Leptomeningeal metastatic disease (LMD) represents a devastating complication of non-small-cell lung cancer (NSCLC) with a poor prognosis. Our understanding of LMD is limited in the era of molecular testing and emerging therapeutic options for lung cancer. We conducted an international, multicenter, retrospective study involving eight institutions across Asia, United States, and Europe. Patients diagnosed with LMD from advanced NSCLC were identified (2007-2024). Clinicopathological characteristics, treatment patterns, and outcomes were analyzed. The primary endpoint was overall survival from the LMD diagnosis (LMOS). A total of 2052 patients with NSCLC and LMD were included and analyzed by molecular subtypes: epidermal growth factor receptor (EGFR) (n = 1610), ALK (n = 141), other actionable genomic alterations (other AGA; n = 137), and non-AGA (n = 164). The cumulative prevalence of LMD by molecular subgroups was EGFR, 11.1%; ALK, 11.2%; ROS1, 16%; ERBB2, 12.3%, non-AGA, 3.6%. A higher proportion of LMD was diagnosed >3 years after initial metastatic diagnosis. By the European Association of Neuro-Oncology (EANO)-European Society for Medical Oncology (ESMO) diagnostic criteria, type I (cerebrospinal fluid cytology positive) had significantly shorter LMOS than type II (magnetic resonance imaging and/or symptom positive). Median LMOS was 10.9 months [95% confidence interval (CI) 10.0-11.8 months] in all patients. Compared with historical cohorts, patients demonstrated improved LMOS in contemporary cohorts (7.3 versus 11.5 months, P < 0.0001), across all molecular subtypes. In AGA NSCLC, tyrosine kinase inhibitors (TKIs) were associated with improved LMOS [hazard ratio (HR) 0.39, 95% CI 0.31-0.48, P < 0.0001]. Immune checkpoint inhibitors (ICIs) conferred survival benefit in non-AGA patients (HR 0.45, 95% CI 0.25-0.84, P = 0.012). For the EGFR-mutated cohort, central nervous system (CNS)-penetrant TKI usage delayed LMD onset (P < 0.0001). Continued CNS-penetrant TKIs after LMD diagnosis were associated with longer LMOS (12.4 versus 6.0 months, P < 0.0001). The prevalence of LMD is rising, largely due to prolonged survival in advanced NSCLC. Contemporary systemic treatments, including TKIs and ICIs, were the main contributors to delayed LMD onset and improved LMD survival.

The incidence of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has increased substantially over the past three decades, and since 2017, it has been recognized in the AJCC staging system as distinct from its HPV-negative counterpart. The underlying mechanisms of HPV-associated carcinogenesis, tumor microenvironment, and host immune response represent opportunities for therapeutic development. While anti-PD-1 immunotherapy is now part of standard treatment for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) in general, there are no established immunotherapeutic strategies specifically for HPV-related HNSCC. In this context, multiple emerging approaches are being actively studied—among these are therapeutic vaccines with or without anti-PD-(L)1 adjuvants, peptide–HLA-based immunotherapeutic platforms, and adoptive cell therapies including tumor-infiltrating lymphocytes (TILs), T-cell receptor (TCR) therapy, and chimeric antigen receptor (CAR) T-cell therapy. Beyond further maturation of these novel immunotherapeutic strategies, additional work is needed to delineate the optimal disease state of application (localized versus recurrent/metastatic), as well as in the development of small molecule inhibitors targeting HPV-specific mechanisms of viral oncogenesis.

First-in-tumor case report of a treatment-refractory bronchial NET that developed TMZ-associated hypermutation responsive to immunotherapy