Trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low, hormone receptor-positive (HR+) unresectable and/or metastatic breast cancer (mBC): Exploratory biomarker analysis of DESTINY-Breast04.

Abstract

1020Background: DESTINY-Breast04 (NCT03734029) showed improved progression-free survival (PFS) and overall survival for T-DXd vs TPC in pts with HER2-low (IHC 1+ or 2+/ISH-negative) mBC. We present exploratory biomarker analysis in pts with HER2-low, HR+ mBC. Methods: Biopsy specimens collected from 326 pts after prior treatment were analyzed using RNA-sequencing and intrinsic subtypes estimated by PAM50 gene expression. ESR1 and PIK3CA mutations and known gene alterations associated with resistance to CDK4/6 inhibitors (CDK4/6i) were assessed in baseline (BL) circulating tumor DNA (ctDNA) samples from 414 pts by Guardant OMNI. Association with objective response rate (ORR) and PFS was evaluated. Results: Frequencies of BL intrinsic subtypes in the T-DXd and TPC arms were 41.3% and 46.6% for Luminal A, 48.0% and 37.9% for Luminal B, and 9.0% and 11.7% for HER2 enriched, respectively. According to ctDNA results in the T-DXd and TPC arms, respectively, ESR1 mutations were observed in 51.3% and 54.0% of pts, PIK3CA mutations in 36.1% and 41.6% of pts, and at least one CDK4/6i resistance marker (pts with prior CDK4/6i) was detected in 71.5% and 70.2% of pts. Improved T-DXd efficacy was seen regardless of intrinsic subtype (Luminal A, Luminal B, HER2-enriched), ESR1 mutation, PIK3CA mutation, or CDK4/6i resistance markers (Table). Conclusions: Greater clinical benefit was consistently observed with T-DXd vs TPC independent of intrinsic subtype, ESR1 mutation, PIK3CA mutation, or known CDK4/6i resistance marker status. Clinical trial information: NCT03734029 . [Table: see text]