Dr Camidge on the Efficacy and Safety of Neladalkib in ALK+ Solid Tumors

“Neladalkib isn’t a panacea in other solid tumors driven by ALK when they’ve seen other ALK TKIs, any more than it is in lung cancer in that same setting, because a proportion of patients will develop second drivers, or they’ll develop histological transformation, and this drug won’t work.”

D. Ross Camidge, MD, PhD, director of the Thoracic Oncology Clinical and Clinical Research Programs at the University of Colorado Health Lung Cancer Clinic and the University of Colorado Cancer Center; as well as a professor of medicine in the University of Colorado Anschutz School of Medicine, discussed key insights gleaned from the phase 1/2 ALKOVE-1 trial (NCT05384626) of neladalkib (NVL-655) in patients with ALK-positive solid tumors.

Neladalkib is a novel fourth-generation ALK inhibitor. This agent is characterized by its activity against most on-target resistance mutations and certain compound mutations within the ALK pathway, Camidge began. A clinically significant attribute of neladalkib is its capacity for central nervous system penetration, he said. Furthermore, this agent is associated with fewer neurocognitive and other adverse effects (AEs) typically associated with NTRK inhibition and often observed with agents such as lorlatinib (Lorbrena) and other drugs in the ALK/ROS1 class, he contextualized.

ALK is a molecular driver of disease across diverse oncological histologies beyond non–small cell lung cancer (NSCLC), Camidge stated. Therefore, ALKOVE-1 enrolled patients with ALK-positive solid tumors, excluding those with NSCLC. Eligibility criteria permitted the enrollment of patients who were ALK TKI naive, as well as those who had prior exposure to ALK TKIs.

The patient population encompassed a wide spectrum of tumor types, including inflammatory myofibroblastic tumors, where ALK is a recognized driver, alongside rarer subsets such as colorectal adenocarcinoma, pancreatic adenocarcinoma, various sarcomas, peritoneal mesothelioma, small bowel adenocarcinoma, renal cell carcinoma, cholangiocarcinoma, medullary glioma, and clear cell odontogenic carcinoma. Unlike in NSCLC, where the EML4-ALK fusion dominates, these non-NSCLC histologies demonstrated a higher proportion of ALK fused with alternative driver genes, according to Camidge. This phenomenon is hypothesized to occur because the fusion event brings in a regulatory sequence of a gene that is actively expressed in the tissue and coupled to the ALK gene, he explained.

Neladalkib was generally considered well tolerated, Camidge expressed. The reported AEs included transaminitis, disturbances in cardiac pacing, and peripheral edema. Notably, treatment with the agent was differentiated by the absence of NTRK-related AEs, he emphasized.

The efficacy data, though preliminary in some cohorts, demonstrated clear therapeutic activity of the agent, Camidge reported. In the ALK TKI–naive patients who were evaluable for response (n=13), the overall response rate was 69.2%, a predictable outcome when targeting a primary oncogenic driver, he stated. Efficacy outcomes in the ALK TKI–pretreated cohort (n = 21) were heterogeneous, he noted. A critical finding was the strong correlation between clinical response and the presence of on-target ALK mutations, including compound mutations, he added.

The overall clinical implication of these data is that although neladalkib is effective, it may not be the optimal treatment for all patients, Camidge summarized. Additionally, a proportion of patients will experience disease progression due to the emergence of secondary drivers or histological transformation, he noted. Therefore, upfront tumor biopsy and molecular profiling may pre-emptively identify nonresponders, he concluded.