The FDA priority review of neladalkib for TKI-pretreated ALK-positive NSCLC is supported by data from the phase 1/2 ALKOVE-1 trial.
The FDA has accepted a new drug application (NDA) seeking the approval of neladalkib (NVL-655), an investigational ALK-selective inhibitor, for patients with tyrosine kinase inhibitor (TKI)–pretreated advanced ALK-positive non–small cell lung cancer (NSCLC).1
The agency granted the application priority review and set a Prescription Drug User Fee Act target action date of November 27, 2026. The submission is based on data from TKI-pretreated patients enrolled in the global, registration-directed phase 1/2 ALKOVE-1 trial (NCT05384626). Top-line data from the study revealed that ALK TKI–pretreated patients who received neladalkib (n = 253) achieved an overall response rate (ORR) per blinded independent central review (BICR) of 31% (95% CI, 26%-37%).2 The estimated 12- and 18-month duration of response (DOR) rates were 64% (95% CI, 51%-75%) and 53% (95% CI, 34%-68%), respectively. Additional data from ALKOVE-1, including preliminary data for TKI-naive patients, will be presented during the
“With today’s announcement, NDAs for both zidesamtinib [NVL-520] and neladalkib in TKI -pretreated populations are now under review with the FDA, and TKI-naive expansion strategies are under way,” James Porter, PhD, chief executive officer of Nuvalent, stated in a news release. “Our US commercial and medical affairs teams are in place and focused on establishing the strong foundational systems and infrastructure required to effectively deliver on multiple synergistic launches in biomarker-driven NSCLC.”
ALKOVE-1 was a first-in-human trial evaluating neladalkib in patients with advanced ALK-positive NSCLC and other ALK-positive solid tumors.2,3 Other notable inclusion criteria included having measurable disease per RECIST 1.1 criteria, as well as adequate organ function and bone marrow reserve.3 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 the phase 2 portion was ORR per BICR. Secondary end points included DOR, clinical benefit rate, time to response, progression-free survival, overall survival, quality of life, safety, and pharmacokinetic measures.
Further top-line efficacy data revealed that TKI-pretreated, lorlatinib (Lorbrena)-naive patients who received neladalkib (n = 63) experienced an ORR per BICR of 46% (95% CI, 33%-59%); the estimated 12- and 18-month DOR rates were 80% (95% CI, 58%-91%) and 60% (95% CI, 19%-85%), respectively.2 Among patients with disease harboring ALK G1202R mutations who had received a prior ALK TKI with or without chemotherapy (n = 47) or were TKI-pretreated and lorlatinib-naive (n = 12), the respective ORRs were 68% (95% CI, 53%-81%) and 83% (95% CI, 52%-98%).
In terms of safety, neladalkib had a generally well-tolerated safety profile consistent with its ALK-selective, TRK-sparing design. The most frequent treatment-emergent adverse effects (TEAEs) in patients with ALK-positive NSCLC who were treated at the RP2D (n = 656) 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 due to TEAEs were reported in 17% of patients, and 5% of patients discontinued treatment due to TEAEs.
“Nuvalent presents a unique near-term opportunity to advance multiple potential best-in-class product candidates for patients with cancer, backed by robust clinical experience demonstrating clear global medical need and enthusiasm,” Georg Pirmin Meyer, MD, the newly appointed chief international officer of Nuvalent, added in the news release.1 “I am excited to join at this pivotal moment and to partner with the team to realize our shared vision of global leadership in ROS1- and ALK-positive NSCLC.”
