1442P - Correlation between intratumor HER2 heterogeneity and circulating tumor DNA in HER2 positive advanced gastric cancer: A phase Ib trial of HER2 and PD-1 dual targeted therapy (Ni-High) substudy

Background

We previously reported that intratumoral HER2 heterogeneity was associated with limited treatment efficacy to trastuzumab-based chemotherapy for HER2 positive advanced gastric cancer (AGC). In this study, we investigated the mechanism of resistance associated with intratumoral HER2 heterogeneity through ctDNA analysis.

Methods

We enrolled tissue-confirmed HER2 positive AGC patients who received chemotherapy with anti-HER2 and anti-PD-1 dual-targeted therapy from a phase Ib clinical trial. We compared clinical characteristics, gene alterations that obtained by ctDNA panel (Guardant 360®), and clinical outcomes of chemotherapy with the dual targeted therapy according to the intratumor HER2 heterogeneity status.

Results

Somatic alterations in ctDNA were detected in 20 of 21 (95.2%) patients. Among them, HER2-homo was observed in 8 of 20 patients (40.0%). AGC patients with HER2-homo tended to have a higher proportion of immunohistochemistry 3+ than those with HER2-hetero (100% vs 58.3%, P = 0.055), and the ERBB2 copy number variant (CNV) detection rate in HER2-homo tended to be higher than those in HER2-hetero (87.5% vs 41.7%, P = 0.07). In addition, ctDNA ERBB2 copy number in HER2-homo was significantly higher than those in HER2-hetero (4.5 copies vs 2.51 copies, P = 0.045). In contrast, the proportion of single nucleotide variant (SNV)s or CNVs associated with the cell cycle tended to be lower in HER2 homo than in HER2 hetero (25% vs 75%, P = 0.065). Regarding clinical outcomes of chemotherapy with HER2 and PD-1 dual targeted therapy, both median progression free survival (PFS) and overall survival (OS) in the HER2-homo was tended to be longer than that in the HER2-hetero (PFS: 20.8 months [95% CI] 8.4–NA] vs. 11.3 months [95% CI 5.5–16.3]; hazard ratio (HR) 0.36; 95% CI 0.11–1.24; P = 0.1, OS: NA [95% CI 14–NA] vs. 21.0 months [95% CI 10–NA]; HR 0.36; 95% CI 0.06–1.98; P = 0.24).

Conclusions

Intra-tumor HER2 heterogeneity, classified to homogenous or heterogenous, may be a useful biomarker associated with distinct tumor biology to predict the clinical efficacy of anti-HER2 and anti- PD-1 dual targeted therapy in patients with HER2 positive AGC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Ono Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.