Nuvalent Publishes Cancer Discovery Study on ALK-selective Inhibitor NVL-655

Nuvalent, Inc., a clinical-stage biopharmaceutical company specializing in targeted cancer therapies, recently published a manuscript in the journal Cancer Discovery. The manuscript discusses the design, characterization, and clinical potential of NVL-655, a novel inhibitor aimed at treating advanced ALK-positive non-small cell lung cancer (NSCLC) and other solid tumors. NVL-655 is currently under investigation in the ALKOVE-1 Phase 1/2 clinical trial.

The manuscript titled "NVL-655 is a selective and brain-penetrant inhibitor of diverse ALK mutant oncoproteins, including lorlatinib-resistant compound mutations," elaborates on the scientific rationale behind NVL-655. According to Dr. Alexander Drilon, Chief of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center and an investigator in the ALKOVE-1 trial, current ALK tyrosine kinase inhibitors (TKIs) face several limitations such as drug resistance, neurological adverse events, and insufficient control of brain metastases. NVL-655 is designed to address these issues by offering enhanced selectivity and brain penetrance.

The manuscript further elucidates the molecular design principles that make NVL-655 effective against ALK single and compound resistance mutations, including the prevalent ALK G1202R mutation. It also explains the drug's selectivity for ALK over the tropomyosin receptor kinase (TRK) family, whose inhibition often results in limiting neurological side effects.

In preclinical studies, NVL-655 demonstrated significant activity and selectivity. These studies included in vivo xenograft models, assessments of brain penetrance, intracranial activity, and comparisons of NVL-655 with eight other ALK TKIs across various biochemical and cellular assays.

Moreover, the manuscript presents three preliminary clinical case studies from the ALKOVE-1 trial. These cases involve patients with ALK fusion-positive lung cancers who had previously been treated with multiple ALK TKIs, including lorlatinib, and presented with brain metastases or tumors harboring ALK G1202R mutations. NVL-655 showed tumor responses in these patients without causing central nervous system (CNS) side effects typically associated with TRK inhibition. These findings suggest that NVL-655 could be a promising future treatment, potentially improving tolerability and efficacy for patients with ALK-positive NSCLC.

Joshua Horan, Ph.D., Vice President of Chemistry at Nuvalent, emphasized the importance of this publication in advancing their focused strategy for treating ALK-positive NSCLC. He noted that NVL-655, along with another lead program for ROS1-positive NSCLC, forms the cornerstone of Nuvalent's pipeline aimed at developing highly selective and effective cancer therapies.

The ALKOVE-1 Phase 1/2 clinical trial is ongoing, with the Phase 2 portion currently enrolling patients globally. Updated data from the Phase 1 segment of the trial will be presented at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain.

NVL-655, designed to overcome the limitations of existing ALK inhibitors, aims to remain effective in tumors resistant to first-, second-, and third-generation ALK inhibitors. It is formulated to penetrate the CNS, making it a potential treatment option for patients with brain metastases. NVL-655 has received breakthrough therapy designation for treating locally advanced or metastatic ALK-positive NSCLC in patients who have been treated with two or more ALK TKIs. It also holds orphan drug designation for ALK-positive NSCLC.

Nuvalent, Inc., aims to develop innovative small molecules that address resistance, minimize adverse events, and provide durable responses. Their pipeline includes investigational candidates for ROS1-positive, ALK-positive, and HER2-altered non-small cell lung cancer. The company leverages deep expertise in chemistry and structure-based drug design to overcome multiple challenges in cancer treatment.