Trastuzumab plus endocrine therapy is non-inferior to trastuzumab plus chemotherapy in patients with metastatic HR-positive/HER2-positive breast cancer
For patients with metastatic breast cancer with hormone receptor-positive and HER2-positive disease, the SYSUCC-002 trial demonstrated that trastuzumab plus endocrine therapy is non-inferior to trastuzumab plus chemotherapy. Not surprisingly, the combination of trastuzumab and endocrine therapy was better tolerated than the chemotherapy-based regimen. Interestingly, exploratory analyses revealed that the trastuzumab plus endocrine therapy was likely to be more beneficial in patients with a disease free interval (DFI) of more than 24 months.
HR-positive and HER2-positive (HR+/HER2+) metastatic breast cancer accounts for approximately 10% of all metastatic breast cancer (MBC) cases. Anti-HER2 therapy combined with chemotherapy as a first-line treatment has shown survival benefit in patients with HER2+ MBC. In patients with HR+ MBC, endocrine therapy is preferred over chemotherapy given its better tolerability. For metastatic breast cancer patients with both HR+ and HER2+ disease, there is currently no consensus on the optimal treatment and both anti-HER2 therapy plus endocrine therapy or anti-HER2 therapy plus chemotherapy are being used. The SYSUCC-002 study aimed to determine whether trastuzumab plus endocrine therapy is as efficacious as trastuzumab plus chemotherapy and whether it is associated with decreased toxicity.
The SYSUCC-002 trial
The SYSUCC-002 trial is an open-label, non-inferiority, phase III, randomised, controlled trial performed in nine Chinese hospitals. Patients with HR+/HER2+ histologically confirmed advanced breast cancer and a DFI of more than twelve months were randomly assigned (1:1) to receive trastuzumab plus chemotherapy (CT group) or endocrine therapy (ET group). Endocrine therapy consisted of oestrogen-receptor modulators or aromatase inhibitors while chemotherapy consisted of taxanes, capecitabine or vinorelbine. The primary endpoint was progression-free survival (PFS) with a non-inferiority upper margin of 1.35 for the hazard ratio (HR).
Between September 16, 2013, and December 28, 2019, 392 patients were enrolled and randomly assigned to receive trastuzumab plus endocrine therapy (N=196) or trastuzumab plus chemotherapy (N=196). After a median follow-up of 30.2 months, in the intention-to-treat population, the median PFS was 14.8 months in the CT group and 19.2 months in the ET group (HR [95%CI]: 0.88 [0.71-1.09], p=0.250). Subgroup analyses of PFS demonstrated no significant difference between ET and CT groups for age (≤40 and > 40 years), receptor status, visceral involvement, previous adjuvant endocrine therapy or metastasis number. However, patients with a disease-free interval (DFI) of more than 24 months benefit more from trastuzumab plus endocrine therapy (HR [95%CI]: 0.77 [0.53-1.10), whereas patients with a DFI of ≤24 months seem to benefit more from the trastuzumab-chemotherapy regimen (HR [95%CI]: 1.39 [0.97-1.98]). No significant difference was seen between the two treatment arms in terms of overall survival (HR [95%CI]: 0.82 [0.65-1.04], p=0.090). In contrast, a significantly higher rate of toxicity was reported in the chemotherapy group compared to endocrine therapy, including: leukopenia (50% vs. 6.6%), nausea (47% vs. 12%), fatigue (24% vs. 16%), vomiting (23% vs. 6%), headache (33% vs. 12%) and alopecia (64% vs. 4%). No patients died from treatment-related causes.
Trastuzumab plus endocrine therapy was non-inferior to trastuzumab plus chemotherapy in patients with HR+/HER2+ metastatic breast cancer, with a lower rate of toxicity. Exploratory analyses revealed that trastuzumab plus endocrine therapy was likely to be more beneficial in patients with a DFI of more than 24 months while trastuzumab plus chemotherapy was like to be more beneficial in patients with a DFI of less than 24 months.
Yuan Z, et al. Trastuzumab plus endocrine therapy or chemotherapy as first-line treatment for metastatic breast cancer with hormone receptor-positive and HER2-positive: The sysucc-002 randomized clinical trial. Presented at ASCO 2021; Abstract 1003.