76P Monitoring pembrolizumab response in patients with metastatic non-small cell lung cancer using circulating tumour DNA and circulating tumour cells

Liquid biopsies of cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), and circulating tumour cells (CTCs) can be used to monitor the efficacy of systemic therapy. We investigated the predictive value of CTCs and ctDNA in patients with advanced non-small cell lung cancer (NSCLC) treated with pembrolizumab. cfDNA was evaluated in 127 patients' plasma samples at baseline(t0), after 3-weeks(t1), 6-weeks(t2) and 9-weeks(t3) from 46 individuals and analysed by next-generation sequencing to identify and quantify somatic mutations. CTCs were detected in peripheral blood mononuclear cells and characterised according to PD-L1 and Ki67. Patients presenting an increase in cfDNA at t1/t2 had shorter progression-free survival (PFS) (2.05 vs 6.1 months, p=0.04) and overall-survival (OS) (8.35 vs 20.0 months, p=0.004) than those with decreased cfDNA. Somatic mutations were found in TP53, EGFR, KRAS, ALK, PI3KCA and MAP2K1 in 58.14% of patients. Carriers of KRAS mutations at t2 had a worse overall survival (OS) than non-carriers (Hazard ratio (HR)=3.2, p=0.03). Patients with >50% decrease or clearance in ctDNA from baseline to early treatment, had lower risk for progression (HR=0.14, p=0.03) and mortality (HR=0.29, p=0.03), respectively. In addition, a high Ki67 CTC-index (iKi67), negatively affected patient progression (HR=10.13, p=0.03) and survival (HR=6.1, p=0.01). We then layered the assessment of iKi67 and ctDNA markers to establish a sensitive and robust combinatorial risk classification approach for detecting patients with PD. Importantly, the combination of ctDNA and iKi67 was superior in identifying patients with disease progression. Early assessment of these circulating markers provides predictive information regarding the efficacy of pembrolizumab immunotherapy in patients with metastatic NSCLC and may be used for treatment stratification.