Non-Small Cell Lung Cancer (NSCLC) in Vulnerable and Special Populations: Towards Personalized Care.

Non-small cell lung cancer (NSCLC) encompasses a heterogeneous patient population whose clinical needs, biological features, and treatment outcomes differ substantially from those represented in pivotal studies. Adolescents and young adults (AYA), women, pregnant patients, individuals with actionable genomic alterations (AGAs) or constitutional pathogenic variants (CPVs), immunocompromised patients, including those with chronic viral infections, older adults, patients with brain metastases, and survivors with second primary lung cancers (SPLC) remain consistently underrepresented in research programs. This limits the generalizability of current evidence and challenges the delivery of equitable precision oncology. Across these populations, distinct disease biology, differential genomic landscapes, sex- and age-related variations in pharmacology, and complex psychosocial or ethical considerations shape clinical decision-making. Advances in molecular testing and targeted therapies have improved outcomes for some subgroups, yet persistent disparities in diagnostic access, trial eligibility, and supportive care remain major barriers. In parallel, modern systemic agents including brain-penetrant targeted therapies, immunotherapy combinations, and antibody-drug conjugates have broadened therapeutic options, although their safety, effectiveness, and long-term consequences require dedicated evaluation in underrepresented populations. This review synthesizes contemporary evidence from these special NSCLC populations, highlighting shared challenges and unique considerations. We discuss implications for clinical practice, supportive care, survivorship, and research design, and outline opportunities to strengthen inclusivity in precision oncology. Addressing longstanding gaps in representation, trial methodology, and structural inequities is essential to ensure that recent therapeutic advances translate into improved outcomes for the full spectrum of patients living with NSCLC.