Pyrotinib plus trastuzumab/docetaxel prolongs PFS in HER2+ metastatic breast cancer

Adding pyrotinib to trastuzumab (Herceptin) and docetaxel significantly improved progression-free survival (PFS) compared to trastuzumab/docetaxel alone in patients with HER2-positive metastatic breast cancer, according to data from the phase 3 PHILA trial (NCT03863223).1

Data presented at the 2022 ESMO Congress showed that the median PFS was 24.3 months (95% CI, 19.1-33.0) as assessed by the investigator with the pyrotinib regimen versus 10 .4 months (95% CI, 9.3-12.3) with trastuzumab plus docetaxel alone, resulting in a 59% reduction in risk of disease progression or death (RR, 0.41; 95% CI %, 0.32-0.53; P

“To our knowledge, this is the second Phase 3 trial to demonstrate that PFS benefits from dual HER2 inhibition in the first-line treatment of HER2-positive metastatic breast cancer,” said the lead author of the study, Binghe Xu, from the Department of Medical Oncology at Cancer Hospital. The Chinese Academy of Medical Sciences and Peking Union Medical College, and their colleagues, said during a presentation of the data.

The irreversible pan-HER inhibitor, pyrotinib, has previously demonstrated encouraging antitumor activity when combined with capecitabine in patients with HER2-positive metastatic breast cancer. More specifically, the data from the phase 3 PHOEBE trial (NCT03080805), showed that the doublet resulted in a median PFS of 12.5 months (95% CI, 9.7-NR) vs 6.8 months (95% CI, 5.4-8.1) with lapatinib (Tykerb) plus capecitabine (HR, 0.39; 95% CI, 0.27-0.56; P 2

The Phase 3, multicenter, double-blind, placebo-controlled PHILA trial enrolled patients with pathologically confirmed, treatment-naïve HER2-positive metastatic breast cancer. These patients were required to have measurable disease according to RECIST v1.1 criteria and an ECOG performance status of 0 or 1.

A total of 590 participants were randomized 1:1 to receive oral pyrotinib 400 mg daily (n=297) or placebo (n=293) plus intravenous (IV) trastuzumab 8 mg/kg during cycle 1 and 6 mg/kg in subsequent cycles and docetaxel IV at 75 mg/m2 on day 1 of each 21-day cycle. Treatment was continued until disease progression, intolerable toxicity, withdrawal of the patient or decision of the investigator.

Patients were stratified by history of neoadjuvant or adjuvant trastuzumab (yes vs. no) and hormone receptor status (estrogen receptor (ER) positive and/or progesterone receptor disease vs ER negative and ER negative disease. progesterone receptors).

The primary endpoint of the trial was PFS as assessed by the investigator. Primary secondary endpoints included PFS as assessed by independent review committee, overall survival, objective response rate (ORR), duration of response (DOR), clinical benefit rate, and security.

The data cut-off date for the pre-specified interim analysis was May 25, 2022. The median follow-up for pyrotinib treatment was 15.8 months (range, 0.4-36.2) and 14.9 months (range, 0.4-35.3) with trastuzumab plus docetaxel.

According to the IRC assessment, the median PFS with pyrotinib plus trastuzumab/docetaxel was 33.0 months (95% CI, 19.4 – not reached [NR]) vs 10.4 months with trastuzumab plus docetaxel alone, resulting in a 65% reduction in risk of disease progression or death (RR, 0.35; 95% CI, 0.27-0.46 ; P

Within the subset of patients who received prior (neo)adjuvant trastuzumab, those who received the pyrotinib regimen had a median PFS that has not yet been achieved (95% CI, 14.6-NR) vs 9.3 months (95% CI, 6.3-12.4) with trastuzumab/docetaxel (HR, 0.23; 95% CI, 0.12-0.46). In those who had not received prior (neo)adjuvant trastuzumab, the median PFS in the investigation and control arms was 21.9 months (95% CI, 16.5-30.5) and 10.4 months (95% CI, 9.5-12.4), respectively (HR, 0.45; 95% CI, 0.34-0.59).

Additionally, in those with a treatment-free interval with prior adjuvant therapy of at least 12 months and less than 24 months who received the pyrotinib regimen, the median PFS was not yet achieved (95% CI, 14.7-NR) vs 8.3 months (95% CI, 6.2-11.8) with trastuzumab plus docetaxel (HR, 0.22; 95% CI, 0.10-0.50). In those who had a treatment-free interval of at least 24 months and received either pyrotinib treatment or control treatment, the median PFS was 22.2 months (95% CI, 12.5-NR) and 13.0 months (95% CI, 10.3-16.6), respectively (HR, 0.57; 95% CI, 0.37-0.87).

Adding pyrotinib to trastuzumab and docetaxel resulted in an ORR of 82.8% (95% CI, 78.1% to 86.9%) per investigator assessment versus 70.6% (CI 95%, 65.1% to 75.8%) with trastuzumab plus docetaxel. Of those who responded to pyrotinib treatment, 6.4% achieved a complete response, 76.4% had a partial response, and 10.4% had stable disease; 2.7% of patients showed disease progression. The median DOR in the investigation and control arms was 25.9 months (95% CI, 17.3-NR) and 9.5 months (95% CI, 8.3-10.6) , respectively.

The safety profile of the pyrotinib regimen was manageable, and adverse events (AEs) were consistent with prior reports for each agent.

All patients experienced treatment-related AEs (TRAE) in the investigation group versus 99.7% of those in the control group; these effects were grade 3 or higher in 89.9% and 76.5% of patients, respectively. Severe EITRs occurred in 24.9% of people in the experimental group versus 6.1% of those in the control group.

EITRs led to interruption, reduction, and discontinuation of treatment in 56.6%, 25.9%, and 13.1%, respectively, of patients who received the pyrotinib regimen; these rates were 24.2%, 3.1%, and 7.2%, respectively, in those who received trastuzumab plus docetaxel. No patient in the investigation group died as a result of TRAE versus 1 patient in the control group.

The most common side effects were diarrhea, white blood cell count decreased, neutrophil count decreased, anemia, vomiting, weight loss, nausea, hypokalemia, blood glucose increased aspartate aminotransferase, increased alanine aminotransferase, alopecia, increased blood creatinine, asthenia, decreased appetite, hypoalbuminemia, hypertriglyceridemia and hypercholesterolemia.


  1. Xu B, Yan M, Ma F, et al. Pyrotinib or placebo in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer (PHILA): a phase III randomized trial. Anne Oncol. 2022;33(supplement 7):S1387. doi:10.1016/j.announce.2022.08/014
  2. Xu B, Yan M, Ma F, et al. Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicenter, open-label, randomized, controlled phase 3 trial. Lancet Oncol. 2021;22(3):351-360. doi:10.1016/S1470-2045(20)30702-6

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