Neladalkib Shows Durable Responses in Heavily Pretreated ALK-Positive Lung Cancer

Topline data from the ALKOVE-1 phase 1/2 clinical trial (NCT05384626) demonstrate neladalkib’s (NVL-655; Nuvalent) promise for treatment of patients with advanced ALK-positive non-small cell lung cancer (NSCLC) previously treated with tyrosine kinase inhibitors (TKI). The data showed an objective response rate (ORR) of 31% (95% CI: 26, 37), with an estimated durability of response of 64% and 53% at 12 and 18-months, respectively.^1,2

ALK fusions are detected in approximately 1% to 4% of lung cancers, most often in adenocarcinomas. Although less common than other genetic alterations, they present a significant treatment challenge for affected patients.³

Neladalkib is a next-generation, brain-penetrant ALK inhibitor developed to address key shortcomings of the current ALK-targeted therapies. Its design allows it to stay effective even when tumors acquire resistance to earlier ALK inhibitor classes—including first-, second-, and third-generation agents—and it has shown activity against a range of treatment-emergent ALK mutations, such as the difficult-to-treat G1202R substitution.²

The drug is engineered to cross the blood–brain barrier while avoiding activity against the closely related TRK receptor family. By bypassing TRK inhibition, neladalkib aims to reduce the CNS toxicities that have been associated with dual ALK/TRK inhibitors, while still enabling robust and lasting tumor control across multiple treatment settings.²

The ALKOVE-1 study is a global, open-label phase 1/2 trial evaluating neladalkib in patients with advanced ALK-positive NSCLC who had previously received ALK tyrosine kinase inhibitors (TKIs). Phase 1 established the recommended phase 2 dose of 150 mg once daily.²

Phase 2 included a pivotal, single-arm cohort of 253 patients who were heavily pretreated—a median of 3 prior lines of therapy, with 78% receiving 2 or more prior ALK TKIs and many previously treated with lorlatinib. The population also included patients with chemotherapy exposure, those with baseline brain metastases, and individuals with treatment-emergent ALK mutations such as G1202R.²

In this cohort, neladalkib achieved an ORR) of 31% with responses that appeared durable; an estimated 64% of responders maintained benefit for at least 12 months and 53% for at least 18 months. Outcomes were stronger in the subset of lorlatinib-naïve patients, who demonstrated a 46% ORR and an estimated 80% 12-month durability.

Neladalkib also demonstrated meaningful intracranial activity: among patients with measurable central nervous system (CNS) disease, intracranial ORR was 32%, rising to 63% in lorlatinib-naïve patients. Activity was particularly notable in patients with the difficult-to-treat ALK G1202R mutation, who achieved a 68% ORR.²

Across 656 patients treated at the recommended dose, neladalkib showed a manageable safety profile characterized primarily by laboratory abnormalities such as elevated ALT and AST, as well as gastrointestinal and constitutional symptoms including constipation, dysgeusia, peripheral edema, cough, and nausea.²

Dose reductions occurred in 17% of patients, and treatment discontinuations were uncommon at 5%. Overall, the results suggest neladalkib delivers clinically meaningful systemic and intracranial efficacy, including in patients with highly resistant disease biology, while maintaining tolerability consistent with its ALK-selective, TRK-sparing design.²

"In treating ALK-positive lung cancer, our goal is not only to help patients live longer, but also to help them live well with their disease," said Alice T. Shaw, MD, PhD, a thoracic oncologist at Dana-Farber Cancer Institute and ALKOVE-1 trial investigator, in a press release. "These encouraging topline data suggest that neladalkib may represent a new and differentiated treatment option for ALK positive lung cancer, offering durable clinical benefit while potentially reducing the risk of side effects that can affect quality of life."²

REFERENCES

1. 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 October 30, 2025. Accessed November 17, 2025. https://clinicaltrials.gov/study/NCT05384626

2. Nuvalent announces positive topline pivotal data from ALKOVE-1 clinical trial of neladalkib for TKI pre-treated patients with advanced ALK-positive NSCLC. Nuvalent. November 17, 2025. Accessed November 17, 2025. https://investors.nuvalent.com/2025-11-17-Nuvalent-Announces-Positive-Topline-Pivotal-Data-from-ALKOVE-1-Clinical-Trial-of-Neladalkib-for-TKI-Pre-treated-Patients-with-Advanced-ALK-positive-NSCLC

3. Gerlach A. Navigating EGFR mutations and ALK Fusions in early-stage non-small cell lung cancer. Pharmacy Times. June 19, 2025. Accessed November 17, 2025. https://www.pharmacytimes.com/view/navigating-egfr-mutations-and-alk-fusions-in-early-stage-non-small-cell-lung-cancer