Impact of Genomic Alterations on Efficacy of Trastuzumab Deruxtecan Against Human Epidermal Growth Factor Receptor-2-Positive Advanced Gastric Cancer.

Abstract

The impact of genomic alterations on response and resistance to trastuzumab deruxtecan (T-DXd) has not been elucidated. Thus, we sought to identify factors predicting sensitivity to T-DXd in gastric or gastroesophageal junction (G/GEJ) cancer. We conducted a retrospective study using real-world clinical data and next-generation sequencing-based comprehensive genomic profiling (CGP) data from patients with advanced G/GEJ cancers, collected by the nationwide database in Japan. We analyzed the associations between genomic alterations and the patients' survivals after T-DXd treatment. In 114 patients with human epidermal growth factor receptor-2 (HER2)-positive G/GEJ cancer treated with T-DXd, the most frequently altered genes were <i>TP53</i> (82%), <i>ERBB2</i> (80%), and <i>CCNE1</i> (36%). Multivariate Cox regression analysis revealed <i>CCNE1</i> amplification to be a significant predictor of shorter progression-free survival (PFS) after T-DXd treatment among 91 patients whose CGP samples were obtained before T-DXd (median PFS, 131 days <i>v</i> 189 days; hazard ratio [HR], 1.90 [95% CI, 1.02 to 3.53]; <i>P</i> = .044). Analyses of 1,450 G/GEJ cancers revealed significant <i>CCNE1</i>/<i>ERBB2</i> coamplification (41% relative to 11% <i>CCNE1</i> amplification in <i>ERBB2</i>-nonamplified tumors; <i>P</i> < .0001). <i>ERBB2</i>-activating mutations were also detected in 3.7% of G/GEJ cancers and in 8.8% of HER2-positive G/GEJ cancers treated with T-DXd. Patients with <i>ERBB2</i>-mutated tumors showed shorter PFS than those without <i>ERBB2</i> mutations after T-DXd treatment (mPFS, 105 <i>v</i> 180 days; <i>P</i> = .046). <i>CCNE1</i> amplification may confer primary resistance to T-DXd in HER2-positive G/GEJ cancer, suggesting that the cell cycle could be a potential therapeutic target in <i>CCNE1/ERBB2</i> coamplified tumors. <i>ERBB2</i>-activating mutation may also attenuate T-DXd efficacy in HER2-positive G/GEJ cancer.