Patient selection for local consolidative therapy in advanced non-small cell lung cancer after first line systemic therapy: a prospective study

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Background The benefit of local consolidative therapy (LCT) in advanced non-small cell lung cancer (NSCLC) following first-line systemic treatment remains controversial. This study integrated circulating tumor DNA (ctDNA), genomic, and transcriptomic data to address three critical clinical questions: how to identify the most suitable advanced NSCLC patients for LCT, how to determine the optimal timing for implementing LCT, and whether systemic treatment strategies should be modified after LCT. Methods In this prospective study (NCT05648370), patients with induced oligometastatic NSCLC (previous history of polymetastatic disease thatconverted to an oligometastatic disease during systemic therapy, with a median treatment duration of 7.5 months [range: 2–41]) who received first-line systemic therapy. According to physician assessment, the patients were stratified into an LCT group (receiving surgery) and a non-LCT group (continuing systemic therapy). In the LCT group, high-depth ctDNA monitoring was performed both before and after LCT, and whole-exome and transcriptome sequencing were conducted when tumor tissue samples were available. Progression-free survival (PFS) and overall survival (OS) was compared between the two groups. Results A total of 127 patients with induced oligometastatic NSCLC were included for final analysis. The LCT group ( n = 71; median PFS, 28.1 months; median OS, not reached) had better survival benefits than the non-LCT group ( n = 56; median PFS, 15.8 months; median OS, 38.5 months) ( P < 0.001). Importantly, within the LCT cohort, a distinct subgroup of patients with favorable outcomes was identified and termed molecular oligometastatic disease (MOD), defined as induced oligometastatic NSCLC with undetectable ctDNA after systemic therapy and before LCT. MOD was characterized by lower genomic tumor burden, and reduced genomic and transcriptomic activation of cell proliferation pathways. Patients with MOD who underwent LCT achieved significantly longer overall and post-LCT PFS than non-MOD patients ( P < 0.001). Furthermore, clinical multivariate analysis identified that systemic therapy duration and MOD status as independent predictors of PFS, suggesting that both factors should be considered when determining the optimal timing for LCT. By integrating surgical pathology, ctDNA dynamics, gene expression signatures, and survival outcomes, we found that patients exhibiting resistance-related features or an immune-depleted tumor microenvironment had poorer prognosis and might benefit from switching systemic therapy after LCT. Conclusions MOD defines a distinct subtype of advanced NSCLC with less aggressive clinical and molecular characteristics, which derive maximal benefit from LCT. The timing of LCT should consider both treatment duration and MOD status. Patients with resistance-related features or immune-depleted tumor microenvironments may require a systemic therapy switch following LCT. This study is limited by the single-center design and relatively limited sample size, and may require prospective validation in larger multicenter cohort studies and randomized controlled trials.

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