Nuvalent’s Neladalkib Shows Durable Response in ALK-Positive Lung Cancer After TKI Therapy

Pivotal Data Reveal Durable Responses for Resistant ALK-Positive NSCLC

Nuvalent (NASDAQ: NUVL) reported new pivotal results from the ALKOVE-1 clinical trial for neladalkib, an investigational ALK-selective inhibitor. In patients with advanced ALK-positive non-small cell lung cancer (NSCLC) who had received previous tyrosine kinase inhibitor (TKI) treatments, neladalkib achieved a confirmed objective response rate (ORR) of 31%. Notably, responses were long-lasting, with 64% of patients maintaining benefit at 12 months and 53% at 18 months. These outcomes are significant, as most patients in the trial had already exhausted multiple therapies, including lorlatinib, and faced disease progression.

Greater Response Observed in Lorlatinib-Naïve Patients and Mutation-Driven Subsets

A deeper dive into trial subsets revealed enhanced benefit in patients who had not received lorlatinib. Among these 63 lorlatinib-naïve patients, ORR reached 46%, with 80% of responses maintained at 12 months. Results were even stronger for patients with the challenging ALK G1202R mutation—a known driver of drug resistance—where response rates climbed to 68% (prior ALK TKI exposure) and 83% (lorlatinib-naïve), and durability at one year ranged from 77% to 80%.

Consistent Intracranial Activity Offers Hope for CNS Involvement

Central nervous system (CNS) metastases remain a critical concern for advanced ALK-positive NSCLC. Neladalkib demonstrated meaningful activity against brain lesions: 32% of TKI pre-treated patients and 63% of lorlatinib-naïve patients with measurable CNS disease saw intracranial responses, with most maintaining response for over a year.

Preliminary Results Show Even Stronger Efficacy in TKI-Naïve Patients

Exploratory data for TKI-naïve patients—a group with less pre-treatment—were striking: the ORR reached 86%, with most responses lasting beyond 12 months and 78% of patients with CNS lesions seeing an intracranial response. These results are especially noteworthy as enrollment continues in Nuvalent’s ALKAZAR Phase 3 head-to-head trial versus alectinib.

Favorable Safety Profile and Regulatory Progress Ahead

Across 656 advanced ALK-positive NSCLC patients treated at the recommended phase 2 dose, neladalkib was generally well-tolerated. Only 5% of patients discontinued due to adverse events and 17% required dose reduction, mostly for asymptomatic and manageable lab abnormalities. This safety, coupled with the high rate of durable responses, underlines the drug’s potential to address current gaps in ALK-positive lung cancer care.

What Comes Next for Nuvalent?

Nuvalent plans to meet with the FDA to discuss the path to regulatory submission and present detailed study results at upcoming medical conferences. As the company advances neladalkib, these results set the stage for potential approval in a population with limited options and persistent resistance. For patients, the prospect of durable, brain-penetrant responses may mark an important shift in the treatment landscape.

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