Editor’s Note: The 47th San Antonio Breast Cancer Symposium (SABCS) successfully concluded in San Antonio, USA. On December 11 (local time), during the second day of the conference, Academician Binghe Xu from the Cancer Hospital Chinese Academy of Medical Sciences delivered a significant presentation in the "General Session 1," unveiling the latest data from the PHILA study (Abstract No.: GS1-03). This nationwide, multicenter randomized controlled trial evaluated the remarkable efficacy of Pyrotinib combined with Trastuzumab and Docetaxel as a first-line treatment for HER2-positive advanced breast cancer. Results showed a striking progression-free survival (PFS) of 22.1 months in the Pyrotinib group, significantly longer than the 10.5 months in the HT group.Oncology Frontier interviewed Academician Binghe Xu on-site to gain in-depth insights into the latest PHILA study data and explore the profound impact of the Pyrotinib combination regimen on the treatment of HER2-positive breast cancer.

Additionally, on December 12, Academician Binghe Xu shared the final PFS analysis results from the DAWNA-2 study during the “Poster Spotlight 2: Personalizing CDK 4/6 inhibitor therapy for patients with Metastatic Breast Cancer: Survival, QOL and biomarkers” session. These results further supported Dalpiciclib combined with aromatase inhibitors as a first-line treatment for HR+/HER2- advanced breast cancer patients, regardless of menopausal status.

Oncology Frontier: Congratulations on presenting your latest research on the SABCS stage. Could you introduce the latest PHILA study data you reported?

Academician Binghe Xu:The PHILA study is a randomized, double-blind, multicenter, placebo-controlled Phase III clinical trial conducted across China. It aimed to compare the efficacy of Pyrotinib combined with Trastuzumab and Docetaxel (PyroHT group) versus a placebo combined with Trastuzumab and Docetaxel (HT group) as first-line treatment for HER2-positive advanced breast cancer.

We previously published the initial analysis in The BMJ (during the grand launch of the PHILA research results in Beijing). At a median follow-up of 15.8 months, the median PFS was 24.3 months in the PyroHT group versus 10.4 months in the HT group, with a hazard ratio (HR) of 0.41 (95% CI: 0.32–0.53; P < 0.001).

At this SABCS, we presented the final PFS analysis. The results reaffirmed that the PyroHT group had significantly better outcomes than the HT group.

Specifically, the median follow-up times were 35.7 months for the PyroHT group and 34.3 months for the HT group. The investigator-assessed median PFS was 22.1 months for the PyroHT group versus 10.5 months for the HT group (HR = 0.44, 95% CI: 0.36–0.53; P < 0.0001). This nearly doubled PFS in the PyroHT group is particularly notable in first-line treatment. Although we didn’t directly compare different first-line regimens, this combination showed exceptional efficacy in patients with HER2-positive breast cancer who had failed previous adjuvant systemic therapies.

Oncology Frontier: In this extended final analysis, we observed sustained PFS benefits with PyroHT. However, there were discrepancies between investigator assessments and independent review committee evaluations of PFS. How do you interpret this difference?

Academician Binghe Xu:Differences in PFS assessments are common in clinical research. Variations can arise due to differences in evaluation criteria and perspectives between investigators and independent review committees. However, we focus more on the hazard ratio (HR) for risk-benefit analysis.

In this study, although the early PFS values differed—at the median 15.8-month follow-up, the investigator-assessed median PFS was 24.3 months (HR = 0.41), whereas the independent review committee assessed it at 33.0 months (HR = 0.35)—the final analysis confirmed that the PyroHT group maintained a significant PFS benefit that met the study’s predefined statistical significance criteria.

The independent review committee’s assessment may appear more optimistic, but the consistency in HR values between both assessments provides strong evidence supporting the efficacy of the PyroHT regimen.

Oncology Frontier: You also reported the overall survival (OS) results of this study. Considering the wide range of treatment options for HER2-positive advanced breast cancer and the complexity of later-line therapies, how do you interpret the significant OS benefit observed in the PHILA study?

Academician Binghe Xu:In this study, the number of OS events in both groups has not yet reached the predefined statistical threshold, so the current report does not represent the final OS analysis but rather an update on the OS data. However, the available data already suggest a survival advantage for the PyroHT group compared to the HT group (HR = 0.64, 95% CI: 0.46–0.89; one-sided P = 0.0038).

The 4-year OS rate in the PyroHT group was 74.5%, which is 10% higher than the 64.3% in the HT group—a highly significant difference. Notably, the survival curves of the two groups began to diverge as early as six months after treatment initiation, with a clear difference evident by one year. This provides a strong signal suggesting the potential for even more favorable OS outcomes in the future. We look forward to further validating these findings through continued follow-up.

Oncology Frontier: Following the PHILA study, first-line treatment options for HER2-positive breast cancer now include traditional dual-target therapies, small and large molecules, and potentially ADCs in the future. How should first-line treatments be selected based on individual patient characteristics, and how might this influence later-line therapy?

Academician Binghe Xu:Currently, in Western countries, the standard first-line treatment for HER2-positive breast cancer is the dual-target regimen of Trastuzumab and Pertuzumab combined with Docetaxel. Some patients, however, receive single-target therapy with Trastuzumab and Docetaxel.

With the widespread use of Trastuzumab and Pertuzumab in neoadjuvant and adjuvant settings, directly applying this regimen as first-line treatment may yield limited efficacy. Interestingly, we observed that Pyrotinib combined with Trastuzumab demonstrated superior efficacy in patients who had previously received anti-HER2 therapy compared to those who had not.

This suggests that switching to a novel small-molecule targeted therapy, like Pyrotinib, could achieve better outcomes for patients who have experienced treatment failure or developed resistance to prior targeted therapies. Therefore, I believe that the Pyrotinib and Trastuzumab combination is a viable and effective alternative for first-line treatment, offering patients more diversified therapeutic options.

Oncology Frontier: At this conference, the final PFS analysis results of the DAWNA-2 study were released, showing that Dalpiciclib combined with endocrine therapy significantly prolonged PFS compared to endocrine therapy alone. What is the clinical significance of this finding? Based on the DAWNA-2 results, what are your next research steps?

Academician Binghe Xu:The DAWNA-2 study provides robust evidence supporting the use of Dalpiciclib combined with aromatase inhibitors as a first-line treatment for HR-positive advanced breast cancer. The study confirmed that the efficacy of the CDK4/6 inhibitor Dalpiciclib combined with aromatase inhibitors was significantly superior to that of non-steroidal aromatase inhibitors alone.

We previously published the interim analysis results in The Lancet Oncology (highlighting the DAWNA-2 study as a new first-line treatment option for HR+/HER2- advanced breast cancer). The final PFS analysis presented at this conference further solidifies this conclusion.

Therefore, I believe that the Dalpiciclib plus endocrine therapy regimen should be established as the standard first-line treatment for HR-positive advanced breast cancer. Moving forward, my research will focus on optimizing this regimen, exploring combination strategies with other targeted therapies, and identifying biomarkers to further personalize treatment.

Academician Binghe Xu

• Academician, Chinese Academy of Engineering
• Member, Chinese Academy of Medical Sciences
• Tenured Professor, Peking Union Medical College
• Director, National Clinical Research Center for Anti-tumor New Drugs
• Honorary Chairman, Breast Cancer Expert Committee and Clinical Oncology Drug Research Committee, Chinese Anti-Cancer Association
• President, Beijing Oncology Society and Beijing Breast Disease Prevention and Treatment Society