Trastuzumab deruxtecan for HER2-positive metastatic breast cancer: DESTINY-Breast01 subgroup analysis.

Abstract

1036 Background: Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable linker, and a cytotoxic topoisomerase I inhibitor. In the pivotal DESTINY-Breast01 trial, efficacy of T-DXd in HER2-positive metastatic breast cancer (mBC) was demonstrated, with an objective response rate (ORR) of 60.9% and median progression-free survival (mPFS) of 16.4 months. Methods: DESTINY-Breast01 was a single-group, open-label, multicenter, phase II trial of 184 patients with HER2-positive mBC previously treated with trastuzumab emtansine (T-DM1) who received T-DXd at 5.4 mg/kg. Multivariate analysis using logistic regression models (ORR) and Cox proportional hazards models (duration of response [DOR], mPFS) explored 15 relevant clinical predictor variables. Circulating tumor DNA (ctDNA) was collected prior to the first dose, every 3 cycles of treatment, and at the end of treatment. Sequencing was done via GuardantOMNI (Guardant Health) for single-nucleotide variation/insertion and deletion, amplification, and fusion of ≈ 500 genes. Results: Efficacy in all evaluated clinical subgroups was similar to the overall ORR 60.9% and mPFS 16.4 months with ranges from ORR 46.4%-74.5% and mPFS 12.3-18.1 months. Variables associated with improved ORR, DOR, or mPFS included hormone receptor positive status, fewer prior treatment regimens (continuous variable), pertuzumab given in the first or second line, and normal renal and hepatic function. Variables that did not impact efficacy outcomes compared to the overall population include age, race, region, ECOG PS, HER2 IHC 3+ status, progesterone receptor status, best response to T-DM1, time since diagnosis, and history of brain metastases. In 48 subjects with progression as of data cut date, metastases were most commonly observed in the liver, lung, and lymph nodes. Only 8% (4 of 48) had progression involvement in the brain upon disease progression. Decrease of ERBB2 copy number in ctDNA was seen on treatment and correlated with clinical response. Additional changes in molecular markers on treatment and following progression will be described. Conclusions: T-DXd demonstrated strong efficacy in all clinical subgroups analyzed. Further exploration of both clinical and molecular variables to determine biomarkers of efficacy may be warranted. Clinical trial information: NCT03248492 .