The distribution of human epidermal growth factor receptor 2 (HER2) expression and the efficacy and safety of treatments in HER2-expressing advanced or metastatic gastroesophageal cancer: A systematic literature review (SLR).

Abstract

405 Background: HER2 overexpression plays an important role in determining treatment options for patients with gastroesophageal cancer (GEC). HER2 overexpression has historically been defined dichotomously as HER2-positive (HER2+) or HER2-negative. An emerging potentially clinically relevant category is HER2-low, which could be targeted with HER2-directed antibody drug conjugates. However, data on the epidemiology and outcomes associated with HER2-low GEC are limited. Methods: An SLR of PubMed, Embase, and Cochrane Central Register of Controlled Trials databases was conducted to identify clinical trials, observational studies, and meta-analyses reporting clinical outcomes or distribution of HER2 expression by IHC and ISH in advanced or metastatic (a/m) GEC. Key inclusion criteria were: English language, published between 2013-2023, and sample size ≥100 HER2-expressing patients. HER2+ was defined as IHC score of 3+ or IHC 2+ and ISH+. HER2-low was defined as IHC 1+ or IHC 2+ and ISH-. Weighted averages were calculated for the proportion of patients who were HER2+ and HER2-low to estimate of the proportion of patients in each HER2 expression category. Results were categorized by patient population (all GEC or gastric cancer [GC] only). Results: Of 2,701 non-duplicated records screened, 174 studies met inclusion criteria. Distribution of HER2 expression was reported in 111 studies, 5 of which reported on the frequency of HER2 expression of IHC 1+ and/or IHC 2+ and ISH+. HER2 expression status varied by patient population, with a weighted average of 26.9% for HER2-low and 13.1-16.5% for HER2+ across groups (Table). Different cutoffs for HER2 amplification via ISH also affected the proportion of patients in each HER2 category across studies. Efficacy and safety outcomes were stratified by HER2 status or IHC results in 74 studies. However, only 3 observational studies reported outcomes separately for the HER2-low population, and results were inconclusive. Conclusions: The distribution of HER2 expression in a/m GEC in the identified studies is highly heterogenous, likely due to variability in IHC scoring and patient populations. Few studies with sufficient samples size (≥100 patients with HER2-expression a/mGEC) reported outcomes for HER2-low a/m GEC, and those that were identified were of low quality. The HER2-low a/m GEC population constitutes an unmet need for effective therapy. There is a need for consistent use of a standardized definition of HER2-low in a/mGEC and additional studies to better evaluate treatment options and outcomes for this patient population. [Table: see text]