Advances in Pharmacological Treatment of Thoracic Malignancies

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Abstract
Lung cancer remains the leading cause of cancer-related death worldwide, with over two million new cases annually. Advances in molecular biology and immuno-oncology have fundamentally transformed treatment strategies. Comprehensive genomic profiling has enabled precision medicine approaches, allowing the selection of targeted therapies based on driver alterations such as EGFR, ALK, and HER2. For EGFR-mutant NSCLC, sequential development of tyrosine kinase inhibitors (TKIs) from first- to third-generation agents―culminating in osimertinib―has markedly improved survival. Similarly, successive generations of ALK inhibitors, including alectinib, brigatinib, and lorlatinib, have extended disease control, particularly within the central nervous system. The introduction of antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan for HER2-mutant NSCLC, and emerging TKIs like zongertinib, represent new therapeutic milestones. Immunotherapy has become central to the management of both NSCLC and SCLC, with immune checkpoint inhibitors (ICIs) demonstrating unprecedented survival benefits. Beyond lung cancer, our group, in collaboration with Juntendo University ARO (academic research organization) and fifteen institutions in Japan, conducted the MARBLE phase II trial of atezolizumab plus chemotherapy for thymic carcinoma, achieving a 56% objective response rate and 9.6-month median progression-free survival, supporting potential ICI approval in Japan. Furthermore, novel immune strategies such as bispecific T-cell engagers (BiTEs) have shown promise. The DLL3-targeted BiTE tarlatamab significantly improved overall survival to 13.6 months in the phase III DeLLphi-304 trial for relapsed SCLC, with manageable cytokine release syndrome. Collectively, these advances signify a shift toward biologically driven, molecular-targeted or immune-integrated therapy, aiming to transform lung cancer into a chronic, manageable disease in the future, hopefully.

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