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

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Conference Proceeding

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J Thorac Oncol


Background: Aberrations of the ALK oncogene drive tumor cell proliferation, survival, and metastasis in multiple adult and pediatric cancers. ALK gene fusions are detected in ~5% of advanced non-small cell lung cancers (NSCLC); among these patients, the incidence of central nervous system (CNS) metastases at diagnosis is ~40%. Although 5 tyrosine kinase inhibitors (TKIs) are approved by the FDA and EMA for ALK-positive NSCLC, therapeutic limitations remain, such as acquired resistance due to secondary and compound ALK mutations and/or neurologic adverse events attributed to off-target inhibition of TRK. NVL-655 is a novel, brain-penetrant ALK-selective TKI that exhibits preclinical activity against diverse ALK fusions and mutations, including G1202R and G1202R compound mutations, while sparing inhibition of TRK. The ALKOVE-1 study is evaluating the safety and preliminary activity of NVL-655 in patients with solid tumors harboring oncogenic ALK alterations, including those with acquired ALK resistance mutations and CNS metastases. Trial design ALKOVE-1 consists of a phase I dose escalation followed by a phase II expansion in cohorts defined by tumor type and prior therapies. Phase I includes adult patients with any solid tumor type harboring an oncogenic ALK gene fusion or activating mutation (by local testing), including ALK fusion-positive NSCLC after ≥ 1 prior 2nd or 3rd generation ALK TKI. Prior platinum-based chemotherapy and/or immunotherapy, CNS disease without progressive neurological symptoms or increasing corticosteroid doses, and evaluable but non-measurable disease are allowed. Patients will receive NVL-655 by daily oral administration. Primary phase I objectives are to determine the NVL-655 recommended phase II dose and, if applicable, maximum tolerated dose. Additional objectives include evaluation of safety/ tolerability, preliminary activity, and characterization of the pharmacokinetic and pharmacodynamic profiles of NVL-655. Longitudinal analysis of circulating tumor DNA will be performed, including ALK mutation profiling and other relevant biomarkers. The phase I portion of the study is ongoing. Clinical trial identification NCT05384626 (May 20, 2022).





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