Predictive impact of complete molecular response in plasma: A phase II, liquid biopsy study in EGFR mutated NSCLC patients treated with afatinib (WJOG 8114LTR).

Abstract

9027 Background: Liquid biopsy has been approved as an alternative method to detect clinically relevant EGFR mutations in NSCLC. However, it is unknown whether the early assessment of molecular response in plasma could be a surrogate of clinical response and/or longer efficacy. Here, we conducted a prospective, multi-institutional study of liquid biopsy in EGFRmutated NSCLC patients (WJOG 8114LTR). Methods: Chemotherapy naïve, advanced NSCLC patients with EGFR-sensitizing mutation received afatinib monotherapy (40 mg/body) until progressive disease (PD) or unacceptable toxicity. Plasma DNA was obtained from patients at baseline, weeks 2, 4, 8, 12, 24, 48, and at PD. Three types of clinically relevant EGFRmutations (exon 19 deletion, exon 20 T790M and exon 21 L858R) will be analyzed using plasma DNA with multiplexed, pico-droplet digital PCR assay (RainDrop system, RainDance Technologies, Billerica, MA). Complete molecular response (CMR) was defined as mutant allele event/frequency of exon 19 deletion or exon 21 L858R below the cutoff for the positivity by digital PCR in plasma. This study was registered at UMIN (ID: 000015847). Results: Fifty-seven patients were registered in the study. Efficacy of afatinib was comparable to previous reports (overall response rate: 78.6%, and median progression-free survival (mPFS): 14.2 months). At baseline, 62.5% of patients were positive for EGFR mutation in plasma. Plasma positive patients had slightly shorter PFS than plasma negative patients, but not significant (p = 0.24, log-rank). Among those who were positive at baseline, CMR was achieved in 60.6% of patients at two weeks, and 87.5% at four weeks, respectively. Patients with CMR at two weeks had significantly longer PFS than those without one (13.6 versus 7.5 months, p = 0.0001). Patients with CMR at four weeks also demonstrated longer PFS than those without one (13.6 versus 5.1 months, p < 0.0001). Among patients who achieved CMR by week four, time to achieve CMR did not affect PFS ( p= 0.59). Conclusions: This is the first report on the predictive impact of early CMR in plasma for longer therapeutic efficacy of afatinib in EGFR mutated NSCLC patients. Clinical trial information: 000015847.