Pyrotinib plus trastuzumab-docetaxel prolongs PFS in HER2-positive metastatic breast cancer

Treatment with pyrotinib in combination with trastuzumab and docetaxel (tras/doc) results in longer progression-free survival (PFS) than placebo combined with tras/doc in patients with untreated HER2-positive metastatic breast cancer, a study has shown. In addition, the safely profile of tras/doc plus pyrotinib is manageable.

“The results of this study show that pyrotinib, trastuzumab, and docetaxel constitute a novel first-line therapy for patients with untreated HER2-positive metastatic breast cancer, as well as an alternative strategy to the current treatment landscape in this patient population,” the investigators said.

A total of 590 female patients (median age 52 years) with untreated HER2-positive metastatic breast cancer participated in this randomized, placebo-controlled phase III trial conducted in 40 centres across China between 6 May 2019 and 17 January 2022.

Eligible women were randomly assigned to receive either oral pyrotinib 400 mg once daily (n=297) or placebo (n=293), both in combination with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m²) on day 1 of each 21-day cycle. PFS, as assessed by the investigators, served as the primary endpoint. Median follow-up was 15.5 months.

Median PFS was substantially longer in the pyrotinib-treated group than in the placebo-treated group (24.3 vs 10.4 months; hazard ratio, 0.41, 95 percent confidence interval [CI], 0.32‒0.53; p<0.001). [BMJ 2023;383:e076065]

In terms of safety, treatment-related adverse events of grade 3 or higher occurred in 267 patients (90 percent) in the pyrotinib group and in 224 (76 percent) in the placebo group. One treatment-related death (<1 percent; diabetic hyperosmolar coma) was recorded in the placebo group and none in the pyrotinib group. Survival and toxicities are still under assessment.

Two-year survival

The current standard of care with pertuzumab plus tras/doc had a median PFS of 18.7 months. [Lancet Oncol 2013;14:461-471; Lancet Oncol 2020;21:519-530]

In the current study, PFS with pyrotinib plus tras/doc exceeded 2 years. This result suggested the promising dual HER2 inhibition activity with the use of an intracellular small molecule in combination with an extracellular antibody, according to the investigators.

“Regarding the generalizability of the combination of pyrotinib, trastuzumab, and docetaxel to populations outside China, we propose that the efficacy of this combination therapy may generally remain consistent across different racial groups of patients with HER2-positive metastatic breast cancer, on the basis of several pieces of evidence,” the investigators said.

For instance, the molecular characteristics of HER2-positive advanced breast cancer in the global population and the Chinese population had similarities in their genomic profiles. [Ann Transl Med 2019;7:179]

In addition, the efficacy and safety of different therapies used for the treatment of HER2-positive advanced breast cancer were consistent between the global and Chinese populations. [N Engl J Med 2006;355:2733-2743; J Clin Oncol 2020;38:3138-3149; Lancet Oncol 2020;21:519-530]

“Furthermore, the pharmacokinetic characteristics of pyrotinib were found to be consistent in Chinese and US participants,” the investigators said.

“These pieces of evidence potentially support the extrapolation of the results from the [current] study to other populations with HER2-positive metastatic breast cancer, but this hypothesis needs further validation in subsequent studies,” they added.