2 Clarke Drive
Suite 100
Cranbury, NJ 08512
© 2025 MJH Life Sciences™ and OncLive - Clinical Oncology News, Cancer Expert Insights. All rights reserved.
Neladalkib showed durable responses and good tolerability in ALK-positive solid tumors, including TKI-pretreated patients, in early ALKOVE-1 results.
Neladalkib (NVL-655) elicited durable responses and showcased favorable tolerability in patients with ALK-positive solid tumors, including those refractory to standard-of-care therapies, according to data from a preliminary analysis of the phase 1/2 ALKOVE-1 study (NCT05384626) shared during the 2025 ESMO Congress.1
In all patients (n = 34), the agent elicited an objective response rate (ORR) of 44% by investigator assessment and RECIST 1.1 criteria, with responses observed across several tumor types. Moreover, 9 of 13 patients who did not have prior exposure to an ALK TKI achieved a response, as did 6 of 21 patients who were pretreated with an ALK TKI. Overall, the median time to response (TTR) was 6.1 weeks (range, 5.4-12.3). Most patients (80%) remain on the drug without progressive disease.
“Durable responses observed in patients with ALK-positive solid tumors, including an intracranial complete response in a patient who previously received the brain-penetrant TKI, alectinib [Alecensa],” Benjamin Solomon, MBBS, PhD, of Peter MacCallum Cancer Centre, in Melbourne, Australia, and colleagues, wrote in a poster. “Neladalkib was generally well tolerated, with low rates of dose reduction [8.8%] and no discontinuations due to [treatment-related adverse effects (TRAEs)], and a preliminary overall safety profile consistent with avoiding TRK-related neurotoxicity.”
Neladalkib is designed to have activity against oncogenic ALK alterations, which comprise fusions such as EML4-ALK, activating point mutations like ALK F1174L and R1275Q, and partial deletions. It is also designed to be active against or prevent on-target resistance mutations like ALK G1202R single and compound mutations. The agent was also designed for use in brain metastases or primary brain tumors and to limit disease progression in the brain, as well as to limit neurologic toxicities.
Although ALK alterations represent oncogenic drivers in many tumors, ALK TKIs have only been approved for use in non–small cell lung cancer (NSCLC), anaplastic large cell lymphoma, and inflammatory myofibroblastic tumors (IMT). In preclinical models of NSCLC, cholangiocarcinoma, neuroblastoma, soft tissue sarcoma, and lymphoma, neladalkib has shown activity against a range of ALK fusions, activating point mutations, and resistance mutations. The preclinical evidence supported further exploration of the drug in ALK-positive solid tumors as a part of this trial.
The first-in-human, phase 1/2 study enrolled patients with advanced ALK-positive NSCLC and other solid tumors. To participate, patients were required to be at least 12 years of age, have ALK rearrangements or activating ALK mutations, and have evaluable or measurable disease per investigator assessment for the phase 1 or 2 portions, respectively. Those with concurrent oncogenic drivers were excluded.
In the phase 1 portion of the research, neladalkib was evaluated at doses ranging from 15 mg once daily to 200 mg once daily in a dose-escalation design in patients with advanced ALK-positive solid tumors. In the phase 2 portion, the agent was evaluated at the recommended phase 2 dose (RP2D) of 150 mg once daily in ALK-positive NSCLC cohorts and the other ALK-positive solid tumors cohort. The former cohorts explored the agent in those who were TKI naive and pretreated. The latter solid tumors cohort included patients who received at least 1 prior ALK TKI or systemic therapy, or for whom no satisfactory standard therapy was available; any previous chemotherapy or immunotherapy was permitted.
ORR by blinded independent central review served as the primary objective of the study, and secondary objectives comprised duration of response (DOR), time to response, clinical benefit rate, progression-free survival, overall survival, intracranial activity, safety and tolerability, confirmation of the pharmacokinetic profile, and patient-reported outcomes.
Previous data from the study were shared at the 2024 ESMO Congress and indicated that the agent elicited responses in patients with advanced ALK-positive NSCLC, including those with prior exposure to lorlatinib (Lorbrena).2 Across all doses (n = 103), the agent induced an ORR of 38%. Those who received the RP2D (n = 39) also experienced an ORR of 38%. For all doses, the median DOR was 14.4 months; 78% of patients experienced a response that lasted for at least 6 months. At the RP2D, the median DOR had not been reached, with responses continuing beyond 6 months.
As of June 7, 2025, a total of 34 patients with 14 different ALK-positive tumor types were enrolled and received a dose of neladalkib spanning both phases of the trial. Of these patients, 13 had no prior exposure to an ALK TKI, and 21 were ALK TKI pretreated. The most common tumor type was IMT (n = 10), followed by colorectal carcinoma (n = 4), pancreatic adenocarcinoma (n = 3), and sarcoma (n = 3).
In the total population, the median age was 53 years (range, 19-74), and 53% were female. Regarding ECOG performance status, 44% had a status of 0 and 56% had a status of 1. Almost one-third (29%) had a history of or current central nervous system metastases. The majority (97%) had ALK fusion partners, which included EML4-ALK for 32% of patients, STRN-ALK for 12% of patients, SPTBN1-ALK for 6% of patients, other for 26%, and unknown for 21%. ALK resistance mutations were observed in 12% of patients.
With regard to treatment history, patients received a median of 2 prior lines of anticancer treatment (range, 0-8). More than half of patients (62%) had previously received chemotherapy. Patients had received a median of 1 prior ALK TKI (range, 0-4) with or without chemotherapy; 38% had received 0, 35% had received 1; and 26% had received 2 or more. Moreover, 18% of patients had received a first-generation ALK TKI in the form of crizotinib (Xalkori); 47% had received a second-generation ALK TKI in the form of alectinib (41%), brigatinib (6%; Alunbrig), or ceritinib (6%; Zykadia); and 24% had received a third-generation ALK TKI.
The data cutoff date was August 7, 2025. Among the 15 patients who responded to neladalkib, 3 had colorectal cancer, 2 had pancreatic adenocarcinoma, 1 had sarcoma, 2 had peritoneal mesothelioma, 1 had neuroendocrine carcinoma of the lung, 1 had salivary duct carcinoma, 1 had small bowel adenocarcinoma, and 1 had renal cell carcinoma.
The agent was found to be well tolerated. The median duration of treatment was 5.3 months (range, 0.9-15.8). TRAEs led to dose reductions in 8.8% of patients and included grade 3 increased alanine (ALT) and aspartate (AST) aminotransferase levels (n = 2) and grade 1 hyperglycemia (n = 1). The 3 patients continued to receive the agent at the reduced dose. No grade 4 or 5 TRAEs were experienced, and no patients discontinued treatment due to these effects.
The TRAEs that occurred in more than 10% of patients included increased AST levels (any grade, 38%; grade 3, 15%), increased ALT levels (35%; 15%), dysgeusia (18%; 0%), and peripheral edema (15%; 0%).
Previously, in May 2024, the FDA granted breakthrough therapy designation to NVL-655 for use as a potential therapeutic option in patients with locally advanced or metastatic ALK-positive NSCLC who previously received 2 or more ALK TKIs.3 The decision was supported by prior data from the trial.2 As part of an OncLive® Rapid Readout, Alexander Drilon, MD, of Memorial Sloan Kettering Cancer Center (MSKCC), presented the ALKOVE-1 update and the significance of those prior data.4
In a past OncLive News Network, Gregory J. Riely, MD, PhD, also of MSKCC, and Benjamin Besse, MD, of Gustave Roussy, further spotlighted prior data with NVL-655 in ALK-positive NSCLC and other ALK-positive tumors.5 In a more recent OncLive Peer Exchange, a panel of experts unpacked how resistance mechanisms in ALK-positive disease are driving the development of next-generation inhibitors like NVL-655 that spare TRK to reduce neurocognitive toxicity while targeting compound resistance mutations.6
The safety and efficacy of neladalkib continues to be evaluated in patients with advanced or metastatic ALK-positive solid tumors as part of the ALKOVE-1 study.1 “Enrollment is ongoing,” the study authors concluded.