Metronomic Chemotherapy Boost To Dual HER2 Blockade Feasible In Older Breast Cancer Patients

In older patients with metastatic HER2-positive breast cancer, adding metronomic cyclophosphamide to pertuzumab plus trastuzumab may improve outcomes without worsening toxicity

medwireNews: Adding metronomic chemotherapy with oral cyclophosphamide to the human epidermal growth factor receptor 2 (HER2) inhibitors pertuzumab and trastuzumab may be an option for older patients with metastatic HER2-positive breast cancer, phase II trial findings suggest.

Researcher Hans Wildiers, from KU Leuven in Belgium, and colleagues explain that the combination of pertuzumab, trastuzumab and docetaxel has been shown to improve outcomes in the metastatic HER2-positive breast cancer setting.

But they add that the substantial toxicity associated with docetaxel can be a particular problem for older patients, especially in a palliative metastatic setting, prompting the team to compare dual HER2-blockade with a regimen also containing metronomic chemotherapy, which involves treatment being given at regular, short intervals and at doses that are markedly lower than the maximum tolerated dose.

In the EORTC 75111-10114 trial, estimated progression-free survival at 6 months was 73.4% for the 41 patients who were randomly assigned to receive metronomic oral cyclophosphamide 50 mg/day alongside trastuzumab (loading dose of 8 mg/kg, then 6 mg/kg every 3 weeks) and pertuzumab (loading dose of 840 mg, then 420 mg every 3 weeks). This compared with a rate of 46.2% for the 39 control participants given the same doses of trastuzumab and pertuzumab alone.

The between-group difference of 27.2% was higher than the 10.0% difference threshold specified in the protocol, and therefore the study met its primary endpoint, the study authors say in The Lancet Oncology. They point out that the difference between groups was not statistically significant, but stress that the trial was not powered for a direct comparison.

Other trial endpoints, such as overall survival and cumulative breast cancer-specific survival at 1 year, were comparable between the trial arms, as was the incidence of grade 3–5 adverse events, at 56% and 54% in the metronomic chemotherapy and control groups, respectively.

The most common grade 3 or worse toxicity in the metronomic chemotherapy study arm was lymphopenia, occurring at a rate of 37% versus 3% for the dual HER2-blockade arm. Other frequent high-grade side effects were hypertension (12 vs 15%), diarrhoea (12 vs 10%), dyspnoea (10 vs 5%) and a thromboembolic event (10 vs 0%).


Given that patients were eligible for enrolment either if they were at least 70 years old or were aged 60–69 years but with documented functional restrictions, and 71–81% met different criteria for frailty, Hans Wildiers et al note that the favourable toxicity profile of both regimens is "a major asset."<\p>

They add, however, that the study results suggest that “the benefit of avoiding the side-effects of chemotherapy with the use of dual anti-HER2 blockade only does not compensate for an important loss of activity in the metastatic setting.”

The team concludes that further comparison of the two regimens in a randomised phase 3 study should be considered, “although financial support for such studies in the older population remains a challenge.”


Wildiers H, Tryfonidis K, Dal Lago L, et al. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer (EORTC 75111-10114): an open-label, randomised, phase 2 trial from the Elderly Task Force/Breast Cancer Group. Lancet Oncol; Advance online publication 9 February 2018 . doi:

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