1566P Clinical Relevance of Circulating Tumor DNA in HER2 -Positive Advanced Gastric Cancer: Results from Phase Ib Trial of HER2 and PD-1 Dual Targeted Therapy (Ni-High)

Anti-PD-1 antibody in addition to HER2-targeted therapy and chemotherapy may enhance antibody-dependent cell-mediated cytotoxicity and add further chemotherapeutic efficacy for HER2 -positive advanced gastric cancer (AGC). On the other hand, it remains unclear molecular profiles related to efficacy and resistance to this dual targeted therapy. Real-time tracking of these changes of the alteration using ctDNA may contribute to the treatment optimization. We enrolled tissue-confirmed HER2 -positive AGC who received chemotherapy with HER2 and anti-PD-1 dual targeted therapy from phase Ib clinical trial. Genomic profiling of 74 genes of their plasma by next-generation sequencing was carried out using ctDNA panel (Guardant 360®) to compare with their clinical parameters, clinical outcomes of dual targeted therapy and HER2 gene amplifications in matched tissue samples. Twenty-one patients were eligible in this study. HER2 gene amplification and single nucleotide variant (SNV) / Indels were detected in 12 (57.1%), 3 (14.3%) patients, respectively. Maximum mutant allele frequency (mMAF) in diffuse type histology were significantly lower than intestinal type histology (P = 0.01), and mMAF were associated with tumor diameter (r = 0.626, P = 0.0032). Tissue and ctDNA HER2 copy numbers were significantly correlated (r = 0.662, P = 0.019). Patients without HER2 SNV / Indels (n=17) had significantly longer PFS and OS than patients with HER2 SNV / Indels (n=3) (median PFS: 20.8 vs 8.4 months; P = 0.04; HR, 0.24, median OS: NA vs 14.0 months; P = 0.037; HR, 0.18). Moreover, patients with focal HER2 gene amplification (n = 9) had significantly longer PFS and OS than patients with HER2 aneuploidy (n=3) (median PFS: 20.8 vs 8.4 months; P = 0.007; HR, 0.08, median OS: NA vs 14.8 months; P = 0.0046; HR, 0.077). In patients achieving CR or PR (n=16), mMAF 3 weeks after initiation of chemotherapy was significantly lower than those in patients achieving SD (n=4) (P = 0.0087). Our data confirmed that HER2 SNV / Indels and gene amplification status may be predictor of treatment efficacy in patients with HER2- positive AGC who received chemotherapy with HER2 and PD-1 dual targeted therapy.