Sequential antibody-drug conjugate therapy in patients with metastatic breast cancer treated with sacituzumab govitecan and trastuzumab deruxtecan Journal Article
| Authors: | Mai, N.; Lieberman, M. M. K.; Ferraro, E.; Bromberg, M.; Chen, Y.; Razavi, P.; Modi, S.; Chandarlapaty, S.; Walsh, E. M.; Drago, J. Z. |
| Article Title: | Sequential antibody-drug conjugate therapy in patients with metastatic breast cancer treated with sacituzumab govitecan and trastuzumab deruxtecan |
| Abstract: | PURPOSESacituzumab 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.METHODSPatients 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 (rwPFS) of both T-DXd and SG.RESULTSEighty-five patients were eligible. Regardless of which ADC was deployed first (rwPFS1), median rwPFS with the second ADC (rwPFS2) 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 rwPFS2 included longer rwPFS1 (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 rwPFS2.CONCLUSIONSequential 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. © 2025 American Society of Clinical Oncology. |
| Keywords: | immunohistochemistry; adult; major clinical study; missense mutation; systemic therapy; progression free survival; epidermal growth factor receptor 2; multivariate analysis; hazard ratio; heterozygosity loss; kaplan meier method; metastatic breast cancer; univariate analysis; loss of function mutation; disease exacerbation; nonsense mutation; dna topoisomerase; cross resistance; clinical outcome; time to treatment; human; female; article; antibody drug conjugate; sacituzumab govitecan; trastuzumab deruxtecan; govitecan; line of treatment |
| Journal Title: | JCO Precision Oncology |
| Volume: | 9 |
| ISSN: | 2473-4284 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2025-07-01 |
| Start Page: | e2400898 |
| Language: | English |
| DOI: | 10.1200/po-24-00898 |
| PUBMED: | 40440568 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Joshua Z. Drago -- Source: Scopus |
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