Background: Accurately predicting treatment outcomes in patients with advanced non-small cell lung cancer (NSCLC) remains a significant clinical challenge. While circulating tumor DNA (ctDNA) within plasma cell-free DNA (cfDNA) has emerged as a promising non-invasive biomarker, conventional targeted sequencing approaches require prior tumor genetic profiling and may miss the full spectrum of tumor-associated alterations. Low-coverage whole-genome sequencing (lcWGS) offers a cost-effective and unbiased alternative that enables genome-wide detection of copy number alterations (CNAs) and fragmentation-based features without prior tumor genotyping. In this pilot prospective study, plasma cfDNA was collected from 33 patients with advanced NSCLC receiving either EGFR tyrosine kinase inhibitors (EGFR-TKIs) or chemotherapy at diagnosis, and during treatment at week 4, and week 12, as well as from 10 healthy controls. This cfDNA was subjected to lcWGS to explore the potential of ctDNA fraction, CNAs, short-to-long fragment ratio, and ctDNA estimation score (CES) as candidate predictors of treatment response and progression-free survival (PFS). Results: In this small cohort, patients with progressive disease tended to maintain persistently elevated cfDNA concentrations and ctDNA fractions (.3%) throughout treatment, with extensive CNA at weeks 4 and 12, which appeared to be associated with shorter PFS in patients receiving chemotherapy (p = 0.011). Patients with partial response or stable disease generally demonstrated early clearance or reduction of ctDNA and CNAs. The ctDNA fraction showed promising discriminatory performance for disease progression, with area under the curve (AUC) values of 0.93 and 0.92 at weeks 4 and 12, respectively, although these estimates should be interpreted with caution given the limited sample size. The fragmentation-based analysis showed potentially comparable predictive utility, with AUC values of 0.86 and 0.91 at weeks 4 and 12, respectively. Conclusion: These preliminary findings suggest that lcWGS of plasma cfDNA may be a feasible and informative approach for monitoring treatment response and exploring factors associated with PFS in patients with advanced NSCLC. The patterns observed across both EGFR-TKI and chemotherapy contexts are encouraging, although the small sample size limits generalizability. Larger prospective validation studies are needed to confirm these findings and establish lcWGS-based cfDNA analysis as a reliable tool in precision oncology.