Proffered paper session metastatic breast cancer – 2

The second proffered paper session on metastatic breast cancer at ESMO 2025 featured several important presentations that have potential implications for the treatment landscape across different breast cancer subtypes. In this video, Prof François Duhoux, medical oncologist at the Cliniques Universitaires Saint-Luc in Brussels shares the key results of 4 clinical trials presented in that session.

Updated results from the DESTINY-Breast09 trial provided further evidence supporting trastuzumab deruxtecan (T-DXd) in combination with pertuzumab in the first-line treatment of HER2-positive metastatic breast cancer. Subgroup analyses compared outcomes with T-DXd plus pertuzumab against the standard regimen of taxane, trastuzumab, and pertuzumab (THP). In patients with de novo metastatic disease, median progression-free survival (PFS) was not reached in the experimental arm vs. 31.2 months in the control arm, with a hazard ratio of 0.49 (95%CI: 0.35-0.70). Also among patients with recurrent disease, a significant benefit was observed, with a median PFS extending from 22.5 months in the THP group to 38 months in the T-DXd plus pertuzumab arm (HR[95%CI]: 0.63[0.46-0.87]). Additional subgroup analyses highlighted the consistency of benefit of T-DXd-pertuzumab over THP irrespective of hormone receptor status and PIK3CA mutation status. Across the different subgroups, T-DXd-pertuzumab also outperformed THP in terms of response rate, duration of response and PFS2.¹ Altogether, these data strengthen the case for T-DXd plus pertuzumab as a preferred first-line approach in HER2-positive disease.

The HORIZON-Breast01 trial introduced data from China evaluating SHR-A1811 (trastuzumab rezetecan), a novel HER2-directed antibody-drug conjugate (ADC). In a phase III comparison with pyrotinib plus capecitabine in patients previously treated with a taxane and trastuzumab, SHR-A1811 significantly extended median PFS from 8.3 to 30.6 months, with a hazard ratio of 0.22 (95%CI: 0.15-0.34). Although overall survival (OS) results remain immature, separation of the survival curves suggests a benefit, with a hazard ratio of 0.31 (95%CI: 0.14-0.69). The safety profile was encouraging, with only 5% treatment discontinuation due to adverse events and low rates of interstitial lung disease (ILD). These findings identify SHR-A1811 as a promising ADC within the HER2-positive metastatic breast cancer setting.²

In triple-negative breast cancer (TNBC), interesting data were presented from 2 clinical trials. The ASCENT-03 trial evaluated sacituzumab govitecan (SG) in patients who were ineligible for immune checkpoint inhibitors, the vast majority of whom were PD-L1 negative. Patients were randomized to SG or physician’s choice of chemotherapy, including paclitaxel, nab-paclitaxel, or carboplatin/gemcitabine. The median PFS was significantly longer with SG (9.7 vs. 6.9 months; HR[95%CI]: 0.62[0.50-0.77]). SG demonstrated manageable toxicity, with fewer dose reductions and discontinuations compared to chemotherapy. Safety findings were consistent with the known toxicity profile of this agent, including neutropenia, nausea, and diarrhea.³ These data support SG as a valuable first-line option for patients with TNBC lacking checkpoint inhibitor eligibility.

Arguably the most practice-changing data from the session came from the TROPION-Breast02 trial. This trial evaluated datopotamab deruxtecan (Dato-DXd), an anti-TROP2 ADC, against physician’s choice chemotherapy in first-line metastatic TNBC. Notably, the study allowed patients with short disease-free intervals, reflecting real-world clinical scenarios where relapses are increasingly rapid following intensive adjuvant therapy. In fact, approximately 20% of enrolled patients had a disease-free interval shorter than 12 months. Dato-DXd significantly improved the PFS from 5.6 to 10.8 months (HR[95%CI]: 0.57[0.47-0.69]). In addition, also the OS was superior, increasing from 18.7 months with chemotherapy to 23.7 months with Dato-DXd (HR[95%CI]: 0.79[0.64-0.98]). Overall,  the incidence of adverse event–related discontinuations was lower with the ADC than with chemotherapy. Of note, the safety profile of Dato-DXd differed from that of SG, with stomatitis, nausea, and dry eyes being more frequent, and diarrhea being less prominent. ILD occurred in 3% of patients overall, with <1% grade ≥3 events. Finally, Dato-DXd also doubled the overall response rate compared to chemotherapy (62.5% vs. 29.3%). The latter is a clinically meaningful result in aggressive TNBC, particularly for patients with rapidly progressing or bulky disease requiring quick tumor shrinkage.⁴