KEY TAKEAWAYS
- The ALKOVE-1 trial is set to evaluate the safety and preliminary activity of NVL-655 in patients with tumors that exhibit oncogenic ALK variations.
- The main objectives of Phase I are to establish the optimal dosage for Phase II and determine the maximum tolerable dosage.
- Secondary objectives include determining safety/tolerability, preliminary activity, and characterization of the pharmacokinetic and pharmacodynamic profiles of NVL-655.
The ALK oncogene abnormalities stimulate tumor cell proliferation, survival, and spread in various adult and pediatric cancers. Approximately 5% of advanced non-small cell lung cancers (NSCLC) exhibit ALK gene fusions, and of these patients (pts), nearly 40% show central nervous system (CNS) metastases at the initial diagnosis. Although five tyrosine kinase inhibitors (TKIs) have received FDA and EMA approval for treating ALK-positive NSCLC, challenges such as resistance stemming from specific ALK mutations and neurological side effects from unintentional TRK inhibition persist.
NVL-655 is a new TKI, optimized for brain penetration targeting ALK. Preclinical studies have demonstrated efficacy against various ALK alterations, including certain compound mutations, without affecting TRK. The ALKOVE-1 trial aimed to assess the safety and initial activity of NVL-655 in patients with solid tumors that exhibit oncogenic ALK changes, especially those who have developed resistance to ALK and have CNS metastases.
The structure of ALKOVE-1 is split into a phase I dose-increasing study and a phase II expansion based on tumor classification and previous treatments. Phase I enrolls adult pts who have any solid tumor type with oncogenic ALK gene fusion or an active mutation. This includes those with ALK fusion-positive NSCLC who have previously been treated with at least one 2nd or 3rd generation ALK TKI. Patients who have undergone prior platinum-based chemotherapy and/or immunotherapy, have CNS disease without worsening neurological symptoms or increased corticosteroid dosages, and have a disease that can be evaluated but not measured are also considered eligible.
Participants will be given NVL-655 orally on a daily basis. The main objectives of phase I are to identify the recommended dosage of NVL-655 for phase II and, if relevant, to establish the highest dosage that can be tolerated. Other goals involve assessing safety, initial efficacy, and understanding both the pharmacokinetics and pharmacodynamics of NVL-655.
There will also be a longitudinal analysis of circulating tumor DNA, focusing on ALK mutation profiling and other relevant biomarkers. Currently, the phase I segment of the study is in progress.
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT05384626
Johnson, M.L., Ou, S.I., Felip, E., Baik, C., Besse, B., Mazieres, J., Camidge, D.R., Gadgeel, S., Drilon, A., Elamin, Y.Y., Liu, G., Reuss, J., Kehrig, T., Pelish, H.E., Zhu, V., Lin, J.J. 81TiP – NVL-655, a selective anaplastic lymphoma kinase (ALK) inhibitor, in patients with advanced ALK-positive solid tumors: The phase I/II ALKOVE-1 study. Journal of Thoracic Oncology (2023) 18 (4S): S35-S88.
