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

Purpose: 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 (HER2)-amplified progressive stage solid tumors detected by cell-free DNA (cfDNA) testing.

Patients and methods: Patients exhibited advanced solid tumors with HER2 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.

Results: Overall, 4,734 patients underwent cfDNA testing from December 2019 to January 2022, and 252 demonstrated HER2 amplification. Finally, the study included 62 patients with 16 cancer types with a median baseline plasma HER2 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 KRAS-mutant colorectal (1/3), PIK3CA-mutant endometrial (5/6), and tissue HER2-negative gastric (1/2) cancers. Plasma HER2 CN above versus below the baseline median value did not differ for impact response; however, clearance of HER2 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.

Conclusion: T-DXd treatment demonstrated high ORR with durable response in patients with advanced HER2-amplified solid tumors determined with cfDNA testing.

FIG 1.

Waterfall plot. Waterfall plot of maximum change in tumor size for the 62 evaluated patients, as per investigator assessment.

FIG 2.

Spider plot of response depth and duration according to cancer type.

FIG 3.

Survival outcomes. (A) PFS per investigator. (B) OS per investigator. OS, overall survival; PFS, progression-free survival.

FIG 4.

Biomarker analysis. HER2 pCN at baseline and dynamics. ORR was 88.0% in the clearance group and 22.7% in the nonclearance group. C2D1, cycle 2 day 1; HER2, human epidermal growth factor receptor 2; NE, not evaluable; ORR, overall response rate; pCN, plasma copy number; PD, progressive disease; PR, partial response; SD, stable disease.

FIG A1.

Trial profile. Flow diagram for the HERALD trial. cfDNA, cell-free DNA; ERBB2, Erb-B2 receptor tyrosine kinase 2; FAS, full analysis set; ITT, intention-to-treat; T-DXd, trastuzumab deruxtecan.

FIG A2.

Patient flow. Flow diagram for the HERALD trial by cancer type. ERBB2, Erb-B2 receptor tyrosine kinase 2; H&N, head and neck.

FIG A3.

Tumor shrinkage by baseline cfDNA status. Waterfall plot of maximum change in tumor size for the 62 evaluated patients, as per investigator assessment according to cancer type and baseline cfDNA. cfDNA, cell-free DNA; HER2, human epidermal growth factor receptor 2; PD, progressive disease; PR, partial response; SD, stable disease; VUS, variant of uncertain significance.