Wang Z, et al. - Researchers conducted a prospective clinical trial to validate the strategy of using circulating tumour DNA (ctDNA)-based EGFR mutation detection as a selection criterion for patients with lung adenocarcinoma receiving gefitinib as first-line treatment. Outcomes support the efficacy of this strategy for identifying patients who might benefit from first-line gefitinib treatment.

Methods

• Researchers performed BENEFIT, a multicentre, single-arm, phase 2 clinical trial, at 15 centres in China.
• They administered oral gefitinib 250 mg once daily as first-line treatment to patients aged 18–75 years with stage IV metastatic lung adenocarcinoma and EGFR mutations detected in ctDNA.
• The proportion achieving an objective response was assessed as the primary endpoint.
• Median progression-free survival and safety were assessed as the secondary endpoints.
• Genetic analysis of baseline blood samples was performed by using next-generation sequencing (NGS) of a 168-gene panel.
• In patients who had at least one post-baseline tumour assessment, they performed the primary efficacy analysis by intention to treat.
• They performed safety analysis in all patients who received at least one dose of study treatment. 

Results

• Researchers screened 426 patients for the trial between Dec 25, 2014, and Jan 16, 2016; among these, 188 with EGFR mutations in ctDNA were enrolled and received gefitinib.
• The primary efficacy analysis included 183 patients who had one or more post-baseline tumour assessment.
• They performed a median follow-up of 14·5 months (IQR 12·2–16·5).
• One hundred and fifty two patients had progressive disease or had died at the time of data cutoff (Jan 31, 2017).
• An objective response was achieved in 72·1% (95% CI 65·0–78·5).
• They noted a median progression-free survival of 9·5 months (95% CI 9·07–11·04).
• Blood samples were available of 167 patients; 147 (88%) of these showed clearance of EGFR mutations in ctDNA at week 8 and had longer median progression-free survival than the 20 patients whose EGFR mutations persisted at week 8 (11·0 months [95% CI 9·43–12·85] vs 2·1 months [1·81–3·65]; hazard ratio [HR] 0·14, 95% CI 0·08–0·23; p<0·0001).
• Three subgroups of patients were identified from baseline NGS data in 179 patients: those with EGFR mutations only (n=58), those with mutations in EGFR and tumour-suppressor genes (n=97), and those with mutations in EGFR and oncogenes (n=24).
• In these subgroups, the corresponding median progression-free survival was 13·2 months (95% CI 11·5–15·0), 9·3 months (7·6–11·0), and 4·7 months (1·9–9·3), respectively (EGFR mutations only vs mutations in EGFR and tumour-suppressor genes, HR 1·78, 95% CI 1·23–2·58; p=0·002; EGFR mutations only vs mutations in EGFR and oncogenes, 2·66, 1·58–4·49; p=0·0003).
• Hepatic function abnormalities were the most common grade 3 or 4 adverse events (n=24).
• Seventeen (9%) patients reported serious adverse events.
• They identified no unexpected safety events for gefitinib.