Résumé
Background: This is the first exploratory biomarker analysis from DB-03 (NCT03529110), which showed a 22-mo improvement in median progression-free survival (mPFS) with T-DXd vs T-DM1 in patients (pts) with HER2+ mBC previously treated with trastuzumab and taxane. Methods: This analysis assessed the impact of genomic alterations (alt) on efficacy (objective response rate [ORR] and mPFS), at baseline (BL) and alt emerging at progression. Genomic alt from the GuardantINFINITY panel of >700 genes were examined in circulating tumor DNA (ctDNA) samples collected at BL from 204 pts and 217 pts, and at end of treatment due to disease progression (DP) for 67 pts and 141 pts, treated with T-DXd and T-DM1, respectively. Data cutoff was July 25, 2022. Median follow-up was 28.4 mo and 26.5 mo in the T-DXd and T-DM1 arms, respectively. Results: The DB-03 genomic landscape largely recapitulated that of HER2+ BC, with most frequent alt (single nucleotide variants, amplifications [amp], and indels) observed in TP53 (73%), HER2 (ERBB2; 61%), CDK12 (52%) and PIK3CA (48%). HER2 genomic status Detection rate of HER2 amp in ctDNA was relatively low: 56% (235/420) detected, including aneuploidy and focal HER2 amp. HER2 plasma copy number (CN; adjusted for ctDNA tumor fraction) was higher in the subgroup of pts with HER2 IHC3+ vs IHC2+ tumors. Efficacy was comparable in the T-DXd arm regardless of high/low median HER2 plasma CN at BL, whereas numerically shorter PFS and lower ORR were observed in the T-DM1 arm with lower HER2 plasma CN at BL. T-DXd: HER2 CN high (n = 62 [30.4%]) vs CN low (n = 59 [28.9%]) vs not detected (ND; n = 83 [40.7%]) ORR, % (95% CI): 87.1 (76.1-94.3) vs 81.4 (69.1-90.3) vs 77.1 (66.6-85.6) mPFS, mo (95% CI): 23.9 (18.0-not estimable [NE]) vs 21.1 (12.3-NE) vs 37.3 (26.2-NE) T-DM1: HER2 CN high (n = 56 [25.8%]) vs CN low (n = 59 [27.2%]) vs ND (n = 102 [47.0%]) ORR, % (95% CI): 50.0 (36.3-63.7) vs 35.6 (23.6-49.1) vs 31.4 (22.5-41.3) mPFS, mo (95% CI): 9.7 (6.8-25.7) vs 5.4 (3.0-6.8) vs 8.1 (4.4-10.9) No difference in response based on BL HER2 activating mutation (mut) status was observed in either arm. Data to be presented. PI3K pathway T-DXd efficacy was comparable irrespective of PI3K pathway mut status. In contrast, a trend towards reduced efficacy was observed in pts with PI3K mut in the T-DM1 arm. T-DXd: PI3K mut (n = 87 [42.6%]) vs ND (n = 117 [57.4%]) ORR, % (95% CI): 80.5 (70.6-88.2) vs 82.1 (73.9-88.5) mPFS, mo (95% CI): 27.6 (15.0-NE) vs NE (22.1- NE) T-DM1: PI3K mut (n = 87 [40.1%]) vs ND (n = 130 [59.9%]) ORR, % (95% CI): 33.3 (23.6-44.3) vs 40.0 (31.5-49.0) mPFS, mo (95% CI): 4.4 (3.2-6.8) vs 9.7 (6.8-12.1) Homologous recombination deficiency (HRD) and BRCA1/2 alt status ORR was similar regardless of HRD status in the T-DXd arm and numerically lower in the HRD+ subgroup of the T-DM1 arm. mPFS tended to be shorter in both arms with HRD+ status. T-DXd: HRD+ (n = 23 [11.3%]) vs ND (n = 181 [88.7%]) ORR, % (95% CI): 82.6 (61.2-95.0) vs 81.2 (74.8-86.6) mPFS, mo (95% CI): 12.4 (6.8-NE) vs 37.3 (23.7-NE) T-DM1: HRD+ (n = 27 [12.4%]) vs ND (n = 190 [87.6%]) ORR, % (95% CI): 14.8 (4.2-33.7) vs 40.5 (33.5-47.9) PFS, mo (95% CI): 2.8 (1.4-4.3) vs 7.1 (5.7-9.7) m Similar trends were observed based on BRCA1/2 alt status. Data to be presented. Conclusions Genomic alt at BL were not significantly associated with response to T-DXd vs T-DM1. T-DXd maintained superior activity to T-DM1 regardless of the presence of detectable BL genomic alt. T-DXd was comparably active in pts with PI3K pathway mut whereas T-DM1 activity appeared lower. T-DXd outperformed T-DM1 regardless of HRD+/- or BRCA1/2 alt status, although HRD+ status and BRCA1/2 alt were poor prognosticators for PFS in both arms. Mutational analysis at DP will be presented.
Citation Format: William Jacot, Seock-Ah Im, Sherene Loi, Thomas Bachelot, Sara Hurvitz, Srinivasan Madhusudan, Hiroji Iwata, Giuseppe Curigliano, Javier Cortés, Anton Egorov, Vinit Kumar, Aislyn Boran, Yusuke Kuwahara, Erika Hamilton. Exploratory biomarker analysis of Trastuzumab deruxtecan (T-DXd) vs Trastuzumab emtansine (T-DM1) efficacy in human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (mBC) in DESTINY-Breast03 (DB-03) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS8-03.