Evolution and clinical impact of EGFR mutations in circulating free DNA in the BELIEF trial

Abstract

Background: BELIEF, a single-arm, phase 2 trial, showed a median (med) progressionfree survival (PFS) of 13.2 months (m) with erlotinib and bevacizumab in patients (pts) with advanced EGFR mutated NSCLC (Rosell et al 2017). We prospectively and longitudinally examined the evolution of sensitizing EGFR and p.T790M mutations, in circulating free DNA (cfDNA). Methods: Blood samples were collected at baseline (BaS), at time of response (6w) and at progression (PD) and sent to a central laboratory. cfDNA was purified, and EGFRmutations were analyzed with real-time PCR assay. The fully validated assay is highly specific (>99%) and sensitive (76%) for EGFR sensitizing mutations. Results: As of 12 March 2018, at a med follow-up of 47m (IQR: 42, 59), 2 pts (2%) are still on full protocol treatment, while 95 PFS events (87%) and 70 deaths (64%) have occurred. The med PFS is 13.2m (95% CI: 10.3, 15.5), the med overall survival (OS) is 30.2m (95% CI: 23.1, 39.6) and the 2-year OS is 58.4% (95% CI: 48.2-67.2%). cfDNA are available at BaS for 91 pts, at 6w for 72 pts and at PD for 58 pts. EGFR mutations identified in blood were also originally found in tissue. 69 pts had cfDNA assessment both at BaS and 6w. Med PFS was 19.1m for 24 pts without EGFR mutations in cfDNA at BaS and at 6w, versus 12.6m for 43 pts with EGFR mutations detected in cfDNA at BaS, but not at 6w (p=0.019). 46 pts had the 3-pronged assessments (BaS, 6w, PD). The med PFS for the BaS negative group that remained negative at PD was 17.4m (12 pts), while for the BaS positive group that converted to negative at 6w and remained negative at PD was 13.1m (7pts; p=0.72). For those BaS positive who converted to negative at 6w, but later became positive again at PD, the med PFS was 10.6m (p=0.20). At PD, 41% of pts harbored T790M. For pts with BaS EGFR mutations, the med PFS was 13.4m (16 pts) in those without T790M, and 9m (17 pts) for the T790M mutated at PD (p=0.14). Conclusions: These data suggest the absence of sensitizing EGFR mutations in cfDNA at BaS confers significantly better PFS than in pts with EGFR mutant cfDNA. A trend of shorter PFS is seen in the subgroup of pts with BaS EGFR mutant cfDNA, from whom, at PD, EGFR mutations were again detected. EGFR mutant cfDNA could be an indicator for co-occurring oncogenic events and the use of cfDNA exome platforms should be encouraged.