Nuvalent announces publication on design, characterization of NVL-655

Nuvalent announced the publication of a manuscript in Cancer Discovery, a journal of the American Association for Cancer Research, which describes the design and characterization of NVL-655 and details Nuvalent’s approach to rationally targeting ALK. NVL-655 is currently being studied in the ongoing ALKOVE-1 Phase 1/2 clinical trial for patients with advanced ALK-positive non-small cell lung cancer and other solid tumors. The manuscript, entitled “NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK mutant oncoproteins, including lorlatinib-resistant compound mutations,” is published online. The manuscript details the design principles underlying the activity of NVL-655 against ALK single and compound resistance mutations, including the most commonly occurring resistance mutation, ALK G1202R. Additionally, it outlines a molecular rationale for the selectivity of NVL-655 for ALK over the structurally related tropomyosin receptor kinase family, whose inhibition has been associated with neurological adverse events that can be dose limiting. Preclinical characterization of the activity and selectivity of NVL-655 is presented, including in vivo xenograft studies, preclinical assessments of brain penetrance and intracranial activity, and a comparison of eight ALK TKIs across multiple biochemical and cellular assays. The manuscript further documents three case studies from the ALKOVE-1 trial of patients with ALK fusion-positive lung cancers who had received a range of ALK TKIs, including lorlatinib, and presented with brain metastases or with tumors that harbored ALK G1202R. NVL-655 elicited tumor responses in these patients without accompanying CNS effects attributed to off-target TRK inhibition. These findings support the potential for NVL-655 as a future treatment for these patient populations that may also enhance tolerability through improved selectivity for ALK. Enrollment is ongoing in the global Phase 2 portion of the ALKOVE-1 Phase 1/2 clinical trial, designed with registrational intent. Updated data from the Phase 1 portion of the trial will be presented at the European Society for Medical Oncology Congress 2024 in Barcelona, Spain.