Editor’s Note: The DESTINY-Breast09 (DB-09) study, recently presented at the ASCO Annual Meeting, has sparked widespread attention among oncology experts and is poised to reshape the first-line treatment landscape for HER2-positive metastatic breast cancer (HER2+ mBC). Beyond the impressive data, the study has also prompted new thinking around optimal sequencing of anti-HER2 therapies, treatment strategies, and safety management. At the 6th Annual Oncology Comprehensive Therapy Conference of the Dalian Xinghai Medical Forum (June 12–15), Oncology Frontier invited Professor Quchang Ouyang (Hunan Cancer Hospital), Professor Huihua Xiong (Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology), and Professor Biyun Wang (Fudan University Shanghai Cancer Center) to provide expert interpretations of the latest findings and their implications for clinical practice.DB-09 Redefines the First-Line Standard in Advanced Disease
Oncology Frontier: The DB-09 study presented at ASCO 2025 has drawn significant attention and set a new benchmark for median PFS in HER2+ mBC first-line treatment. How do you interpret these results and their potential impact on clinical practice?
Professor Quchang Ouyang: The DB-09 study represents a major milestone in the treatment of HER2-positive metastatic breast cancer and is the third phase III clinical trial—after CLEOPATRA and PHILA—to report positive results in this field. Compared with the conventional THP regimen (docetaxel plus trastuzumab and pertuzumab) used in CLEOPATRA, DB-09 reported a median progression-free survival (PFS) of 40.7 months in the T-DXd + pertuzumab (T-DXd+P) group, assessed by both blinded independent central review (BICR) and investigators. This sets a new record for first-line therapy in HER2+ mBC.
In comparison, the median PFS for the THP group was 26.9 months by BICR. The T-DXd+P regimen extended PFS by 13.8 months and significantly reduced the risk of disease progression or death by 44% (HR 0.56, 95% CI: 0.44–0.71). Both the absolute PFS benefit and its duration are remarkable and clinically meaningful.
From a safety perspective, the adverse event (AE) profile of T-DXd+P was consistent with previously reported data for each individual agent. No new safety signals were identified. The most common treatment-emergent adverse events (TEAEs) of any grade included nausea (71.1% vs. 28.8%), diarrhea (55.9% vs. 54.2%), neutropenia (48.8% vs. 44.5%), and fatigue (48.3% vs. 34.6%). These were largely comparable to those seen in the chemotherapy group. Importantly, T-DXd+P showed good overall tolerability, with a lower treatment discontinuation rate than the chemotherapy arm (20.7% vs. 28.3%). Notably, there was no observed increase in the risk of interstitial lung disease (ILD) or cardiac toxicity.
In summary, the DB-09 trial demonstrated a statistically significant and clinically meaningful PFS advantage with T-DXd plus pertuzumab in the first-line setting, while maintaining a manageable safety profile. These results mark a potential paradigm shift in the first-line treatment of HER2+ mBC and are likely to have a profound impact on clinical practice. That said, overall survival (OS) data are still immature, and we eagerly await future updates to confirm whether T-DXd+P also delivers a survival benefit over THP.
Strategic Considerations for Sequencing in HER2+ mBC
Oncology Frontier: The DB-09 study has not only set a new standard in first-line therapy for HER2+ mBC, but also sparked renewed discussions on sequencing strategy. The SONIA study explored the timing of CDK4/6 inhibitors in first- versus second-line settings, though its conclusions aren’t broadly applicable. What are your views on placing T-DXd in the first versus second line, or using T-DXd followed by HP maintenance?
Professor Huihua Xiong: At the 2025 ASCO Annual Meeting, the DB-09 trial was undoubtedly one of the most closely watched studies in the breast cancer field. As Professor Ouyang mentioned, the combination of T-DXd and pertuzumab (T-DXd+P) in the first-line setting achieved a median PFS of over 40 months for HER2+ mBC patients.
Previously, the DB-03 trial comparing T-DXd with T-DM1 in the second-line setting showed that T-DXd achieved a median PFS of 28.8 months. These findings have sparked debate on treatment sequencing: should we deploy our most effective therapies early, or reserve them for later lines? Which strategy ultimately leads to better overall survival (OS)?
Currently, the OS data from DB-09 remain immature—with only 16% maturity at this point—so it is too early to draw final conclusions. In HR+/HER2− mBC, we’ve seen the SONIA trial report that using CDK4/6 inhibitors in the first versus second line made no significant difference in PFS2 (31.0 vs. 26.8 months; HR 0.87; P = 0.10) or OS (45.9 vs. 53.7 months; HR 0.98; P = 0.83), while first-line use increased side effects and cost.
However, we should be cautious in applying these findings to HER2+ disease. The SONIA trial was geographically and drug-specific, and more importantly, HR+ and HER2+ breast cancers differ significantly in biology, drug mechanisms, and resistance patterns—they are not directly comparable.
Interestingly, in the DB-09 interim analysis, the T-DXd+P group had not yet reached a median PFS2, whereas the control group had a PFS2 of 36.5 months. The hazard ratio (HR) was 0.6 (95% CI: 0.45–0.79; P = 0.00038), indicating a 40% reduction in risk of disease progression or death after the next line of therapy.
Moreover, the T-DXd+P group achieved a complete response (CR) rate of 15.1%, meaning a significant proportion of patients may experience long-term disease control. Both PFS2 and CR are considered important surrogate indicators of OS. These signals strongly suggest that the DB-09 trial may eventually yield a positive OS outcome.
Given the aggressive nature of HER2+ metastatic breast cancer, initiating treatment with a high-efficacy regimen like T-DXd+P may provide a survival advantage in the long run.
That said, it’s worth noting that in the DB-09 study, between 60–70% of patients in the T-DXd+P group experienced any-grade nausea and diarrhea, and nearly half experienced neutropenia. While overall tolerability was acceptable, some researchers have proposed whether it might be possible to “de-intensify” after achieving tumor remission—switching to maintenance therapy with HP or even single-agent HER2 blockade. This concept merits further investigation.
Future disclosures from the DB-09 trial’s T-DXd monotherapy arm could also provide valuable insights into how best to optimize long-term treatment strategies.
T-DXd “Rechallenge” after ILD Event
Oncology Frontier: The long-term use of T-DXd must be grounded in effective safety management, especially concerning ILD events. At this year’s ASCO Annual Meeting, Professor Hope Rugo presented a multicenter real-world study on rechallenging T-DXd in patients who had previously experienced ILD. How do you view ILD management and the possibility of T-DXd retreatment?
Professor Biyun Wang: T-DXd has been increasingly adopted in clinical practice, and interstitial lung disease (ILD) remains one of the most concerning adverse events associated with its use. Published data report ILD incidence rates around 10% or higher. In our own clinical setting, we’ve seen relatively few cases—possibly due to short hospital stays and fast patient turnover. However, a recent case served as a stark reminder of the risks.
One patient, after completing three cycles of T-DXd, appeared clinically stable and reported no respiratory symptoms, yet a chest CT revealed bilateral “white-out” lungs—indicative of severe ILD. Fortunately, we detected it early and initiated high-dose corticosteroid pulse therapy, which led to a resolution of symptoms. This experience taught us that even in the absence of respiratory symptoms during early treatment, we must remain vigilant. Personally, I recommend performing a chest CT scan after two treatment cycles to proactively assess for ILD.
Most ILD events related to T-DXd are grade 1 or 2 and can be managed effectively. This leads to an important question: is it safe to rechallenge with T-DXd after ILD resolution? Given the strong efficacy of T-DXd, it’s a difficult decision to discontinue therapy prematurely. Current clinical guidelines suggest that for patients who develop grade 1 ILD and recover fully, retreatment with T-DXd can be considered.
At ASCO 2025, Professor Rugo’s real-world study provided valuable evidence. Among 1,476 patients treated with T-DXd, 44 patients who experienced grade 1 ILD were rechallenged. Over a median retreatment duration of 215 days, only 12 patients (27%) experienced ILD recurrence, the majority of which were mild (9 grade 1, 2 grade 2, and 1 grade 3), with a median time to recurrence of 211 days.
Interestingly, in three patients who experienced grade 1 ILD recurrence, T-DXd was administered again following symptom resolution—one with dose reduction, and two without. Moreover, the study included 19 patients with grade 2 ILD who, contrary to guideline recommendations, were also rechallenged. After a median of 49 days, only 3 of these patients (16%) experienced recurrent ILD—one each at grades 2, 3, and 4. These results suggest that even select patients with grade 2 or recurrent grade 1 ILD may be eligible for careful retreatment under close monitoring.
Although the sample size is small, these data offer new hope and confidence for both clinicians and patients considering T-DXd retreatment after ILD. Moving forward, multidisciplinary team (MDT) collaboration will be essential to further explore predictive markers, clinical-pathological features, and risk models to better guide safe and effective T-DXd rechallenge decisions.
Professor Quchang Ouyang Director, Department of Breast Medical Oncology Hunan Cancer Hospital
Professor Huihua Xiong Professor, Chief Physician, Doctoral Supervisor Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
Professor Biyun Wang Director, Department of Breast and Genitourinary Medical Oncology Fudan University Shanghai Cancer Center
