Background

Oligometastatic non-small cell lung cancer (NSCLC) patients may uniquely benefit from personalized therapies via liquid biopsy. Widespread metastatic disease is incurable, yet some patients with oligometastatic disease experience prolonged progression-free survival when treated with aggressive local stereotactic body radiotherapy (RT). Distinguishing patients who would benefit from aggressive RT from those who would benefit from systemic therapies remains a challenge. We hypothesized that pre-RT ctDNA can be used to risk-stratify those with oligometastatic NSCLC and enable earlier personalized approaches when considering systemic therapy versus aggressive local RT.

Methods

A retrospective multi-institutional cohort of 1,487 patients (median age: 65 years, 53% female [n=784], 47% male [n=703]) who were diagnosed with oligometastatic NSCLC was selected. Each patient underwent liquid biopsy ctDNA analysis using the Tempus xF assay (v2) at least once, with a subset of patients undergoing serial sampling at 2–8 timepoints for a total of 1,880 ctDNA assays. 309 of the patients (20%) underwent RT after liquid biopsy was obtained and oligometastatic NSCLC was diagnosed. Outcomes for overall survival (OS) and progression-free survival (PFS) were defined with respect to the initiation time of RT (i.e., time from RT to death, time from RT to progressive disease).

Results

Across all ctDNA assays, 3,520 pathogenic or likely pathogenic (P/LP) variants were identified (1.8 variants/sample, mean). Among patients with a liquid biopsy obtained prior to RT, 48% (n=151) experienced progressive disease and 11% (n=34) died during the study period. Focusing on patients with ctDNA obtained pre-RT, P/LP variants were detected in 74% (n=230) while 26% (n=79) had zero variants detected. Of those with detectable variants, 76% (n=175) had 1–3 variants, while 24% (n=55) had ≥4 P/LP variants detected in ctDNA. Both overall survival and progression-free survival were significantly worse in patients with detectable ctDNA from pre-RT liquid biopsy compared to those without (median OS 16.8 months vs. 25 months; p=0.027, HR=1.65; median PFS 5.4 months vs. 8.8 months; p=0.021, HR=1.57). Remarkably, survival correlated inversely with the number of detected variants from pre-RT liquid biopsies; when patients were stratified by variant quantity, both OS and PFS were significant (OS p=0.045, PFS p=0.003; stratified by 0, 1–3, and ≥4 variants). This finding was also significant in a multivariate Cox proportional hazards analysis (OS HR=1.15, CI 1.04–1.24; PFS HR=1.16, CI 1.06–1.25), but was not significant for parameters such as age at diagnosis or squamous histology.

Conclusions

These data suggest that a ctDNA-informed approach may be a powerful pre-RT biomarker to help risk-stratify oligometastatic NSCLC patients and potentially enable personalized decision-making for RT versus systemic therapy.

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