Sequential Antibody-Drug Conjugate Therapy in Patients With Metastatic Breast Cancer Treated With Sacituzumab Govitecan and Trastuzumab Deruxtecan

PURPOSE Sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADCs) approved for the treatment of human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (MBC). Both carry topoisomerase-1–inhibiting payloads, and it is unknown whether these drugs retain activity when used sequentially. METHODS Patients who received both T-DXd and SG for treatment of MBC were eligible. The primary objective was to describe clinical outcomes and clinicogenomic characteristics associated with improved real-world progression-free survival ( rw PFS) of both T-DXd and SG. RESULTS Eighty-five patients were eligible. Regardless of which ADC was deployed first ( rw PFS1), median rw PFS with the second ADC ( rw PFS2) was shorter in 75.2% of patients, with 14 patients remaining on treatment at the data cutoff. Individual patient cases of prolonged benefit were however observed with both T-DXd and SG when used second. In multivariate analyses, predictors of better rw PFS2 included longer rw PFS1 (hazard ratio [HR], 0.94 [95% CI, 0.89 to 1.00]; P = .04) and earlier overall treatment line (HR, 1.10 [95% CI, 1.01 to 1.21]; P = .03). Genomic analysis of pretreatment tissue samples revealed that PTEN loss is associated with de novo resistance to T-DXd (HR, 3.20 [95% CI, 1.47 to 6.97]; P = .003) but not SG (HR, 1.18 [95% CI, 0.54 to 2.56]; P = .68). There were no significant associations between estrogen receptor or HER2 status and rw PFS2. CONCLUSION Sequential ADC therapy with topoisomerase-1–inhibiting payloads is a viable treatment strategy in HER2-low MBC. These results have hypothesis-generating clinical and translational implications. Further studies are needed to better understand ADC cross-resistance as more of these agents enter our clinical armamentarium.