Clinical utility of plasma EGFR mutation detection with quantitative PCR in advanced lung cancer: A meta-analysis

To assess the clinical utility of quantitative PCR (qPCR) assays, a routinely used test for detection of epidermal growth factor receptor (EGFR) mutation in circulating tumour DNA (ctDNA) in treatment-naive advanced lung cancer patients.We performed a meta-analysis of randomized controlled trials (RCTs) with individual patient data. Eligible RCTs compared EGFR-tyrosine kinase inhibitor (EGFR-TKI) and chemotherapy in first line setting for advanced lung cancer, and included tumour EGFR+ (tEGFR+) with paired ctDNA results using real-time (quantitative) PCR. We assessed the proportion of tEGFR + detected by ctDNA, and compared the effectiveness of EGFR-TKI versus chemotherapy in ctDNA + and ctDNA- subgroups.Six randomized clinical trials included 1058 tEGFR + patients with paired baseline EGFR ctDNA testing. Of these, 460 (43 %) tested ctDNA- (ctDNA+ 57 %). Progression-free survival was longer for EGFR-TKI versus chemotherapy for both ctDNA+ (HR 0.28; 95 % CI 0.22-0.36, p < 0.00001) and ctDNA- subgroups (HR 0.37; 95 % CI 0.28-0.49, p < 0.00001; p-interaction = 0.14). Objective response rate (odds ratio 6.21; 95 % CI 4.25-9.07, p < 0.00001 vs 6.44; 95 % CI 4.21-9.87, p < 0.00001) and overall survival (HR 0.82; 95 % CI 0.70-1.04 vs HR 0.77; 95CI% 0.59-1.00) similarly favoured EGFR-TKI in both ctDNA + and ctDNA- subgroups respectively.Our findings indicate that approximately two in five tissue EGFR mutation-positive patients will not be detected using a qPCR assay, but would still potentially benefit from highly effective EGFR-TKI treatment. A negative EGFR ctDNA result via qPCR testing is therefore insufficient to exclude benefit from EGFR-TKI. Attempts should be made to repeat EGFR testing with a tissue biopsy in this patient group. As newer ctDNA assays with better sensitivity become available, the clinical impact for any false negatives will remain an important consideration.