Editor's Note: The Chinese Society of Clinical Oncology (CSCO) Annual Meeting was grandly held in Jinan. This conference brought together authoritative experts in the field of oncology from home and abroad, focusing on the deep integration of cutting-edge research and clinical practice. Among the highlights, in the field of breast cancer treatment, Professor Giuseppe Curigliano, President-Elect of the European Society for Medical Oncology (ESMO), delivered a keynote speech on the first-line treatment strategies for HER2-positive metastatic breast cancer. He systematically elaborated on the evolution from the CLEOPATRA regimen to the DESTINY-Breast09 study and looked ahead to a new paradigm of future treatment. The Current Cornerstone: The Historical Status and Limitations of the CLEOPATRA Regimen
For over a decade, the first-line standard of care for HER2-positive metastatic breast cancer has been established by the CLEOPATRA study. This regimen, combining pertuzumab, trastuzumab, and taxane-based chemotherapy, has brought significant survival benefits to patients. Professor Giuseppe Curigliano recalled that when this study was initially designed, it used the standard therapy of the time—trastuzumab plus chemotherapy—as the control. Ultimately, it not only extended the median Progression-Free Survival (PFS) to 18.5 months but also achieved a remarkable prolongation of Overall Survival (OS). According to the latest follow-up data published by Professor Sandra Swain, 37% of patients were still alive after 8 years, fully demonstrating the powerful efficacy of dual-targeted therapy combined with chemotherapy. However, medical progress never ceases. With the advent of novel antibody-drug conjugates (ADCs), the existing treatment landscape has been strongly challenged. Professor Curigliano pointed out that a core question confronts all clinicians: Trastuzumab Deruxtecan (T-DXd), which achieved tremendous success in the second-line setting, produced a median PFS of 28.8 months in the DESTINY-Breast03 study—a figure that even surpasses the performance of the CLEOPATRA regimen in the first-line setting. This naturally raises a key consideration: should T-DXd be moved to the first line to bring earlier and greater benefits to patients?
A Paradigm Shift: The DESTINY-Breast09 Study Defines a New Height for First-Line Treatment
To answer this critical question, the DESTINY-Breast09 study was initiated. This prospective, randomized, controlled Phase III clinical trial was designed to directly compare the efficacy and safety of T-DXd plus pertuzumab, T-DXd monotherapy (data for this arm remain blinded), and the current standard CLEOPATRA regimen (taxane + dual-targeted therapy). Professor Curigliano focused on interpreting the interim analysis results comparing T-DXd plus pertuzumab to the standard of care, describing the data as “unprecedented.” The results showed that the median PFS in the T-DXd plus pertuzumab arm reached an astonishing 40.7 months, while the data for the standard-of-care arm were similar to historical data. This outcome translates to a Hazard Ratio (HR) of 0.56, representing a 44% reduction in the risk of disease progression or death, a difference of high statistical and clinical significance. Professor Curigliano emphasized, “We are witnessing a revolution. A median PFS of 40.7 months is nearly double that of the CLEOPATRA regimen. This is undoubtedly practice-changing.” Notably, the study’s patient population was globally representative, with Asian patients accounting for a high proportion of 49%, and Chinese investigators, in particular, contributing a large number of cases. Professor Curigliano highly praised this: “The fact that we can now widely use ADC drugs throughout the breast cancer field is largely due to the outstanding contributions of Chinese and other Asian investigators, a point that must be acknowledged.” Furthermore, more than half (52%) of the patients presented with de novo metastatic disease, which may be one of the reasons why the standard-of-care arm performed better than in the historical CLEOPATRA study.
In-depth Data Analysis: A Comprehensive View of Efficacy, Safety, and Subgroup Benefits
The outstanding efficacy of the DESTINY-Breast09 study is not limited to PFS. In terms of Overall Response Rate (ORR), the T-DXd plus pertuzumab arm reached 85.1%, with a Complete Response (CR) rate of 15.1%. More importantly, the median Duration of Response (DOR) was as long as 39.2 months, approaching three years. Professor Curigliano commented, “When a response can last for more than three years, we can even begin to think about the possibility of a ‘cure,’ especially for patients with de novo metastatic disease and a low burden of disease. Among all metastatic solid tumors, HER2-positive breast cancer has the greatest potential to be cured due to its clear dependence on an oncogenic driver pathway.” Subgroup analysis revealed that patients derived consistent and significant benefits from the T-DXd plus pertuzumab regimen, regardless of whether they had de novo or recurrent metastatic disease, were hormone receptor (HR)-positive or -negative, or had the presence of brain metastases. In terms of safety, the adverse event profile of the combination regimen was largely consistent with the known safety profiles of T-DXd and pertuzumab. Interstitial Lung Disease (ILD), an adverse event of special interest for ADC drugs, had an overall incidence of 12.1%, similar to previous reports from the DESTINY series of studies. The majority of cases were low-grade, with only 2 treatment-related deaths due to ILD.
Future Exploration: From “Full-Throttle Attack” to Intelligent De-escalation with an “Induction-Maintenance” Approach
Although the results of the DESTINY-Breast09 study are exciting, Professor Curigliano also raised profound questions for the future: Do we need to keep patients on high-intensity ADC therapy continuously until disease progression? In clinical practice, about 20% of patients discontinue T-DXd due to adverse events while their disease has not progressed. Against this backdrop, the “induction-maintenance” therapy model has become a hot topic for exploration. Professor Curigliano highlighted the insights from the PATINA study. This study, targeting HR-positive/HER2-positive patients, randomized patients who had achieved a response after 6-8 cycles of standard chemotherapy plus dual-targeted induction therapy. One group received a CDK4/6 inhibitor (Palbociclib) combined with dual-targeted therapy and endocrine therapy, while the other received only dual-targeted therapy plus endocrine therapy as maintenance. The results showed that the median PFS in the Palbociclib arm reached 44 months, compared to 29 months in the control arm. “The 44-month PFS data from the PATINA study provides us with an important line of thinking,” Professor Curigliano analyzed. “It suggests that, especially for HR-positive patients, after a potent induction therapy (such as with T-DXd), it might be possible to switch to a maintenance regimen with lower toxicity and better quality of life, such as a CDK4/6 inhibitor combined with targeted and endocrine therapy, to achieve long-term disease control.” Similar concepts are also being explored in investigator-initiated trials like DE-ESCALATE, which aim to find the optimal treatment “de-escalation.”
Guideline Updates and Clinical Considerations: Unanswered Questions in the New Era
Faced with a continuous stream of blockbuster data, clinical practice guidelines are being actively updated. Professor Curigliano revealed that the latest ESMO guidelines have already adopted the concept from the PATINA study, recommending the addition of Palbociclib to the maintenance regimen for HR-positive/HER2-positive patients after completion of induction therapy. Although the data from DESTINY-Breast09 are not yet fully mature, its results have been granted “Breakthrough Therapy” designation by the U.S. Food and Drug Administration (FDA), indicating it will soon be incorporated into first-line treatment guidelines. However, the establishment of a new standard of care also brings new challenges. Professor Curigliano posed a core question to the audience: “When the T-DXd combination regimen becomes the first-line standard, how should we treat patients once they progress?” This will completely disrupt the existing treatment algorithm from the second line onwards and urgently requires the design of new clinical trials to evaluate the efficacy of other drugs in the “post-T-DXd era.” Furthermore, given the superior efficacy of new drugs against brain metastases, whether routine brain Magnetic Resonance Imaging (MRI) screening should be performed for all HER2-positive patients has also become a topic worthy of discussion, involving a balance between early intervention and cost-effectiveness.
Expert Perspective and Clinical Application Outlook
In summary, Professor Curigliano’s presentation clearly depicted that the first-line treatment of HER2-positive metastatic breast cancer is about to enter a new era dominated by ADC drugs. With its record-breaking PFS of 40.7 months, the DESTINY-Breast09 study has powerfully challenged the decade-old CLEOPATRA regimen, heralding that T-DXd plus pertuzumab will become the new standard of care. At the same time, the success of studies like PATINA has opened new paths for future “de-escalation” and personalized maintenance strategies. This revolution not only brings patients the hope of longer survival and higher quality of life but also highlights the importance of global oncology research collaboration, particularly the contributions of Chinese scholars. As advocated by the theme of this year’s CSCO meeting, the continuous deepening of precision medicine and the ongoing exploration of clinical wisdom are steering metastatic breast cancer towards a new future of “chronic disease” management and even the pursuit of a cure.
