Trastuzumab Deruxtecan in Advanced Solid Tumors With Human Epidermal Growth Factor Receptor 2 Amplification Identified by Plasma Cell-Free DNA Testing: A Multicenter, Single-Arm, Phase II Basket Trial.

Abstract

HERALD/EPOC1806 was conducted as a multicenter phase II trial assessing trastuzumab deruxtecan (T-DXd) therapy for patients with human epidermal growth factor receptor 2 (<i>HER2</i>)-amplified progressive stage solid tumors detected by cell-free DNA (cfDNA) testing. Patients exhibited advanced solid tumors with <i>HER2</i> amplification that was identified via next-generation sequencing of cfDNA testing, without the requirement for immunohistochemical HER2 testing. The studied group was administered T-DXd at 5.4 mg/kg once every 3 weeks until onset of disease progression or intolerable toxicity. Overall, 4,734 patients underwent cfDNA testing from December 2019 to January 2022, and 252 demonstrated <i>HER2</i> amplification. Finally, the study included 62 patients with 16 cancer types with a median baseline plasma <i>HER2</i> copy number (CN) of 8.55 (range, 2.4-73.9). Confirmed overall response rate (ORR) by investigator assessment was 56.5% (95% CI, 43.3 to 69.0), thus showing a value beyond the 5% threshold. Responses were evaluated for 13 cancer types, including <i>KRAS</i>-mutant colorectal (1/3), <i>PIK3CA</i>-mutant endometrial (5/6), and tissue HER2-negative gastric (1/2) cancers. Plasma <i>HER2</i> CN above versus below the baseline median value did not differ for impact response; however, clearance of <i>HER2</i> amplification in cfDNA on cycle 2 day 1 had higher response values compared with persistence. Median progression-free survival and response duration were 7.0 (95% CI, 4.9 to 9.7) and 8.8 (95% CI, 5.8 to 11.2) months, respectively, with the majority of complications being mild to moderate. Interstitial lung diseases were identified in 16 (26%) patients, including 14 patients with grade 1 disease, one patient with grade 2 disease, and one patient with grade 3 disease. T-DXd treatment demonstrated high ORR with durable response in patients with advanced <i>HER2</i>-amplified solid tumors determined with cfDNA testing.