FDA Grants Priority Review to Neladalkib NDA for ALK-Positive NSCLC

The FDA has accepted the new drug application (NDA) for neladalkib for filing, granting the investigational agent priority review for the treatment of tyrosine kinase inhibitor (TKI)-pretreated advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). The FDA has established a Prescription Drug User Fee Act (PDUFA) target action date of November 27, 2026, for its regulatory decision.

The regulatory submission is supported by clinical efficacy and safety data from the ongoing, global, registration-directed ALKOVE-1 phase 1/2 clinical trial (NCT05384626).² This trial evaluates the small-molecule agent in patients with advanced ALK-positive NSCLC and other solid tumors who have received prior TKI therapy. Detailed outcomes from the TKI-pretreated patient cohort, alongside preliminary findings in TKI-naive patients, are scheduled for oral presentation at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

Neladalkib is an investigational, brain-penetrant, ALK-selective inhibitor architecturally designed to address the primary therapeutic limitations of currently approved first-, second-, and third-generation ALK inhibitors. Structurally, the molecule is engineered to maintain therapeutic activity in the presence of secondary treatment-emergent resistance mutations within the ALK kinase domain, including single and compound mutations such as G1202R.

Furthermore, neladalkib was developed to optimize central nervous system (CNS) penetrance while simultaneously minimizing the inhibition of the structurally related tropomyosin receptor kinase (TRK) family. In clinical oncology, avoiding TRK inhibition is intended to reduce the incidence of TRK-mediated CNS toxicities such as dizziness, ataxia, and cognitive impairment, thereby expanding the therapeutic window and offering deep, durable intracranial responses for patients presenting with baseline brain metastases.

The regulatory path for neladalkib has been supported by several FDA designations. The agency previously granted neladalkib breakthrough therapy designation for patients with locally advanced or metastatic ALK-positive NSCLC who have experienced disease progression following two or more ALK TKIs. The drug candidate also holds orphan drug designation for the treatment of ALK-positive NSCLC.

While the definitive registrational data remain under regulatory review, global enrollment in the ALKOVE-1 trial continues. The open-label, single-arm phase 2 portion remains active for adult and adolescent cohorts with ALK-positive solid tumors outside of NSCLC, as well as pediatric and adolescent patients presenting with ALK-positive NSCLC.

Therapeutic Challenges in the Post-TKI Treatment Landscape

The treatment paradigm for advanced ALK-rearranged NSCLC has evolved considerably, transitioning from the first-generation TKI crizotinib (Xalkori) to highly potent second-generation inhibitors like alectinib (Alecensa), brigatinib (Alunbrig), and ceritinib (Zykadia), and the third-generation macrocyclic inhibitor lorlatinib (Lorbrena). While these agents provide substantial systemic and intracranial disease control, virtually all tumors eventually develop acquired resistance, presenting a critical therapeutic challenge in clinical oncology.³

Following the failure of second-generation agents, lorlatinib remains the primary targeted option. However, its subsequent use is frequently curtailed by the emergence of complex, compound resistance mutations within the ALK kinase domain. While lorlatinib was specifically engineered to overcome the common G1202R solvent-front mutation, prolonged therapeutic pressure under third-generation inhibition often induces double or triple compound mutations, such as G1202R/L1196M or G1202R/C1156Y. These structural alterations cause severe steric hindrance, rendering currently approved TKIs ineffective.

Consequently, for patients who experience disease progression on sequential second- and third-generation TKIs, standard salvage therapeutic options are heavily restricted. Clinical guidelines typically mandate a transition to platinum-doublet cytotoxic chemotherapy combinations (eg, cisplatin or carboplatin plus pemetrexed) or enrollment in investigational clinical trials. Because chemotherapy offers modest progression-free survival (PFS) in this pretreated demographic and does not specifically address the underlying oncogenic driver or complex compound resistance mechanisms, there is an unmet clinical need for next-generation, selective ALK inhibitors capable of circumventing these mutations.

REFERENCES

1. Nuvalent Announces Key Program and Business Updates, Strengthening Foundation for Global Leadership in ROS1- and ALK-positive NSCLC. News release. Nuvalent Inc. May 27, 2026. Accessed May 27, 2026. https://tinyurl.com/x6fv7bxn

2. A Study of Neladalkib (NVL-655) in Patients With Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1). ClinicalTrials.gov. Updated May 27, 2026. Accessed May 27, 2026. https://clinicaltrials.gov/study/NCT05384626

3. Pan Y, Deng C, Qiu Z, et a;/ The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer. Front Oncol. 2021 Oct 1;11:713530. doi: 10.3389/fonc.2021.713530. PMID: 34660278; PMCID: PMC8517331.