Three generations of tyrosine kinase inhibitors (TKI) have been approved for anaplastic lymphoma kinase (ALK) fusion–positive non–small cell lung cancer. However, none address the combined need for broad resistance coverage, brain activity, and avoidance of clinically dose-limiting TRK inhibition. NVL-655 is a rationally designed TKI with >50-fold selectivity for ALK over 96% of the kinome tested. In vitro, NVL-655 inhibits diverse ALK fusions, activating alterations, and resistance mutations, showing ≥100-fold improved potency against ALKG1202R single and compound mutations over approved ALK TKIs. In vivo, it induces regression across 12 tumor models, including intracranial and patient-derived xenografts. NVL-655 inhibits ALK over TRK with 22-fold to >874-fold selectivity. These preclinical findings are supported by three case studies from an ongoing first-in-human phase I/II trial of NVL-655 which demonstrate preliminary proof-of-concept clinical activity in heavily pretreated patients with ALK fusion–positive non–small cell lung cancer, including in patients with brain metastases and single or compound ALK resistance mutations. Significance: By combining broad activity against single and compound ALK resistance mutations, brain penetrance, and selectivity, NVL-655 addresses key limitations of currently approved ALK inhibitors and has the potential to represent a distinct advancement as a fourth-generation inhibitor for patients with ALK-driven cancers.

Von Hippel–Lindau (VHL) loss is the hallmark event characterizing the clear cell renal cancer subtype (ccRCC). Carriers of germinal VHL mutations have an increased prevalence of kidney cysts and ccRCC as well as hemangioblastoma, pheochromocytoma and pancreatic neuroendocrine tumors. In both sporadic and inherited ccRCC, the primary mechanism of VHL-mediated carcinogenesis is the abnormal stabilization of hypoxia-inducible factors (HIF1A and HIF2A). While HIF1A acts as a tumor suppressor and is frequently lost through inactivating mutations/14q chromosome deletions, HIF2A acts as an oncogene promoting the expression of its target genes (VEGF, PDGF, CAIX Oct4, among others). Selective HIF2a inhibitors block the heterodimerization between HIF2A and ARNT, stopping HIF2A-induced transcription. Several HIF2A inhibitors have entered clinical trials, where they have shown a favorable toxicity profile, characterized by anemia, fatigue and edema and promising activity in heavily pretreated ccRCC patients. Belzutifan, a second-generation HIF2a inhibitor, was the first to receive FDA approval for the treatment of unresectable ccRCC in VHL syndrome. In this review, we recapitulate the rationale for HIF2a blockade in ccRCC, summarize the development of HIF2a inhibitors from preclinical models up to its introduction to the clinic with emphasis on Belzutifan, and discuss their role in VHL disease management.

Pleural mesothelioma (PM) is a locally aggressive tumor associated with asbestos exposure. Despite legislative efforts to regulate asbestos use, its incidence continues to rise in some parts of the world. Chemotherapy and immunotherapy have improved survival in PM patients, but overall survival remains poor. Molecular analysis of PM patients has shown that most alterations occur in tumor suppressor genes, with BAP1 being the most frequently affected. Patients with germline BAP1 mutations have been reported to have a better prognosis, but this is not observed in those with somatic mutations. Interest in developing drugs targeting patients with BAP1 loss has led to several phase II studies in recent years. Unfortunately, initial results have not been very promising. In this review, we conclude that, at this time, with the contradictory results from studies and the limited number of patients evaluated, BAP1, the most commonly altered gene in PM, is not yet suitable for use in clinical practice as a prognostic or predictive factor. Future studies are needed to establish the prognostic or predictive value of BAP1.

Introduction: Colorectal cancer (CRC) is a major public health problem. Despite major progress understanding the biological basis of this tumor added to the incorporation of optimized diagnostic and therapeutic strategies, prognosis after progression on first-line standard treatment remains poor. Several antiangiogenic treatments have demonstrated improvement in overall survival (OS) in the second-line treatment being aflibercept, a fully humanized recombinant protein, one of them. The results of the VELOUR study showed that the addition of aflibercept to second-line FOLFIRI improved OS and progression-free survival (PFS). Areas covered: A literature review of published clinical studies was performed in order to discuss the clinical data on aflibercept in mCRC from early drug development to real-world data. Expert Opinion: The combination of aflibercept with FOLFIRI provides a statistical improvement in OS and in all the efficacy endpoints analysed in the VELOUR trial, showing efficacy independently on time to progression, molecular status, prior biological treatment, or age. Further studies are needed to find new biomarkers and molecular characterization in order to better select patients that could benefit from this treatment.

Oligometastatic non-small-cell lung cancer (OMD-NSCLC) has emerged as a biologically and clinically distinct subtype of advanced disease, characterized by limited metastatic burden and a more indolent course. In this narrative review, we examine the current definition of OMD-NSCLC, diagnostic tests, possible biomarkers, and current therapeutic strategies. Biological insights highlight the role of microRNAs in differentiating true oligometastatic state from polymetastatic disease. The main local ablative therapies (LAT) include surgery and radiotherapy. The integration of LAT with systemic therapies has been explored in clinical trials, yielding promising but occasionally inconsistent results. As the therapeutic landscape of OMD-NSCLC patients continues to evolve, refining definitions, identifying predictive biomarkers, and individualizing care are essential steps toward achieving the potential of radical-intent therapy.

Supplementary Figure S1. Chemistry/X-ray. Supplementary Figure S2. Biochemical activity of ALK TKIs. Supplementary Figure S3. Kinome profiling of NVL-655. Supplementary Figure S4. Potency in cell viability assay. Supplementary Figure S5. Maximal effect (Emax) in cell viability assay. Supplementary Figure S6. Cellular activity of NVL-655. Supplementary Figure S7. Comparing NVL-655 and lorlatinib potency. Supplementary Figure S8. Pathway analysis in cell lines. Supplementary Figure S9. Further evidence for on-target activity of NVL-655. Supplementary Figure S10. TRK activity. Supplementary Figure S11. Selectivity for ALK versus TRK using additional assays. Supplementary Figure S12. In vivo studies for ALK fusion with a wild-type kinase domain. Supplementary Figure S13. In vivo studies for ALK fusion with G1202R or I1171N single mutations. Supplementary Figure S14. In vivo studies for ALK fusion with G1202R compound mutations. Supplementary Figure S15. Pharmacodynamic analysis in G1202R compound mutation models. Supplementary Figure S16. Body weight and H&E staining for the YU-1077 intracranial study. Supplementary Figure S17. Estimating TRKB inhibition in humans and mice.