An NDA for neladalkib in TKI-pretreated, advanced, ALK-positive NSCLC was submitted to the FDA.
A new drug application (NDA) seeking the approval of the investigational ALK-selective inhibitor neladalkib (NVL-655) in patients with TKI-pretreated, advanced, ALK-positive non–small cell lung cancer (NSCLC) has been submitted to the FDA.1
The NDA is supported by findings from the phase 1/2 ALKOVE-1 trial (NCT05384626). Topline data from ALKOVE-1 shared in November 2025 revealed that patients who received neladalkib after any prior ALK TKI with/without chemotherapy (n = 253) achieved an overall response rate (ORR) of 31% (95% CI, 26%-37%). The ORR among TKI-pretreated, lorlatinib (Lorbena)–naive patients (n = 63) was 46% (95% CI, 33%-59%). The 18-month duration of response (DOR) rates were 53% (95% CI, 34%-68%) and 60% (95% CI, 19%-85%), respectively.
"The advancement of neladalkib from first clinical trial initiation to NDA submission in less than four years represents a remarkable pace in oncology drug development, underscoring the vigor and urgency our team brought to this program and our deep commitment to the ALK-positive NSCLC community," Darlene Noci, ALM, chief development officer at Nuvalent, stated in a news release. "We would like to extend our sincere gratitude to the patients, families, and investigators who have made this progress possible, and are committed to working closely with the FDA throughout the NDA review process toward our goal of bringing neladalkib to patients as quickly as possible."
ALKOVE-1 was a first-in-human, dose escalation and expansion study that enrolled patients with advanced ALK-positive NSCLC and other solid tumors.4 Patients needed to be at least 18 years old, except in cohort 2f (age ≥ 12 years and weighing > 40 kg), have measurable disease according to RECIST 1.1 criteria, and have adequate organ and bone marrow function.
Patients were enrolled onto the following 6 cohorts:
Neladalkib was administered orally. The primary end points in the phase 1 portion were the incidence of dose-limiting toxicities, determining the recommended phase 2 dose (RP2D), and safety. The primary end point in phase 2 was ORR per blinded independent central review. Secondary end points included pharmacokinetic measures, DOR, clinical benefit rates, time to response, progression-free survival, overall survival, and quality of life.
Patients with disease harboring G1202R mutations who received any prior ALK TKI with/without chemotherapy (n = 47) experienced an ORR of 68% (95% CI, 53%-81%) and an 18-month DOR rate of 70% (95% CI, 42%-86%).2 The ORR and 18-month DOR rate were 83% (95% CI, 52%-98%) and 77% (95% CI, 34%-94%), respectively, among patients with G1202R mutations who were TKI-pretreated and lorlatinib-naive (n = 12).
Among patients with measurable central nervous system lesions who received any prior ALK TKI with/without chemotherapy (n = 92), the intracranial ORR (IC-ORR) rate was 32% (95% CI, 22%-42%) and the 18-month intracranial DOR (IC-DOR) rate was 71% (95% CI, 48%-85%). Those who were TKI-pretreated and lorlatinib-naive (n = 24) achieved an IC-ORR of 63% (95% CI, 41%-81%) and the 18-month IC-DOR rate was 92% (95% CI, 57%-99%).
In terms of safety, neladalkib was generally well-tolerated. The median duration of exposure among patients with advanced ALK-positive NSCLC who received the RP2D (n = 656) was 6.0 months (range, 0.1-28.4). The most common any-grade treatment-emergent adverse effects (TEAEs) that were reported in at least 15% of patients included increased alanine aminotransferase levels (47%), increased aspartate aminotransferase levels (44%), constipation (28%), dysgeusia (23%), peripheral edema (18%), cough (16%), and nausea (16%). Dose reductions and discontinuations due to TEAEs occurred at respective rates of 17% and 5%.
Nuvalent, the developer of neladalkib, plans to share detailed results from ALKOVE-1 at a future medical meeting.1
