Kok Peey-Sei, Lee Kirsty, Lord Sally, Yang James Chih-Hsin, Rosell Rafael, Goto Koichi, John Thomas, Wu Yi-Long, Mok Tony S K, Lee Chee Khoon
National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney, Australia.
Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong.
Lung Cancer. 2021 Apr;154:113-117. doi: 10.1016/j.lungcan.2021.02.027. Epub 2021 Feb 22.
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.
