Editor's Note: The mid-year meeting of the Youth Expert Committee of the Chinese Society of Clinical Oncology (CSCO YOUNG) was held from June 28-30, 2024, in Shanghai, where young elites from across the country gathered to discuss academic progress. Recent updates and announcements from various DESTINY-Breast (DB) series studies have brought more benefits to patients with HER2-positive, HER2-low, and HER2 ultra-low expression. Oncology Frontier invited Professor Rui Ge from Fudan University Shanghai East Hospital to share the latest findings from the DB series and to discuss the future treatment landscape for HER2-positive breast cancer. 

01

Oncology Frontier: Based on the DB-04 study results, HER2-low breast cancer has become a new treatment category in recent years. The DB-06 study extended the application of T-DXd to patients with HER2 ultra-low expression. How do you evaluate the role of ADCs in treating HER2-low breast cancer patients and the future development directions?

Professor Rui Ge: Everyone was eagerly anticipating the DB-06 study results at this year’s ASCO conference because this study not only refocused attention on HER2-low patients but also expanded the scope to HER2 ultra-low patients. Previous DB-03 study results confirmed that the ADC drug T-DXd benefits patients with HER2 overexpression, and we are very much looking forward to the final OS results of this study. Additionally, we are pleased to see that the DB-04 and DB-06 study results further confirm the efficacy of T-DXd can extend to HER2-low and HER2 ultra-low patients. The application of such ADC drugs aligns well with current clinical practice.

For HR-positive/HER2-negative traditional treatment models, first-line treatment often involves endocrine-targeted therapy represented by CDK4/6 inhibitors. However, there is still no standard answer for subsequent treatment strategies after progression: should traditional chemotherapy, cross-line CDK4/6 inhibitors, drugs targeting other endocrine pathways, or ADCs be chosen? Various clinical explorations have been conducted in the past, with observed efficacy similar to cross-line endocrine treatment, typically around six months. The DB-06 study, however, has pushed PFS for these patients beyond one year, significantly outperforming the control group (13.2 vs. 8.1 months, P<0.0001). In summary, the DB-04 and DB-06 study results once again confirm the good efficacy of T-DXd for HER2-low patients and provide us with stronger related evidence.

02

Oncology Frontier: The DB-03 study established a new standard for second-line treatment of HER2-positive breast cancer. At the 2024 ASCO conference, OS data from this study were released, showing a median OS of 52.6 months with T-DXd second-line treatment. What impact do you think this OS data will have on the treatment and clinical practice for patients in China?

Professor Rui Ge: Since the DB-03 study was first presented at the ESMO conference, its results have gradually rewritten the ESMO guidelines, ABC6 consensus, and NCCN guidelines, bringing new standards and norms for second-line treatment of advanced breast cancer. Past conference reports of the DB-03 study focused more on PFS data and control group analysis, including efficacy-related and safety data. We have been eagerly awaiting the OS data after the follow-up period to provide more answers. For patients, the expected OS results after ADC drug application might be their primary concern.

The latest OS results of the DB-03 study, presented at this ASCO conference, showed a median OS of 52.6 months for the T-DXd treatment group, superior to 42.7 months for the control group, with T-DXd significantly reducing the risk of death by 27% (HR 0.73, 95% CI: 0.56-0.94). The results indicate that ADC drug T-DXd, especially when used as a second-line treatment for advanced stages, can surpass previous OS data achieved with anti-HER2 treatments for HER2-overexpressing populations.

Another highlight of this study is that one-third of patients in the control group, initially treated with T-DM1, crossed over to receive subsequent T-DXd treatment. The study observed the efficacy of ADCs after subsequent ADC applications. Clinicians might consider that if such effective clinical strategies are applied earlier and more standardly during treatment, it could not only bring phase-specific benefits but also overall survival benefits. The OS results from the DB-03 study give us more confidence and answers.

03

Oncology Frontier: T-DXd has also been explored in first-line treatment for HER2-positive advanced breast cancer. At the 2024 ASCO conference, the DB-07 study presented efficacy and safety data for T-DXd + pertuzumab in first-line treatment of HER2-positive advanced breast cancer. Do you see a promising future for T-DXd in first-line treatment for HER2-positive advanced breast cancer?

Professor Rui Ge: The DB-07 study exemplifies the continuous exploration of the DB series. This study pushed the treatment strategy of T-DXd further to the front lines. We were all eagerly awaiting the results of this study. From the follow-up treatment strategies of the DB-01 study to the second-line treatment of the DB-03 study, and now to the DB-07 study, we have been considering whether this effective ADC drug could be pushed to first-line treatment to optimize overall planning and bring better treatment effects to patients.

The DB-07 study was cleverly designed, including both monotherapy and combination therapy with pertuzumab. This year’s ASCO conference presented the PFS, objective response rate (ORR), safety, and tolerability data from the DB-07 study. Consistent with previous results, this report showed PFS nearing 30 months. At median follow-ups of 23.9 months and 25.3 months, 62.7% and 56% of patients in the monotherapy and combination groups, respectively, continued treatment. These numbers are more favorable compared to previous first-line studies in advanced stages. We also look forward to head-to-head, randomized controlled clinical trials comparing T-DXd with dual-target-based combination chemotherapy for first-line treatment of advanced patients to confirm whether T-DXd can become a preferred or optional strategy for first-line treatment in advanced stages. We anticipate further follow-up data from clinical studies, including the DB-07 study, to provide us with more answers.