Chemo-free regimen a promising frontline treatment for metastatic breast cancer in Asians

Trastuzumab plus endocrine therapy is just as effective as the combination of trastuzumab plus chemotherapy in the first-line treatment of Chinese patients with metastatic breast cancer (MBC) harbouring hormone receptor (HR) or HER2 mutation, with the added advantage of better tolerability, according to the results of the phase III SYSUCC-002 trial.

In a cohort of 392 patients (median age 50 years) who were followed for a median of 30.2 months across nine hospitals in China, the primary endpoint of progression-free survival (PFS) was 19.2 months (95 percent confidence interval [CI], 16.7–21.7) with trastuzumab plus endocrine therapy and 14.8 months (95 percent CI, 12.8–16.8) with trastuzumab plus chemotherapy. This established the noninferiority of the chemo-free regimen (hazard ratio [HR], 0.88, 95 percent CI, 0.71–1.09; p_{noninferiority}<0.0001). [Clin Cancer Res 2022;28:637-645]

In terms of safety, trastuzumab plus endocrine therapy showed a better tolerability profile, with fewer grade 3–4 treatment-related toxicities relative to trastuzumab with chemotherapy (3.1 percent vs 51.0 percent; p<0.01).

Most adverse events (AEs) were observed among patients on the chemo-free regimen grade 1–2, with the most common being joint pain (16.8 percent), muscle pain (16.3 percent), and fatigue (15.8 percent). Meanwhile, the most frequently reported AEs with trastuzumab plus chemotherapy were alopecia (63.8 percent), leucopoenia (50.0 percent), and nausea (47.5 percent).

Patients who relapse early not the best candidates

“To our knowledge, the SYSUCC-002 trial is the first randomized, phase III study to compare, in a head–to–head manner, the efficacy and safety of [the anti-HER2 drug] trastuzumab combined with endocrine therapy or with chemotherapy as first-line treatment for HR- or HER2-positive MBC,” the investigators said.

While trastuzumab plus endocrine therapy proved to be noninferior, exploratory analyses revealed that it might not be the best treatment option for patients with early relapse (disease-free interval [DFI] ≤24 months), they added.

There was a significant interaction effect between DFI and the treatment modality seen on PFS (p=0.016). Among patients who received trastuzumab plus endocrine therapy, the risk of disease progression or death was reduced among those with DFI >24 months (HR, 0.77, 95 percent CI, 0.53–1.10) and elevated among those with DFI ≤24 months (HR, 1.39, 95 percent CI, 0.97–1.98).

“The reason why patients with DFI ≤24 months had a worse outcome with anti-HER2 therapy plus endocrine therapy might be because they displayed endocrine resistance, including recurrence and/or metastases within 24 months from the beginning of endocrine therapy,” according to the investigators, adding that the observation of treatment heterogeneity requires further study.

PFS results in previous trials vary

Overall, 196 patients were initiated on trastuzumab plus endocrine therapy and 196 on trastuzumab plus chemotherapy. Trastuzumab was administered on day 1 of study treatment at an initial loading dose of 8 mg/kg bodyweight, which was subsequently lowered to 6 mg/kg every 3 weeks. Endocrine therapy or chemotherapy was given simultaneously with trastuzumab. None of the patients received systemic therapy previously for metastatic disease.

“For the well-known trials evaluating endocrine therapy and HER2-targeted therapy (TAnDEM, EGF30008, and PERTAIN), the PFS results vary widely (range, 4.8–15.8 months)… The PFS of current study (19.2 months) is consistent with that of PERTAIN (15.8 months), considering that we adopted HR positivity as >10 percent, which would contribute to a better efficacy of endocrine therapy,” the investigators noted. [J Clin Oncol 2009;27:5529-5537; J Clin Oncol 2009;27:5538-5546; J Clin Oncol 2018;36:2826-2835]

“In addition, the quality of HER2 tests has improved and the experience of healthcare in managing trastuzumab therapy has increased. Meanwhile, racial differences can also affect treatment outcomes (all participants in this study were Chinese) which may be different from European and American ethnic groups,” they pointed out. [J Natl Cancer Inst 2005;97:439-448; Am J Clin Oncol 2020;43:504-509]

As such, the investigators advised caution when comparing the current study with earlier trials because of inherent differences, such as patient populations and treatments, between studies.

“In general, MBC is incurable, and the goal of treatment is to optimize the quality and length of life. The optimal treatment modality for patients with HR- or HER2-positive MBC is not known,” but the present study, despite its limitations, suggests that anti-HER2 therapy plus endocrine therapy might be a promising alternative to anti-HER2 therapy plus chemotherapy as first-line treatment, they said.