Sponsor: Nuvalent Inc. (industry)
Phase: 3
Start date: Jan. 9, 2025
Planned enrollment: 450
Neladalkib (NVL-655) is an investigational oral drug being studied for cancers driven by alterations in ALK, particularly advanced ALK-positive non-small-cell lung cancer (NSCLC). Human results are available from ALKOVE-1, an ongoing, single-arm phase 1/2 trial. Because it has no comparison group, its response rates cannot establish whether neladalkib is better than existing treatments. (ascopubs.org)
Neladalkib inhibits ALK tyrosine kinase. It was designed to reach the brain and inhibit ALK resistance mutations, including some that arise after lorlatinib, while largely sparing the related TRK kinases. These design goals are supported by preclinical research; clinical benefit must be assessed separately. (aacrjournals.org)
In a 2026 conference abstract reporting ALKOVE-1 results through August 29, 2025, the independently assessed objective response rate was 31% (79/253) among patients previously treated with ALK inhibitors. It was 68% (32/47) among those with an ALK G1202R resistance mutation and 32% (29/92) for measurable brain lesions. In a smaller, preliminary group with no prior ALK-inhibitor treatment, 86% (38/44) had a reported response, including two responses not yet confirmed. These are distinct patient groups and should not be compared directly. (ascopubs.org)
Among 656 patients who received the recommended phase 2 dose, the most frequently reported treatment-emergent events were increased ALT (47%) and AST (44%) liver-enzyme levels, constipation (28%), altered taste (23%), and peripheral edema (18%). Adverse events led to dose reductions in 17% and treatment discontinuation in 5%. These pooled safety figures come from the trial sponsor’s report; “treatment-emergent” does not necessarily mean caused by neladalkib. (sec.gov)
Last updated: Sep 2026
Goal: Determine whether first-line neladalkib prolongs progression-free survival compared with alectinib in advanced ALK-positive non-small cell lung cancer (NSCLC).
Patients: Adults with unresectable locally advanced or metastatic ALK-rearranged NSCLC, measurable disease, ECOG performance status 0–2, and no prior systemic treatment for NSCLC or prior ALK inhibitor. Prior adjuvant or neoadjuvant chemotherapy is permitted if completed at least 12 months before randomization. Pretreatment tumor tissue is required; patients with neurologically progressive brain metastases or increasing corticosteroid requirements are excluded.
Design: Multicenter, open-label, randomized controlled trial assigning patients 1:1 to neladalkib or alectinib. Radiographic progression for the primary endpoint is assessed by blinded independent central review.
Treatments: Neladalkib (NVL-655) is an investigational oral ALK tyrosine kinase inhibitor given at 150 mg once daily. It was designed for CNS penetration and activity against ALK resistance mutations while largely sparing TRK kinases. In the separate, single-arm ALKOVE-1 study, a preliminary ALK-inhibitor-naïve cohort had an 86% reported response rate (38/44, including two unconfirmed responses); these data do not establish superiority over alectinib. Alectinib is an established ALK inhibitor given at 600 mg orally twice daily.
Outcomes: The primary endpoint is progression-free survival by blinded independent central review. Secondary endpoints include overall survival, investigator-assessed progression-free survival, systemic and intracranial response and response duration, time to intracranial progression, adverse events and laboratory changes, and patient-reported quality of life, symptoms, and functioning.
Burden on patient: The burden is likely low to moderate relative to other oncology trials: both treatments are oral, but patients require ongoing visits, imaging, laboratory monitoring, and questionnaires. Pretreatment tumor tissue is required, potentially necessitating a fresh biopsy if archived tissue is unavailable. The supplied information does not specify visit or scan frequency or intensive pharmacokinetic sampling.
Last updated: Sep 2026
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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