 2024 oral presentation summary with Phase 1 efficacy and safety (data cutoff March 23, 2024). (oncologypro.esmo.org)
• Trial-in-progress overview (Journal of Thoracic Oncology). (jto.org)
• Study listings and eligibility details for ALKOVE‑1 (selected academic centers). (dana-farber.org)
• Company update outlining planned registrational path and timelines (January 13, 2025). (investors.nuvalent.com)

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

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