Abstract 1566P
Background
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.
Methods
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.
Results
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).
Conclusions
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.
Clinical trial identification
UMIN000034222.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Ono Pharamceutical Co., Ltd.
Disclosure
H. Shoji: Financial Interests, Personal, Advisory Board: Ono Pharmaceutical Co., Ltd., Zymeworks inc.; Financial Interests, Institutional, Local PI: Ono Pharmaceutical Co., Ltd., MSD, Astellas, Amgen, Daiichi Sankyo; Financial Interests, Institutional, Funding: Ono Pharmaceutical Co., Ltd., Takeda Pharmaceuticals. H. Hirano: Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical, Ono Pharmaceutical, Teijin Pharma, Novartis; Financial Interests, Personal, Writing Engagement: Nichi-Iko; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Ono Pharmaceutical, Janssen Pharmaceutical, Merck Biopharma, Bristol Myers Squibb, Pfizer, Eisai, Amgen, Astellas, Seagen, MSD, Incyte, BeiGene, Novartis. H. Hara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Boehringer Ingelheim, MSD; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Lilly, Merck Biopharma, Taiho, Takeda, Yakult, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Janssen, Merck Biopharma, MSD, Ono, Taiho, ALX oncology. K. Minashi: Financial Interests, Institutional, Research Grant: Amgen, Taiho, Daiichi Sankyo Co., Ltd, Astellas Pharmaceutical Co., Ltd,. K. Kato: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical, Bristol Myers Squibb, Merck and Co; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical, Bristol Myers Squibb, Merck and Co, Bayer, AstraZeneca, BeiGene, Taiho, Merck Biophrma, Amgen, Novartis, Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Ono Pharmaceuticals, Merck & Co; Financial Interests, Institutional, Local PI: Bayer, AstraZeneca, BeiGene, Chugai, Taiho, Oncolys Biopharma, Janssen Pharmaceutical. N. Boku: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb, Eli Lilly, Ono Pharmaceutical, Taiho, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical, Ono Pharmaceutical. K. Yamaguchi: Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Bristol Myers Squibb, Ono Pharm, Eli Lilly Japan; Financial Interests, Institutional, Funding: Taiho. All other authors have declared no conflicts of interest.
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