Clinicomolecular Profile and Efficacy of Human Epidermal Growth Factor Receptor 2 (HER2)-Targeted Therapy for <i>HER2</i>-Amplified Advanced Biliary Tract Cancer.

Abstract

This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in <i>HER2</i>-amplified biliary tract cancer (BTC). This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort. Of the 439 patients in the exploratory cohort, 43 (10%) had <i>HER2</i> amplification. The frequencies of coalterations were higher in patients with <i>HER2</i> amplification versus patients without <i>HER2</i> amplification including <i>HER2</i> mutations (26% <i>v</i> 5%, <i>P</i> < .001), <i>TP53</i> mutations (84% <i>v</i> 61%, <i>P</i> = .003), and <i>BRAF</i> amplification (9% <i>v</i> 2%, <i>P</i> = .030). There were no <i>KRAS</i> mutations identified in patients with <i>HER2-</i>amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without <i>HER2</i> amplification (median, 17.7 <i>v</i> 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with <i>HER2</i>-amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 <i>v</i> 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; <i>P</i> < .001). <i>HER2</i> amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with <i>HER2</i>-amplified BTC derive significant benefit from HER2-targeted therapy.