Regulatory & Policy

Nuvalent's files with FDA for neladalkib in TKI pre-treated ALK-positive lung cancer

Nuvalent submitted a New Drug Application to the US FDA on April 7, 2026, for neladalkib, an investigational ALK-selective tyrosine kinase inhibitor,...

Edited by Robert McTiernan··3 min read

Nuvalent submitted a New Drug Application (NDA) to the US FDA on for neladalkib, an investigational ALK-selective tyrosine kinase inhibitor, seeking approval in patients with TKI pre-treated advanced ALK-positive non-small cell lung cancer. The filing marks the first NDA submission for neladalkib and represents Nuvalent's initial regulatory filing with the agency. The company said the submission was completed in under four years from first clinical trial initiation, a timeline the company highlighted alongside the drug’s breakthrough therapy designation, which the FDA granted for patients with locally advanced or metastatic ALK-positive NSCLC previously treated with two or more ALK TKIs. Neladalkib has also received orphan drug designation for ALK-positive NSCLC.

The NDA is an application for neladalkib in the TKI pre-treated advanced ALK-positive NSCLC population, the company said. The application draws on data from the ALKOVE-1 trial (NCT05384626), a global, first-in-human Phase I/II study enrolling patients with advanced ALK-positive NSCLC and other solid tumors. The Phase I portion evaluated safety, tolerability, pharmacokinetics, and established a recommended Phase II dose of 150 mg once daily. The Phase II portion is a global, single-arm, open-label study designed with registrational intent in TKI pre-treated patients with advanced ALK-positive NSCLC.

Topline pivotal data disclosed in November 2025 showed that neladalkib achieved an objective response rate (ORR) of 31% (95% CI: 26–37) in 253 TKI pre-treated patients treated at the recommended dose, as assessed by blinded independent central review. Responses were durable, with 64% and 53% of responders maintaining benefit at 12 and 18 months, respectively.

Subgroup analyses indicated higher response rates in select populations, including patients who were lorlatinib-naïve and those harboring ALK resistance mutations such as G1202R, where response rates reached 68%. Intracranial activity was also observed, with responses reported in patients with brain metastases, supporting the drug’s CNS-penetrant design.

Across the broader safety population treated at the recommended dose, adverse events were generally manageable, with dose reductions reported in 17% of patients and discontinuations in 5%. Nuvalent said detailed clinical results supporting the NDA will be presented at a future scientific meeting.

The AllSci BriefSystematic R&D and deal news. Daily.

The competitive context

The submission enters a treatment landscape shaped by six FDA-approved ALK inhibitors spanning three generations. Lorlatinib (Pfizer's Lorbrena/Lorviqua) is the only approved third-generation ALK TKI and holds a first-line indication approval for patients previously treated with at least one ALK TKI, but no FDA-approved ALK-targeted therapy is specifically indicated for patients who progress after lorlatinib. Chemotherapy is the standard recourse in that setting.

Neladalkib is designed to address this gap through a mechanism that distinguishes it from existing agents: it is engineered to retain activity against tumors carrying treatment-emergent ALK resistance mutations, including compound mutations such as G1202R, which emerge following sequential TKI use and are refractory to all currently approved ALK inhibitors. Lorlatinib itself can select for compound mutations upon progression, and these represent a recognized and clinically significant resistance mechanism with no approved targeted solution.

The drug's CNS penetrance is a second design feature relevant to the clinical context. Brain metastases occur in a substantial proportion of ALK-positive NSCLC patients over the course of disease, and intracranial progression remains a cause of treatment failure even with agents that have demonstrated systemic activity. Neladalkib's reported intracranial responses in the ALKOVE-1 population are therefore of clinical interest, though the magnitude and durability of those responses await formal data presentation.

A third distinguishing characteristic is the drug's selectivity: neladalkib is designed to avoid inhibition of the tropomyosin receptor kinase family, which shares structural similarity with ALK. Dual ALK/TRK inhibition, as seen with lorlatinib, is associated with CNS adverse events including cognitive effects and mood changes that can affect tolerability and dose continuity. A TRK-sparing profile may reduce this class of toxicity, though clinical confirmation is pending full data disclosure.

Spot something wrong? Report an issue with this article